Panagiotis Kokkoris

Obesity and endocrine disease

Several endocrine abnormalities are reported in obesity. Some of these abnormalities are considered as causative factors for the development of obesity, whereas others are considered to be secondary effects of obesity and usually are restored after weight loss. Thyroid hormones usually are normal in obesity, with the exception of T3 which is elevated. Prolactin is normal but prolactin response to different stimuli is blunted. GH is low and GH response to stimuli is blunted. IGF-I levels are normal or elevated. Cortisol, ACTH, and urine free cortisol levels are usually normal; however, a hyperresponsiveness of the HPA axis with increased cortisol and ACTH response to stimulatory tests is observed in centrally obese individuals. Total testosterone and SHBG levels are low, but free testosterone levels are usually normal in obese men. LH and FSH levels usually are normal and estrogens are elevated. Norepinephrine levels are elevated, whereas epinephrine levels are low or normal. Aldosterone levels are elevated but renin activity is usually normal. Parathyroid hormone levels are elevated with normal serum calcium levels and increased urine calcium levels. Monogenic mutations that result in severe obesity have been described in several individuals. Also, several endocrine diseases have obesity as one their clinical manifestations. Hypothyroidism, Cushings syndrome, GH and testosterone deficiency, polycystic ovarian syndrome, insulinoma, hypothalamic lesions, and genetic syndromes often present with obesity. In most of these conditions, appropriate treatment of the primary disease results in weight loss. In addition, the fat cell has been found to be an endocrine organ that produces several peptides that are bioactive and participate in the regulation of adipocyte function.

Parathyroid hormone changes following denosumab treatment in postmenopausal osteoporosis.

Denosumab is a new potent antiresorptive treatment of osteoporosis that can potentially induce a compensatory increase in parathyroid hormone (PTH) levels. We aimed to evaluate the alteration of PTH 1 and 6 months after denosumabs administration with different regimens of calcium and vitamin D (Ca/D) supplementation.

Denosumab in treatment-naïve and pre-treated with zoledronic acid postmenopausal women with low bone mass: Effect on bone mineral density and bone turnover markers.

PURPOSE To compare denosumab-induced changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone markers and free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) between treatment naïve postmenopausal women with low bone mass (naïve group) and those who were previously treated with a single zoledronic acid infusion (post-Zol group). PROCEDURES Procollagen type 1N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx) and sRANKL levels were measured in serum samples obtained at baseline and 3, 6 and 12months after denosumab initiation. LS and FN BMD were measured at baseline and 12months. RESULTS LS and FN BMD increased significantly in both naïve and post-Zol group (p<0.001 and p=0.025 vs. p<0.001 and p=0.017, respectively). Despite the higher P1NP and CTx levels in naïve patients at baseline (both p<0.001), denosumab caused comparable decreases in both groups at month 3, which returned to post-Zol group baseline levels at month 6 and 12 in all patients. Similarly, sRANKL levels decreased significantly at month 3 in both groups and returned to baseline levels at months 6 and 12. CONCLUSIONS In patients previously treated with zoledronic acid, sequential denosumab treatment is effective in terms of BMD increases and bone turnover suppression. Despite the lower baseline levels in patients pre-treated with zoledronic acid, bone markers are similarly decreased in both groups following denosumab administration and maintain their reversibility. Denosumab reversibly suppresses endogenous free sRANKL levels in both naïve and zoledronic acid pre-treated patients.

Reduced bone mineral density in adult patients with Langerhans cell histiocytosis.

This retrospective study evaluated bone mineral density (BMD) and bone turnover in adults with LCH. Twenty‐five adult patients and 25 matched controls were evaluated with BMD measurement and indices of bone metabolism. A BMD value below the expected range for age (Z‐score ≤ − 2.0) was found in 20% of patients; in particular, all postmenopausal women and men over 50‐years had either osteoporosis or osteopenia. Patients with active disease had significantly lower Z‐scores compared to patients with inactive disease and controls. Reduced bone turnover was found in all 14 patients treated with chemotherapy. No fractures due to osteoporosis were identified during 305.15 patient‐years of follow‐up. Pediatr Blood Cancer 2012; 58: 819–822.

Circulating semaphorin-4D and plexin-B1 levels in postmenopausal women with low bone mass: the 3-month effect of zoledronic acid, denosumab or teriparatide treatment

Objective: The evaluation of circulating semaphorin-4D (sema4D) and plexin-B1 in postmenopausal women with low bone mass and the effect of antiresorptive or osteoanabolic treatment. Methods: Serum samples were obtained from postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion (n = 30), denosumab injection (n = 30) or teriparatide initiation (n = 28) and from controls matched for age, age at menopause and body mass index (n = 30) at the same time points. Main outcome measures: Circulating sema4D and plexin-B1. Results: Circulating sema4D increased following denosumab (p = 0.026), whereas decreased following teriparatide (p = 0.013). Sema4D/plexin-B1 ratio increased following denosumab (p = 0.004). At baseline, sema4D and plexin-B1 levels were higher in patients pre-treated with bisphosphonates compared to naïve ones (p < 0.001 and p = 0.001, respectively). In bivariate correlations sema4D was inversely correlated with serum carboxyterminal telopeptide of type 1 collagen (rs -0.282, p = 0.002), intact parathyroid hormone (rs -0.388, p < 0.001) and 25(OH)D (rs -0.316, p < 0.001), whereas there was a trend towards correlation with lumbar spine bone mineral density (rs -0.191, p = 0.053). Conclusions: Sema4D levels are independently associated with previous bisphosphonate treatment, intact parathyroid hormone and 25(OH)D levels. Denosumab and teriparatide seem to exert an opposite effect on circulating sema4D levels. Further studies are needed to evaluate whether sema4D mediates the coupling effect that occurs following both antiresorptive and osteoanabolic treatment.

