Juraj Payer

Osteoporosis, fractures, and diabetes.

It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus have an increased risk of bone fractures. In type 1 diabetes, the risk is increased by ∼6 times and is due to low bone mass. Despite increased bone mineral density (BMD), in patients with type 2 diabetes the risk is increased (which is about twice the risk in the general population) due to the inferior quality of bone. Bone fragility in type 2 diabetes, which is not reflected by bone mineral density, depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers and examination methods are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. One of these methods can be trabecular bone score. The aim of the paper is to present the present state of scientific knowledge about the osteoporosis risk in diabetic patient. The review also discusses the possibility of problematic using the study conclusions in real clinical practice.

Adipokine Protein Expression Pattern in Growth Hormone Deficiency Predisposes to the Increased Fat Cell Size and the Whole Body Metabolic Derangements

CONTEXT GH deficiency (GHD) in adults is associated with central adiposity, dyslipidemia, and insulin resistance. OBJECTIVE The objective of the study was to test the hypothesis that GHD might change the spectrum of adipokines and thus influence the adipose tissue and the whole-body metabolic and inflammatory status leading to development of insulin resistance. DESIGN This was a single-center observational study with a cross-sectional design. PARTICIPANTS AND METHODS Protein arrays were used to characterize adipokines expressed in the sc adipose tissue obtained from young GHD adults and compared with age-, gender-, and body mass index (BMI)-matched group of healthy individuals. All subjects underwent an oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and magnetic resonance imaging examination. RESULTS Presence of abdominal obesity, enlarged adipocytes, increased circulating high-sensitivity C-reactive protein, impaired glucose tolerance, and decreased insulin action were found in GHD. Changes in adipokine protein expression due to GHD were highly dependent on the obesity phenotype. Lean GHD individuals (BMI approximately 23 kg/m(2)) had decreased protein levels for stem cell factor and epithelial growth factor, indicating a possible defect in adipocyte differentiation and proliferation. Decrease of vascular endothelial growth factor, stromal cell-derived factor, angiopoietin-2, and brain-derived neurotrophic factor advocated for attenuated angiogenesis and neurogenesis. Presence of obesity (BMI approximately 31 kg/m(2)) eliminated these inhibitory effects. However, adipose tissue expansion in GHD individuals was paralleled by an elevation of adipose tissue proinflammatory cytokines (IL-1beta, interferon-gamma) and chemoattractants (interferon-inducible T cell alpha-chemoattractant, monocyte chemotactic protein-2, monocyte chemotactic protein-3, eotaxin). CONCLUSION Our data demonstrate that GHD modulates adipokine and cytokine protein expression pattern, which might influence the adipose tissue growth and differentiation and predispose to tissue hypoxia, inflammation, and a defect in the whole-body insulin action.

Cholelithiasis and markers of nonalcoholic fatty liver disease in patients with metabolic risk factors

Abstract Cholelithiasis and nonalcoholic fatty liver disease (NAFLD) share the same risk factors. The aim of our study was to explore the relationship between these two conditions and to indentify independent predictors of both diseases in a cohort of patients with metabolic risk factors. Consecutive patients with metabolic risk factors referred to the outpatient clinic during a one-year period were included. Cholelithiasis was defined by the presence of gallstones on abdominal ultrasound examination at inclusion or previously performed cholecystectomy. NAFLD was defined by the presence of at least one surrogate marker such as elevated alanine aminotransferase and/or gamma-glutamyl transpeptidase and/or ultrasound signs of fatty liver. Other common liver diseases were thoroughly excluded. The prevalence of cholelithiasis among patients with and without NAFLD was determined and clinical and laboratory parameters were identified as predictors of NAFLD by multivariate logistic regression. In total, 482 consecutive patients were included: mean age 61 years; 61% were women; 52% of patients had more than 2 metabolic risk factors (obesity, type 2 diabetes, hypertension, hypertriglyceridemia, or low HDL cholesterol). NAFLD and cholelithiasis were present in 41% and 34% of all patients, respectively. Significantly higher prevalence of cholelithiasis was found among patients with NAFLD compared with patients without NAFLD (47% vs. 26%, respectively; p < 0.0001). In multivariate logistic regression model, type 2 diabetes (odds ratio (OR) = 1.99), BMI above 25 kg/m2 (OR = 1.78), and cholelithiasis (OR = 1.77) were identified as independent predictors of NAFLD. Fifty six percent of patients with cholelithiasis had NAFLD compared with 33% of patients without cholelithiasis (p < 0.0001). Multivariate logistic regression identified age above 50 years (OR = 3.46), NAFLD (OR = 1.92), triglycerides above 1.7 mmol/l (OR = 1.91), BMI above 25 kg/m2 (OR = 1.84), and total cholesterol concentration (OR = 0.711) as independent predictors of cholelithiasis. In conclusion, patients with metabolic risk factors and cholelithiasis suffer significantly more often from NAFLD compared with the reference group. Cholelithiasis represents an independent risk factor of NAFLD in addition to metabolic risk factors and could be regarded as an additional risk factor of liver damage in patients with NAFLD. Furthermore, NAFLD is an independent risk factor for cholelithiasis and might represent a pathogenetic link between the metabolic syndrome and cholelithiasis.

Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases.

AIM To investigate the effect of vitamin D (VD) concentrations and VD supplementation on health related quality of life in inflammatory bowel disease (IBD) patients. METHODS A cohort of 220 IBD patients including 141 Crohns disease (CD) and 79 ulcerative colitis (UC) patients was followed-up at a tertiary IBD center. A subgroup of the cohort (n = 26) took VD supplements for > 3 mo. Health related quality of life was assessed using the short IBD questionnaire (sIBDQ). VD serum concentration and sIBDQ score were assessed between August and October 2012 (summer/autumn period) and between February and April 2013 (winter/spring period). The mean VD serum concentration and its correlation with disease activity of CD were determined for each season separately. In a subgroup of patients, the effects of VD supplementation on winter VD serum concentration, change in VD serum concentration from summer to winter, and winter sIBDQ score were analyzed. RESULTS During the summer/autumn and the winter/spring period, 28% and 42% of IBD patients were VD-deficient (< 20 ng/mL), respectively. In the winter/spring period, there was a significant correlation between sIBDQ score and VD serum concentration in UC patients (r = 0.35, P = 0.02), with a trend towards significance in CD patients (r = 0.17, P = 0.06). In the winter/spring period, VD-insufficient patients (< 30 ng/mL) had a significantly lower mean sIBDQ score than VD-sufficient patients; this was true of both UC (48.3 ± 2.3 vs 56.7 ± 3.4, P = 0.04) and CD (55.7 ± 1.25 vs 60.8 ± 2.14, P = 0.04) patients. In all analyzed scenarios (UC/CD, the summer/autumn period and the winter/spring period), health related quality of life was the highest in patients with VD serum concentrations of 50-59 ng/mL. Supplementation with a median of 800 IU/d VD day did not influence VD serum concentration or the sIBDQ score. CONCLUSION VD serum concentration correlated with health related quality of life in UC and CD patients during the winter/spring period.

Arthropathy in Acromegaly

Articular involvement in acromegaly is one of the most frequent clinical complications and may be present as the earliest symptom in a significant proportion of patients. The involvement of other organs may be of clinical importance and contribute to increased morbidity and mortality of patients suffered from acromegaly. Early diagnosis and proper treatment of the diseases can prevent the development of irreversible complications of the disease and improve the quality of life in patients suffering from the disease.

Impact of the growth hormone replacement on bone status in growth hormone deficient adults

INTRODUCTION Growth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated. OBJECTIVES The objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD. PATIENTS AND METHODS Adult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2 years. Lumbar spine (L1-L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24. RESULTS In total, 147 GHD patients (age 35.1 years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2 years, respectively; p<0.0001). Bone markers increased during the first 12 months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p=0.02). BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p=0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p=0.004). CONCLUSION GH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.

Rheumatic diseases and Klinefelter's syndrome

The article summarizes reports on the concurrence of Klinefelters syndrome (KS) with inflammatory rheumatic diseases, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, the antiphospholipid syndrome, and ankylosing spondylitis. These include two case reports of patients with KS concurrently associated with RA or antisynthetase syndrome, respectively, previously reported by the author and his coworkers. Attention is paid to the pathogenesis and the course of the disease in patients with KS. The importance of early diagnosis of the syndrome, when occurring simultaneously with other diseases of connective tissue, is emphasized.

