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
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.
Marko Stojanovic, Zida Wu, Craig E Stiles, Dragana Miljic, Ivan Soldatovic, Sandra Pekic, Mirjana Doknic, Milan Petakov, Vera Popovic, Christian Strasburger, and Márta Korbonits
Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients.
Subjects and methods
Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP.
Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT.
Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.
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.
Alberto Bongiovanni, Federica Recine, Flavia Foca, Valentina Fausti, Nada Riva, Greta Fabbri, Stefano Severi, Chiara Liverani, Alessandro De Vita, Chiara Spadazzi, Giacomo Miserocchi, Laura Mercatali, Dino Amadori, and Toni Ibrahim
The incidence of neuroendocrine neoplasia (NEN) is higher in individuals ≥70 years of age (elderly) who are underrepresented in clinical trials because of comorbidities and low performance status. We retrospectively analyzed the outcome of elderly patients with metastatic NEN (mNEN). Comorbidities were summarized by Charlson Comorbidity Index (CCI), Kaplan–Meier method was applied to estimate overall survival (OS) and Cox’s proportional hazard model was used to assess the impact of known prognostic factors. We retrieved data on 145 mNEN patients aged ≥70 years seen at our center from June 2007 to March 2016. Fifty-six (38.6%) were aged ≥75 years. ECOG PS was 0 in 45.7% of cases and CCI was 0 in 41.0% and 1 in 37.4%. A total of 75.4% of patients had grade (G)1/G2 NEN and 24.6%, G3. Octreoscan/Gallium PET/CT and FDG-PET/CT were positive in 94.2% and 70.3% of cases, respectively. Median follow-up was 72.3 (53.2–85.1) months. Seventy-nine patients received first-line somatostatin analogs (SSA), 23 peptide receptor radionuclide therapy (PRRT) and 36 chemotherapy (CHT). Seven did not undergo first-line therapy and 102 received more than one line. Median overall survival (mOS) was 5.1 years (95% CI: 3.4–6.6). No differences in mOS were seen according to CCI. First-line PRRT patients had a mOS of 6.5 years (95% CI: 3.3–not reached (NR)), SSA 5.7 years (95% CI: 4.2–7) and CHT 5.9 years (95% CI: 0.4–NR). mOS in CHT-treated G3 patients was 1.5 years (1.0–2.5). ECOG PS and FDG PET/CT were identified as independent prognostic factors. Results suggest that the above treatments positively impacted OS in elderly mNEN patients, including those aged ≥75 years.
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.
Nella Augusta Greggio, Elisa Rossi, Silvia Calabria, Alice Meneghin, Joaquin Gutierrez de Rubalcava, Carlo Piccinni, and Antonella Pedrini
To estimate the prevalence of subclinical hypothyroidism (SH) among children, by using levothyroxine low dosage as disease proxy, and to describe prescription pattern.
An historical cohort study was performed through administrative databases of 12 Italian Local Health Units covering 3,079,141 inhabitants. A cohort of children (aged 0–13 years) was selected in the period 2001–2014. A subgroup of new users (aged 0–9 years) was identified and followed up for 5 years.
The prevalence was provided as mean value of the whole period, as annual trend, by patient gender and age. Demographic details, information on levothyroxine dosage, comorbidities and co-medications were provided. Therapy duration and medication persistence were evaluated among new users.
644 children treated with levothyroxine low dosage was selected, with a mean annual prevalence of 0.20 per 1000 children. The temporal trend of prevalence was stable, with a slight reduction in the 2005–2008. Prevalence by age showed an increase after 10 years. Patients were treated with an average annual dose of 4290 µg/year and 66.9% of children were affected by comorbidities. Among 197 new users, 62.9% received therapy only for one year, whereas out of those treated two or more years, 89.0% resulted persistent to the therapy.
This study provides real-world epidemiology of SH among children, and it depicts the clinical and therapeutic characteristics of these subjects. Its findings showed that the SH treatment of this disorder was widely variable, also due to lack of evidence concerning paediatric population.
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.
Marlena Mueller, Fahim Ebrahimi, Emanuel Christ, Christian Andreas Nebiker, Philipp Schuetz, Beat Mueller, and Alexander Kutz
Primary hyperparathyroidism is a prevalent endocrinopathy for which surgery is the only curative option. Parathyroidectomy is primarily recommended in younger and symptomatic patients, while there are still concerns regarding surgical complications in older patients. We therefore assessed the association of age with surgical outcomes in patients undergoing parathyroidectomy in a large population in Switzerland.
Population-based cohort study of adult patients with primary hyperparathyroidism undergoing parathyroidectomy in Switzerland between 2012 and 2018. The cohort was divided into four age groups (<50 years, 50–64 years, 65–74 years, ≥75 years). The primary outcome was a composite of in-hospital postoperative complications. Secondary outcomes were intensive care unit (ICU) admission, unplanned 30-day-readmission, and prolonged length of hospital stay.
We studied 2642 patients with a median (IQR) age of 62 (53–71) years. Overall, 111 patients had complications including surgical re-intervention, hypocalcemia, and vocal cord paresis. As compared to <50 year-old patients, older patients had no increased risk for in-hospital complications after surgery (50–64 years: odds ratio (OR): 0.51 (95% CI, 0.28 to 0.92); 65–74 years: OR: 0.72 (95% CI, 0.39 to 1.33); ≥75 years: OR: 1.03 (95% CI, 0.54 to 1.95), respectively. There was also no association of age and rates of ICU-admission and unplanned 30-day-readmission, but oldest patients had longer hospital stays (OR: 2.38 (95% CI, 1.57 to 3.60)).
≥50 year-old patients undergoing parathyroidectomy had comparable risk of in-hospital complications as compared with younger ones. These data support parathyroidectomy in even older patients with primary hyperparathyroidism as performed in clinical routine.