Hepatic thyroid hormone signaling has an important role in the development and progression of nonalcoholic steatohepatitis (NASH). While the systemic levels of thyroid hormone might remain stable, there is evidence that the intracellular signaling machinery consisting of transporters, deiodinases and receptors could be altered in NASH. However, clinical material from human liver biopsies of individuals with NASH has not been studied to date. In a cross-sectional study, we analyzed 85 liver biopsies from patients with different stages of NASH that underwent bariatric surgery. Using qPCR, we analyzed gene expression of thyroid hormone transporters NTCP (SLC10A1), MCT8 (SLC16A2) and OATP1C1 (SLCO1C1), thyroid hormone receptor α and β (THRA and THRB) and deiodinase type I, II and III (DIO1, DIO2, DIO3). The expression was correlated with serum TSH, triglyceride, HbA1c and NASH score and corrected for age or gender if required. While DIO2, DIO3 and SLCO1C1 were not expressed in human liver, we observed a significant negative correlation of THRB and DIO1 with age, and SLC16A2 with gender. THRB expression was also negatively associated with serum triglyceride levels and HbA1c. More importantly, its expression was inversely correlated with NASH score and further declined with age. Our data provide unique insight into the mRNA expression of thyroid hormone transporters, deiodinases and receptors in the human liver. The findings allow important conclusions on the intrahepatic mechanisms governing thyroid hormone action, indicating a possible tissue resistance to the circulating hormone in NASH, which becomes more prominent in advanced age.
Christin Krause, Martina Grohs, Alexander T El Gammal, Stefan Wolter, Hendrik Lehnert, Oliver Mann, Jens Mittag, and Henriette Kirchner
Franca Genest, Michael Schneider, Andreas Zehnder, Dominik Lieberoth-Leden, and Lothar Seefried
Aging and concurrent constitutional changes as sarcopenia, osteoporosis and obesity are associated with progressive functional decline. Coincidence and mutual interference of this risk factors require further evaluation.
Cross-sectional evaluation of musculoskeletal health in a community-dwelling cohort of men aged 65–90 years. Objectives included descriptive analysis of age-related decline in physical performance, prevalence of osteoporosis (FRAX-Score), sarcopenia (EWGSOP criteria) and obesity (BMI > 30 kg/m2) and their coincidence/interference.
Based on 507 participants assessed, aging was associated with progressive functional deterioration, regarding power (chair rise test −1.54% per year), performance (usual gait speed −1.38% per year) and muscle force (grip strength −1.52% per year) while muscle mass declined only marginally (skeletal muscle index −0.29% per year). Prevalence of osteoporosis was 41.8% (n = 212) while only 22.9% (n = 116) of the participants met the criteria for sarcopenia and 23.7% (n = 120) were obese. Osteosarcopenia was found in n = 79 (15.6%), sarcopenic obesity was present in 14 men (2.8%). A combination of all three conditions could be confirmed in n = 8 (1.6%). There was an inverse correlation of BMI with physical performance whereas osteoporosis and sarcopenia did not interfere with functional outcomes.
Based on current definitions, there is considerable overlap in the prevalence of osteoporosis and sarcopenia, while obesity appears to be a distinct problem. Functional decline appears to be associated with obesity rather than osteoporosis or sarcopenia. It remains to be determined to what extend obesity itself causes performance deficits or if obesity is merely an indicator of insufficient activity eventually predisposing to functional decline.
Jan Roar Mellembakken, Azita Mahmoudan, Lars Mørkrid, Inger Sundström-Poromaa, Laure Morin-Papunen, Juha S Tapanainen, Terhi T Piltonen, Angelica Lindén Hirschberg, Elisabet Stener-Victorin, Eszter Vanky, Pernille Ravn, Richard Christian Jensen, Marianne Skovsager Andersen, and Dorte Glintborg
Obesity is considered to be the strongest predictive factor for cardio-metabolic risk in women with polycystic ovary syndrome (PCOS). The aim of the study was to compare blood pressure (BP) in normal weight women with PCOS and controls matched for age and BMI.
From a Nordic cross-sectional base of 2615 individuals of Nordic ethnicity, we studied a sub cohort of 793 normal weight women with BMI < 25 kg/m2 (512 women with PCOS according to Rotterdam criteria and 281 age and BMI-matched controls). Participants underwent measurement of BP and body composition (BMI, waist-hip ratio), lipid status, and fasting BG. Data were presented as median (quartiles).
