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Open access

The STC2–PAPP-A–IGFBP4–IGF1 axis and its associations to mortality and CVD in T2D

Mette Faurholdt Gude, Rikke Hjortebjerg, Mette Bjerre, Morten Haaning Charles, Daniel R Witte, Annelli Sandbæk, and Jan Frystyk

Objective

Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2–PAPP-A–IGFBP4–IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D).

Design

We followed 1284 participants with T2D from the ADDITION trial for 5 years.

Methods

Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model.

Results

During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09–3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98–3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11–1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91–4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16–2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34–0.76); P = 0.001.

Conclusions

This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A–IGF1 axis.

Significance statement

PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2–PAPP-A–IGFBP4–IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2–PAPP-A–IGFBP4–IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

DOI:
https://doi.org/10.1530/EC-22-0451
Volume 12: Issue 3
Open access

Validation of a novel automated system, Fluispotter®, for serial sampling of dried blood spots

Jesper Krogh, Peter Plomgaard, Ruth Frikke-Schmidt, Sten Velschow, Jesper Johannesen, Linda Maria Hilsted, Malene Schrøder, and Ulla Feldt-Rasmussen

Repeated blood sampling is required in certain clinical and research settings, which is currently performed by drawing blood from venous catheters requiring manual handling of each sample at time of collection. A novel body-worn device for repeated serial samples, Fluispotter®, with automated extraction, collection and storage of up to 20 venous dried blood spot samples over the course of 20 hours may overcome problems with current methods for serial sampling. The purpose of this study was to assess the performance and safety of Fluispotter for the first time in healthy subjects. Fluispotter consists of a cartridge with tubing, reservoir for flushing solution, pumps and filter-paper and a multi-lumen catheter placed in the brachial vein. We recruited healthy subjects for testing in an in-hospital setting. Fluispotter was attached by an anesthesiologist to 22 healthy subjects of which 9/22 (40.9 %) participants had all 20 samples taken, which was lower than the goal of complete sampling in 80 % of the subjects (p = 0.02). The main reason for sample failure was clogging of blood flow which was observed in 11/22 (50 %) of the participants. No serious adverse events occurred, and the participants rated the pain from insertion and removal of catheter as very low. A cortisol profile showed nadir values at midnight and highest values at 5 a.m. Although full sampling was not successful in all participants, the Fluispotter technology proved safe and highly acceptable to the participants producing the expected cortisol profile without the requirement of staff during sample collection.

DOI:
https://doi.org/10.1530/EC-23-0087
Accepted Manuscripts
Open access

Association between radioactive iodine uptake and neutropenia in untreated Graves’ disease

Qian Yang, Wencai Ke, Fanfan Pan, Xinmei Huang, Jun Liu, and Bingbing Zha

Objective

Neutropenia is a complication of Graves' disease (GD), but there is currently no means by which to predict its occurrence. This study aimed to investigate the risk factors for the development of neutropenia in untreated GD.

Methods

This was a retrospective cohort study. Between January 1, 2010, and July 31, 2020, 1000 patients with new-onset or relapsing GD without treatment were enrolled in the study and divided into two groups: neutropenia group (neutrophil count < 2 × 109/L) and non-neutropenia group (neutrophil count ≥ 2 × 109/L). Clinical characteristics of subjects were compared between the two groups, and logistic regression analysis was applied to determine risk factors for neutropenia. To further explore the correlation of radioactive iodine uptake (RAIU) with neutropenia, subjects were first classified according to quartile of 3 h RAIU and 24 h RAIU prior to logistic regression analysis.

