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Novel Inflammatory Biomarkers in Thyroid Eye Disease

Hans Olav Ueland, Grethe Åstrøm Ueland, Kristian Løvås, Lars Breivik, Alexander Stanely Thrane, Ann-Elin Meling Stokland, Eyvind Rodahl, and Eystein Sverre Husebye

Purpose:

To identify biochemical inflammatory markers predicting presence or risk of developing thyroid eye disease (TED) in patients with Graves` disease (GD).

Methods:

Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ Specific Diseases (ROAS). Serum samples were analysed for 92 different inflammatory biomarkers using proximity extension assay. Biomarker levels were compared between groups of patients with and without TED, and healthy subjects (n = 120).

Results:

TED was found in 36 of 100 GD patients. Significant (p < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and healthy subjects were compared (42 elevated, 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL-6) (p = 0.022) and macrophage colony-stimulating factor (CSF-1) (p = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significant elevation in serum level of Fms-related tyrosine kinase 3 ligand (Flt3L) (p = 0.009). Furthermore, fibroblast growth factor 21 (FGF-21), was significantly increased (p = 0.008) in patients with GD who had no signs of TED at baseline, but developed TED later.

Conclusion:

We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation related proteins were elevated, while others were decreased. Distinctly increased levels of IL-6, CSF-1, Flt3L, and FGF-21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore may be potentially new biomarkers.

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Our experience with the management of patients with non-metastatic adrenocortical carcinoma.

Massimo Terzolo and Martin Fassnacht

Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon’s expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, i) R0 resection (microscopically free margin), ii) localized disease (stage I-II ACC), and iii) low grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use frequently adjuvant radiotherapy of the tumor bed at our institutions, and we select for this treatment patients with microscopically, or macroscopically, incomplete resection. On long-term, prospective multicenter trials are required to improve patient care.

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Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk

Takuyuki Katabami, Ren Matsuba, Hiroki Kobayashi, Tomoko Nakagawa, Isao Kurihara, Takamasa Ichijo, Mika Tsuiki, Norio Wada, Yoshihiro Ogawa, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Katsutoshi Takahashi, Koichi Yamamoto, Shoichiro Izawa, Miki Kakutani, Akiyo Tanabe, Mitsuhide Naruse, and JPAS/JRAS Study Group

Objective

In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications.

Design

This study is a retrospective cross-sectional study.

Methods

A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications.

Results

The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC.

Conclusions

MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.

Open access

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

A Nordenström, S F Ahmed, E van den Akker, J Blair, M Bonomi, C Brachet, L H A Broersen, H L Claahsen-van der Grinten, A B Dessens, A Gawlik, C H Gravholt, A Juul, C Krausz, T Raivio, A Smyth, P Touraine, D Vitali, and O M Dekkers

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Open access

Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity

Kim Huynh, Marianne Klose, Kim Krogsgaard, Jørgen Drejer, Sarah Byberg, Sten Madsbad, Faidon Magkos, Abdellatif Aharaz, Berit Edsberg, Jacob Tfelt-Hansen, Arne Vernon Astrup, and Ulla Feldt-Rasmussen

Context

Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective.

Objective

To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity.

Methods

Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile.

Results

Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of −6.3% ((−11.3; −1.3); P  = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P  = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((−0.1; 11.5); P  = 0.054).

Conclusion

Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

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Revisiting growth hormone nadir cut-offs for remission in patients with acromegaly

Jiwon Kim, Yoon-a Hwang, Yae Won Park, Ju Hyung Moon, Eui Hyun Kim, Jae Won Hong, Eun Jig Lee, and Cheol Ryong Ku

Objective

Over the past decade, the growth hormone (GH) nadir cut-off during the oral glucose tolerance test for remission in patients with acromegaly was changed from 0.4 to 1.0 μg/L due to the limited use of ultrasensitive detection kits to measure GH levels. However, the optimal cut-off level for GH nadir remains unclear. This retrospective study aimed to investigate the association between different GH nadir cut-offs and prognosis in patients with acromegaly.

Design and methods

A total of 285 patients with acromegaly with a glucose-suppressed GH nadir <1 μg/L at 3–6 months after trans-sphenoidal adenomectomy were divided into two groups according to the glucose-suppressed GH nadir levels at 3–6 months post-operatively (group A: <0.4 μg/L; group B: 0.4–1.0 μg/L). GH levels were measured using an ultrasensitive IRMA. The clinical, hormonal, metabolic, and neuroradiological data of the two groups were compared.