The median age for women with PCOS were 28 (25, 32) years and median BMI was 22.2 (20.7, 23.4) kg/m2. Systolic BP was 118 (109, 128) mmHg in women with PCOS compared to 110 (105, 120) mmHg in controls and diastolic BP was 74 (67, 81) vs 70 (64, 75) mmHg, both P < 0.001. The prevalence of women with BP ≥ 140/90 mmHg was 11.1% (57/512) in women with PCOS vs 1.8% (5/281) in controls, P < 0.001. In women ≥ 35 years the prevalence of BP ≥ 140/90 mmHg was comparable in women with PCOS and controls (12.7% vs 9.8%, P = 0.6). Using multiple regression analyses, the strongest association with BP was found for age, waist circumference, and total cholesterol in women with PCOS.
Normal weight women with PCOS have higher BP than controls. BP and metabolic screening are relevant also in young normal weight women with PCOS.
Li Li, Qifa Song, and Xi Yang
Insufficient insulin release plays a crucial role in the development of unhealthy status in patients with obesity; the present study aimed to classify these patients by the indices for insulin resistance and insulin release. After the indices from OGTT were assessed to achieve high differentiability and low redundancy in classifying patients, HOMA-IR and IGI30min were chosen to classify the patients using K-means clustering method. A total of 249 non-diabetic patients with obesity were classified into four groups. In Group 1, 19 patients were characteristic of high insulin resistance and high insulin release, as well as well-controlled glucose levels, the highest BMI, the youngest age, and the highest early phase release of insulin. In Group 2, 38 patients were unhealthiest in terms of high insulin resistance, reduced insulin release and IGT status. Group 3 consisted of 63 patients that were healthiest with low insulin resistance and high insulin release. In Group 4, 46 IGT patients and 14 IFG patients were identified among 129 patients that showed low insulin resistance, low insulin release, moderate obesity and older age. These concurrent impotent insulin release, older age, and moderate obesity indicated decreasing obesity with increasing age and reduced insulin release. The classification of patients with obesity using K-means clustering method by HOMA-IR and IGI30min provides more information about the development of obesity and unhealthy status. The patients with distinct insulin resistance and insulin release should be followed up, especially for those with reduced or even absent insulin response to glucose stimulation.
Volha V Zhukouskaya, Anya Rothenbuhler, Annamaria Colao, Carolina Di Somma, Peter Kamenický, Séverine Trabado, Dominique Prié, Christelle Audrain, Anna Barosi, Christèle Kyheng, Anne-Sophie Lambert, and Agnès Linglart
X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to a link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH.
We studied 172 XLH-children 5–20 years of age (113 girls/59 boys). Anthropometric parameters (weight, height, and BMI) were collected at birth and during follow-up at mean ages of 5.3, 8.2, 11.3, and 15.9 years (groups 1, 2, 3, and 4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25–30 or ≥30 kg/m2, respectively).
In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4, 28.7, 27.5, and 36.7% in groups 1, 2, 3, and 4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3 ± 4.4 vs 23.8 ± 3.8 vs 25.2 ± 4.5 kg/m2, for subjects with treatment duration of <5, 5–10 and >10 years, respectively, P for trend = 0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF.
One out of three of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight or obesity in comparison to general population. Both the lack of XLH family history and the duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children, and later in adults, with XLH.
Ling Hu, Ting Li, Xiao-Ling Yin, and Yi Zou
The purpose of this study was to explore the prevalence of thyroid nodules (TN) and metabolic syndrome (MS) and to analyze the correlation between TN and the components of MS.
A total of 1526 subjects were divided into two groups: a TN group and a non-thyroid nodules (NTN) group. The height, weight, blood pressure, fasting blood glucose level, fasting plasma insulin level, serum lipid profile, uric acid level, serum thyroid-stimulating hormone (TSH) level, free triiodothyronine (FT3) level, and free thyroxine (FT4) level of each patient were measured. Insulin resistance (IR) was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). Fatty liver and TN were detected by color Doppler ultrasonography.
(i) The overall prevalence of TN was 39.5%; it was significantly higher in women than in men (P < 0.01) and progressively increased with age in both sexes. (ii) The overall prevalence of MS was 25.6%; it was significantly higher in men than in women (P < 0.01) and progressively increased with age in both sexes. (iii) FT3 was significantly lower in the TN group than in the NTN group (P < 0.01). (iv) BMI, triglycerides, and HOMA-IR were higher in the TN group than in the NTN group (P < 0.05). (v) The existence of TN was significantly associated with overweight/obesity (OR = 1.03, 95% CI = 1.024–1.089), and with insulin resistance (IR) (OR = 1.98, 95% CI = 1.645–2.368), after adjusting for age and sex.
The prevalence of thyroid nodules and metabolic syndrome in the Nanchang area increases with age, and overweight/obesity and IR in patients are associated with thyroid nodules.