Results

Of all patients recruited, 293 (29.6%) were diagnosed with neutropenia. Compared with non-neutropenic patients, those with neutropenia had a higher level of free thyroxine (FT4) (56.64 ± 31.80 vs 47.64 ± 39.64, P = 0.001), 3 h RAIU (55.64 ± 17.04 vs 49.80 ± 17.21, P < 0.001) and 24 h RAIU (67.38 ± 12.54 vs 64.38 ± 13.58, P < 0.001). Univariate logistic regression analysis revealed that FT4, 3 h RAIU, 24 h RAIU, creatinine, and low-density lipoprotein were risk factors for development of neutropenia in GD. After adjusting for confounding factors of age, BMI, and sex, we determined that 3 h RAIU and 24 h RAIU (Model 1: OR = 1.021, 95% CI: 1.008–1.033, P = 0.001; Model 2: OR = 1.023, 95% CI: 1.007–1.039, P = 0.004), but not FT4, were associated with the development of neutropenia.

Conclusions

RAIU is associated with neutropenia in patients with untreated GD.

DOI:
https://doi.org/10.1530/EC-22-0474
Volume 12: Issue 2
Open access

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis

Brijesh Krishnappa, Ravikumar Shah, Saba Samad Memon, Chakra Diwaker, Anurag R Lila, Virendra A Patil, Nalini S Shah, and Tushar R Bandgar

Objectives

High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear.

Design

We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5–12 vs >12 weeks) of glucocorticoid treatment according to disease severity.

Results

A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5–48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing glucocorticoid dose group (0% vs 38.1% vs 57.1%), attaining statistical significance (P = 0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. The need for rescue therapy was lower with i.v. route (38% vs 17.5%, P = 0.012) and with increasing glucocorticoid doses (53.3% vs 34.3% vs 17.3%, P = 0.016). In severe disease, visual field and corticotroph axis recovery were significantly higher with i.v. route and very high-dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment.

Conclusions

Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

DOI:
https://doi.org/10.1530/EC-22-0311
Volume 12: Issue 2
Open access

Growth hormone deficiency in adult survivors of childhood brain tumors treated with radiation

Mette Marie Baunsgaard, Anne Sophie Lind Helligsoe, Louise Tram Henriksen, Torben Stamm Mikkelsen, Michael Callesen, Britta Weber, Henrik Hasle, and Niels Birkebæk

Objective

Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD.

Design

This study is a cross-sectional study.

Methods

We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997–2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test.

Results

Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1–33.8 years) at follow-up and 14.8 years (range: 5.1–23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT).

Conclusion

This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1.

Significance statement

This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

DOI:
https://doi.org/10.1530/EC-22-0365
Volume 12: Issue 2
Open access

Mapping of the current transition of care practice for patients with pituitary disease at Endo-ERN reference centers

Savi R Shishkov, Luigi Tuccillo, Violeta M Iotova, Rosario Pivonello, Iris CM Pelsma, Alberto M Pereira, Nienke R Biermasz, and

Rare endocrine conditions present specific diagnostic and management challenges for healthcare providers, one of which is the understudied transition of care. Despite the need for guidance regarding transition, consensus on structured and protocolled approaches is lacking. Therefore, we aimed to map the current clinical practice and identify unmet needs regarding transition of care for patients with pituitary disease in the reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A survey-based, cross-sectional study using the EU Survey tool was performed and completed by 46 physicians (n) from 30 RCs (N). Transition is a common practice among RCs (n  = 44/46), usually accomplished by a multidisciplinary team meeting (N = 20/30). Criteria for start and end of transition were defined in half of the RCs, with 16.7% of centers providing dissimilar answers. Transition readiness was assessed by >75% of the RCs, mostly by unvalidated means (e.g. subjective opinions, informal consultations). Pituitary-specific transition assessment tool was applied in one RC only. Transition protocols were present in only 9% of RCs, while in many RCs, transition decisions were taken in combined adult-pediatric meetings or based on clinicians’ personal judgment. A minority of physicians evaluated the effectiveness of transition-related interventions (n  = 11/46) or medical outcomes (n  = 8/46). Patient-reported outcome measures were infrequently used (n  = 4/46). Identified unmet needs included the development of guidelines (n  = 5/46) and EU-wide approach (n  = 2/46). This study exemplifies the unmet needs for a structural definition of the transition period and transition management for patients with rare hypothalamic and pituitary conditions from healthcare providers’ perspective.