Results

Female sex, as well as confirmed macroadenomas, was significantly overrepresented in group B. The 5-year rate of patients who achieved nadir GH < 1.0 μg/L and age- and sex-matched normal IGF-1 was significantly higher in group A than that in group B. However, there was no significant difference between the two groups in metabolic parameters at 12 months post-operatively.

Conclusion

Different GH nadir cut-offs were associated with different 5-year rates of patients who achieved nadir GH <1.0 μg/L and age- and sex-matched normal IGF-1, suggesting that a strict GH nadir threshold of 0.4 μg/L correlates better with remission.

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Risk of cardiovascular events associated with pathophysiological phenotypes of type 2 diabetes

Jacob Volmer Stidsen, Diana Hedevang Christensen, Jan Erik Henriksen, Kurt Højlund, Michael Hecht Olsen, Reimar Wernich Thomsen, Lotte Brix Christensen, Jens Steen Nielsen, Thomas Bastholm Olesen, and Henning Beck-Nielsen

Objective: Hyperglycaemia in type 2 diabetes is caused by varying degrees of two defects: low insulin sensitivity and beta-cell dysfunction. We assessed if subgrouping of patients into three pathophysiological phenotypes according to these defects could identify individuals with high or low risk of future cardiovascular events.

Design: Prospective cohort study.

Methods: We assessed estimates of insulin sensitivity and beta-cell function from the homeostasis model assessment-2 in 4,209 individuals with recently diagnosed type 2 diabetes enrolled from general practitioners and outpatient clinics in Denmark. Individuals were followed for a composite cardiovascular endpoint (either atherosclerotic outcomes [myocardial infarction, unstable angina pectoris, stroke, coronary or peripheral revascularization], heart failure, or cardiovascular death) and all-cause mortality.

Results: The 417 individuals with the insulinopenic phenotype (high insulin sensitivity and low beta-cell function) had substantially lower risk of cardiovascular events (5-year cumulative incidence 4.6% versus 10.1%; age-/sex-adjusted hazard ratio [aHR] 0.49, 95% CI 0.30-0.82) compared with 2685 individuals with the classical phenotype (low insulin sensitivity and low beta-cell function), driven by atherosclerotic events. Conversely, 1107 individuals with the hyperinsulinemic phenotype (low insulin sensitivity and high beta-cell function) had more cardiovascular events (5-year cumulative incidence 12.6%; aHR 1.33, 95% CI 1.05-1.69), primarily driven by increased heart failure and cardiovascular death, and increased all-cause mortality.

Conclusions: Simple phenotyping based on insulin sensitivity and beta-cell function predicts distinct future risks of cardiovascular events and death in patients with type 2 diabetes. These results suggest that precision medicine according to underlying type 2 pathophysiology potentially can reduce diabetes complications.

Open access

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement

Margaret C S Boguszewski, Cesar L Boguszewski, Wassim Chemaitilly, Laurie E Cohen, Judith Gebauer, Claire Higham, Andrew R Hoffman, Michel Polak, Kevin C J Yuen, Nathalie Alos, Zoltan Antal, Martin Bidlingmaier, Beverley M K Biller, George Brabant, Catherine S Y Choong, Stefano Cianfarani, Peter E Clayton, Regis Coutant, Adriane A Cardoso-Demartini, Alberto Fernandez, Adda Grimberg, Kolbeinn Guðmundsson, Jaime Guevara-Aguirre, Ken K Y Ho, Reiko Horikawa, Andrea M Isidori, Jens Otto Lunde Jørgensen, Peter Kamenicky, Niki Karavitaki, John J Kopchick, Maya Lodish, Xiaoping Luo, Ann I McCormack, Lillian Meacham, Shlomo Melmed, Sogol Mostoufi Moab, Hermann L Müller, Sebastian J C M M Neggers, Manoel H Aguiar Oliveira, Keiichi Ozono, Patricia A Pennisi, Vera Popovic, Sally Radovick, Lars Savendahl, Philippe Touraine, Hanneke M van Santen, and Gudmundur Johannsson

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Open access

Shared etiology of type 1 diabetes and Hashimoto’s thyroiditis: a population-based twin study

Jakob Skov, Ralf Kuja-Halkola, Patrik K E Magnusson, Soffia Gudbjörnsdottir, Olle Kämpe, and Sophie Bensing

Objective

Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors.

Design

This study is a twin cohort study.

Methods

National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models.

Results

Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis.

Conclusions

Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

Free access

THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin – physiology and pharmacology

David S Mathiesen, Asger Lund, Jens J Holst, Filip K Knop, Thomas A Lutz, and Jonatan I Bagger

Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the six amylin receptors, which share the core component with the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce the gastric emptying rate and promote satiation. Preclinical trials with agents targeting the calcitonin receptor and the amylin receptors, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.