Osteoarticular Changes in Acromegaly

Acromegaly is caused by hypersecretion of growth hormone (GH) and consequently of insulin-like growth factor-I (IGF-1) due to pituitary tumor. Other causes, such as increased growth-hormone releasing hormone (GHRH) production, ectopic GHRH production, and ectopic GH secretion, are rare. Growth hormone and IGF-1 play a role in the regulation of bone metabolism, but accurate effect of growth hormone excess on bone is not fully explained. The issue of osteoarticular manifestations is still very actual, due to development of complications in the majority of patients with acromegaly. Traditionally, acromegaly is considered as a cause of secondary osteoporosis. Nowadays, it is discussed if BMD as predictor of osteoporotic fractures in acromegalic patient is decreased or even normal. Thus, bone quality remains to be more important in assessment of fracture risk. GH excess leads to increased bone turnover, defined by changes of bone markers. The articular manifestations are frequent clinical complications and may be present as the earliest symptom in a significant proportion of acromegalic patients. Articular manifestations are the main causes of morbidity and immobility of these patients, and they are persistent even after successful treatment. Quick recognition of osteoarticular changes and aiming the therapy lead to decrease in complication number.

Oral contraception usage in relation to bone mineral density and bone turnover in adolescent girls

Objectives To compare the effect of a low-dose oral contraceptive (OC) containing 30 μg ethinyloestradiol (EE) with that of an ultra-low-dose OC containing 15 μg EE on bone turnover and BMD in healthy adolescent women and, in addition, to ascertain the influence of body mass index (BMI) and exercise on these indices of bone metabolism. Methods We recruited to the study 92 healthy girls aged between 16 and 19. They were divided into three groups. Participants in the first two groups used an OC with either 15 or 30 μg ethinyloestradiol (EE), whereas those in the third group used no hormonal contraception. Bone mineral density (BMD) and bone turnover markers were measured before and after 12 months of treatment. Results The BMD values of the total hip in females using the OC containing 30 μg EE was 0.912 g/cm2 at baseline and 0.918 g/cm2 after one year; in females using the OC containing 15 μg EE the corresponding values were 0.888 g/cm2 and 0.895 g/cm2 whereas in females who used no contraception BMD values were 0.942 g/cm2 and 0.949 g/cm2, respectively. The changes were statistically insignificant. Levels of osteocalcin and CTX had decreased after one year in all groups, but not statistically significantly so. Conclusion Low dose and ultra-low dose oral contraceptives did not significantly differ in their effects on bone mineral density or bone turnover markers in adolescent girls aged 16–19.

The PRIMARA study: a prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice

OBJECTIVE Medical management of primary hyperparathyroidism (PHPT) is important in patients for whom surgery is inappropriate. We aimed to describe clinical profiles of adults with PHPT receiving cinacalcet. DESIGN A descriptive, prospective, observational study in hospital and specialist care centres. METHODS For patients with PHPT, aged 23-92 years, starting cinacalcet treatment for the first time, information was collected on dosing pattern, biochemistry and adverse drug reactions (ADRs). Initial cinacalcet dosage and subsequent dose changes were at the investigators discretion. RESULTS Of 303 evaluable patients with PHPT, 134 (44%) had symptoms at diagnosis (mostly bone pain (58) or renal stones (50)). Mean albumin-corrected serum calcium (ACSC) at baseline was 11.4 mg/dl (2.9 mmol/l). The reasons for prescribing cinacalcet included: surgery deemed inappropriate (35%), patient declined surgery (28%) and surgery failed or contraindicated (22%). Mean cinacalcet dose was 43.9 mg/day (s.d., 15.8) at treatment start and 51.3 mg/day (31.8) at month 12; 219 (72%) patients completed 12 months treatment. The main reason for cinacalcet discontinuation was parathyroidectomy (40; 13%). At 3, 6 and 12 months from the start of treatment, 63, 69 and 71% of patients, respectively, had an ACSC of ≤10.3 mg/dl vs 9.9% at baseline. Reductions from baseline in ACSC of ≥1 mg/dl were seen in 56, 63 and 60% of patients respectively. ADRs were reported in 81 patients (27%), most commonly nausea. A total of 7.6% of patients discontinued cinacalcet due to ADRs. CONCLUSIONS Reductions in calcium levels of ≥1 mg/dl was observed in 60% of patients 12 months after initiation of cinacalcet, without notable safety concerns.