A V Dreval, I V Trigolosova, I V Misnikova, Y A Kovalyova, R S Tishenina, I A Barsukov, A V Vinogradova, and B H R Wolffenbuttel
Early carbohydrate metabolism disorders (ECMDs) and diabetes mellitus (DM) are frequently associated with acromegaly. We aimed to assess the prevalence of ECMDs in patients with acromegaly and to compare the results with those in adults without acromegaly using two population-based epidemiologic surveys. We evaluated 97 patients with acromegaly in several phases of their disease (mean age, 56 years and estimated duration of acromegaly, 12.5 years). An oral glucose tolerance test was done in those not yet diagnosed with DM to reveal asymptomatic DM or ECMDs (impaired glucose tolerance+impaired fasting glucose). Comparisons were made between patients with acromegaly and participants from the general adult population (n=435) and an adult population with multiple type 2 diabetes risk factors (n=314), matched for gender, age and BMI. DM was diagnosed in 51 patients with acromegaly (52.5%) and 14.3% of the general population (P<0.001). The prevalence of ECMDs was also higher in patients with acromegaly than in the general population and in the high-risk group; only 22% of patients with acromegaly were normoglycaemic. The prevalence of newly diagnosed ECMDs or DM was 1.3–1.5 times higher in patients with acromegaly compared with the high-risk group. Patients with acromegaly having ECMDs or DM were older, more obese and had longer disease duration and higher IGF1 levels (Z-score). Logistic regression showed that the severity of glucose derangement was predicted by age, BMI and IGF1 levels. In patients with acromegaly, the prevalence of DM and ECMDs considerably exceeds that of the general population and of a high-risk group, and development of DM depends on age, BMI and IGF1 levels.
Elizaveta Mamedova, Natalya Mokrysheva, Evgeny Vasilyev, Vasily Petrov, Ekaterina Pigarova, Sergey Kuznetsov, Nikolay Kuznetsov, Liudmila Rozhinskaya, Galina Melnichenko, Ivan Dedov, and Anatoly Tiulpakov
Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial.
To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age.
We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome.
The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed.
NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8.
Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.
Iulia Soare, Anca Sirbu, Mihai Mircea Diculescu, Bogdan Radu Mateescu, Cristian Tieranu, Sorina Martin, Carmen Gabriela Barbu, Mirela Ionescu, and Simona Fica
Background and aim
Low bone mineral density (BMD) is a common complication in patients with inflammatory bowel disease (IBD). However, debates are ongoing with regard to the other involved factors, especially in younger patients. This study aimed to evaluate the parameters that contribute to decreased BMD, focusing on premenopausal women and men aged <50 years.
This study included 81 patients with IBD and 81 age-, sex- and BMI-matched controls. Blood tests were conducted on IBD patients, and a dual-energy X-ray absorptiometry (DXA) scan was performed on both groups.
Low BMD and fragility fracture were found to be more prevalent in IBD patients than in healthy subjects (49.3% vs 23.4%, P = 0.001 and 9.8% vs 1.2%, P = 0.01, respectively). Patients with low BMD were older, with a longer disease duration, higher faecal calprotectin (FC) levels and lower magnesium and lean mass (appreciated as appendicular skeletal muscle index (ASMI)). Multiple regression analysis revealed that ASMI, age and use of glucocorticoids were the independent parameters for decreased BMD. Although 91.3% of the patients had a 25-hydroxy vitamin D level of <30 ng/mL, it was not a statistically significant factor for decreased BMD.
In our study, the levels of vitamin D did not seem to have an important impact on BMD. Conversely, FC, magnesium and lean mass are important factors, suggesting that good control of disease, adequate magnesium intake and increased lean mass can have a good impact on bone metabolism in patients with IBD.
David Mark Robertson, Chel Hee Lee, and Angela Baerwald
It is recognised that ovarian factors, including steroid and protein hormones, are critical in the feedback regulation of pituitary gonadotropins; however, their individual contributions are less defined. The aim of this study was to explore the reciprocal relationships between ovarian and pituitary hormones across the normal ovulatory menstrual cycle as women age. FSH, LH, oestradiol, progesterone, inhibin A, inhibin B and anti-mullerian hormone (AMH) were measured in serum collected every 1–3 days across one interovulatory interval (IOI) from 26 healthy women aged 18–50 years. The antral follicle count (AFC) for follicles 2–5 mm, >6 mm and 2–10 mm were tabulated across the IOI. Independent associations between ovarian hormones/AFC vs pituitary follicle-stimulating hormone (FSH) and luteinising hormone (LH) were investigated using multivariate regression analysis. The data were sub-grouped based on the presence or absence luteal phase-dominant follicles (LPDF). Serum oestradiol and AMH were inversely correlated with FSH in both follicular and luteal phases. Inhibin B correlated inversely with FSH and LH in the late follicular phase and directly in the luteal phase. AFC, inhibin A and progesterone were not key predictors of either FSH or LH. The strong association between AMH and FSH with age implies that AMH, as well as oestradiol and inhibin B are important regulators of FSH. The change in feedback response of inhibin B with both FSH and LH across the cycle suggests two phases of the negative feedback.