The AGT and the GNB3 polymorphisms and insulin resistance in prehypertension

OBJECTIVEThis study surveyed the frequencies of single nucleotide polymorphisms (SNPs) M235T AGT and C825T GNB3, and their association with insulin resistance, other biochemical markers and qualitative variables in subjects with high normal blood pressure and/or prehypertension in the Greek population.DESIGN330 men and women of Greek origin were divided into 3 groups: a) hypertensive, b) prehypertensive and c) control group. These groups were genetically tested for these polymorphisms and insulin resistance with the HOMA index.RESULTSNo statistically significant differences were found among the polymorphisms of the compared groups. However, the T allele carriers (CT/TT vs. CC) of the C825T polymorphism were associated with an increased BMI in all 3 groups (p = 0.004). The HOMA index was higher in the hypertensive (p = 0.006) and prehypertensive (p = 0.016) versus the control group, and similar results were found for insulin (hypertensive vs. control p=0.012, prehypertensive vs. control p = 0.001) without statistical significance between the first 2 groups (p = 0.522). Additionally, there was a statistically significant difference between the control group and the hypertensive and prehypertensive groups regarding cholesterol (control vs. hypertensive p=0.001, control vs. prehypertension p = 0.018) and triglycerides (control vs. hypertensive p = 0.0001, control vs. prehypertension p = 0.007). Differences were also noted between the control and the hypertensive group regarding the value of HDL (p = 0.005) and LDL (p = 0.013).CONCLUSIONThis study failed to demonstrate a correlation between specific SNPs, blood pressure and insulin resistance in the 3 groups. However, T allele carriers of the polymorphism C825T were found to have an increased BMI. similarly, increased insulin resistance and lipidemia were more common in the hypertensive and prehypertensive populations.

Circulating periostin in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, ranges from nonalcoholic simple steatosis (SS) to nonalcoholic steatohepatitis (NASH), characterized by inflammation and/or fibrosis, and to NASH-related cirrhosis and hepatocellular carcinoma [1]. Liver biopsy still is regarded as the reference for the diagnosis of NAFLD, although identification of noninvasive biomarkers is a field of intense research, expected to help both clinical trials and clinical practice, which are to date impaired due to the need of paired biopsies [2]. Periostin (encoded by POSTN) is a 90 kDa extracellular matrix protein expressed in collagen-rich connective tissues and involved in cell recruitment, adhesion and fibrosis [3]. It was initially identified in periosteal osteocytes and osteoblasts. Beyond the bone, periostin has been linked with several mainly inflammatory diseases, including asthma, skin inflammation, obesity, type 2 diabetes, atherosclerosis, cardiovascular events, and malignancies [3]. Based on experimental studies implicating periostin in hepatic steatosis, inflammation and fibrosis, as we summarized [4], a previous case-control study showed higher serum periostin levels in ultrasound-proven NAFLD patients than controls [5]. The aim of this study was to evaluate whether comparative circulating periostin levels in histologically confirmed patients with SS and NASH could serve as a noninvasive index for the diagnosis of NASH or hepatic fibrosis, considered the main prognostic histological endpoint for advanced liver disease.

Low periostin levels in adult patients with Langerhans cell histiocytosis are independently associated with the disease activity

PURPOSE Langerhans cell histiocytosis (LCH) is a rare proliferative disease of cells of the CD1a+/CD207+ myeloid dendritic cell lineage that may infiltrate one or more organs or systems at all ages. We aimed to evaluate periostin and sclerostin serum levels in adult patients with LCH. PROCEDURES This was a cross-sectional study comparing 38 adult patients with LCH with 38 age- and sex-matched healthy controls. Serum periostin and sclerostin levels were measured to compare between LCH patients and controls as well as between patients with active and non-active disease. RESULTS Serum periostin levels were significantly lower in LCH patients than controls (457±72ng/ml vs. 721±79ng/ml, p=0.014) but this was not the case for sclerostin levels which did not differ between patients and controls, respectively (29.0±1.8pmol/L vs. 39.5±3.8pmol/L, p=0.12). Patients with active disease had significantly lower periostin levels than those with inactive disease (240±78ng/ml vs. 558±94ng/ml, p=0.008). No effect of specific site involvement, extend of disease, or treatment administered was found on any of the above parameters measured. CONCLUSIONS Lower serum periostin levels were observed in adult LCH patients with active disease. The finding warrants further investigation to define whether periostin could serve as a serum biomarker for LCH activity.