DOI:
https://doi.org/10.1530/EC-22-0308
Volume 12: Issue 2
Open access

Modification of TSH-related genetic effects by indicators of socioeconomic position

Sophie-Charlotte Drogge, Mirjam Frank, Carolin Girschik, Karl-Heinz Jöckel, Dagmar Führer-Sakel, and Börge Schmidt

Objective

Thyroid-stimulating hormone (TSH) is influenced by genetic and environmental factors such as socioeconomic position (SEP). However, interactions between TSH-related genetic factors and indicators of SEP have not been investigated to date. The aim of the study was to determine whether education and income as SEP indicators may interact with TSH-related genetic effect allele sum scores (GESTSH_2013 and GESTSH_2020) based on two different GWAS meta-analyses that affect TSH values in a population-based study.

Methods

In 4085 participants of the Heinz Nixdorf Recall Study associations between SEP indicators, GESTSH and TSH were quantified using sex- and age-adjusted linear regression models. Interactions between SEP indicators and GESTSH were assessed by GESTSH × SEP interaction terms, single reference joint effects and calculating genetic effects stratified by SEP group.

Results

Participants within the highest education group showed the strongest genetic effect with on average 1.109-fold (95% CI: 1.067–1.155) higher TSH values per GESTSH_2013 SD, while in the lowest education group, the genetic effect was less strong (1.061-fold (95% CI: 1.022–1.103)). In linear regression models including interaction terms, some weak indication for a positive GESTSH_2013 by education interaction was observed showing an interaction effect size estimate of 1.005 (95% CI: 1.000–1.010) per year of education and GESTSH_2013 SD. No indication for interaction was observed for using income as SEP indicator. Using the GESTSH_2020, similar results were observed.

Conclusion

Our results gave some indication that education may affect the expression of TSH-related genetic effects. Stronger genetic effects in high-education groups may be explained by environmental factors that have an impact on gene expression and are more prevalent in high SEP groups.

DOI:
https://doi.org/10.1530/EC-22-0127
Volume 12: Issue 2
Open access

Multiple endocrine neoplasia type 4: a new member of the MEN family

Hélène Singeisen, Mariko Melanie Renzulli, Vojtech Pavlicek, Pascal Probst, Fabian Hauswirth, Markus K Muller, Magdalene Adamczyk, Achim Weber, Reto Martin Kaderli, and Pietro Renzulli

Objective

Multiple endocrine neoplasia type 4 (MEN4) is caused by a CDKN1B germline mutation first described in 2006. Its estimated prevalence is less than one per million. The aim of this study was to define the disease characteristics.

Methods

A systematic review was performed according to the PRISMA 2020 criteria. A literature search from January 2006 to August 2022 was done using MEDLINE® and Web of ScienceTM.

Results

Forty-eight symptomatic patients fulfilled the pre-defined eligibility criteria. Twenty-eight different CDKN1B variants, mostly missense (21/48, 44%) and frameshift mutations (17/48, 35%), were reported. The majority of patients were women (36/48, 75%). Men became symptomatic at a median age of 32.5 years (range 10–68, mean 33.7 ± 23), whereas the same event was recorded for women at a median age of 49.5 years (range 5–76, mean 44.8 ± 19.9) (P  = 0.25). The most frequently affected endocrine organ was the parathyroid gland (36/48, 75%; uniglandular disease 31/36, 86%), followed by the pituitary gland (21/48, 44%; hormone-secreting 16/21, 76%), the endocrine pancreas (7/48, 15%), and the thyroid gland (4/48, 8%). Tumors of the adrenal glands and thymus were found in three and two patients, respectively. The presenting first endocrine pathology concerned the parathyroid (27/48, 56%) and the pituitary gland (11/48, 23%). There were one (27/48, 56%), two (13/48, 27%), three (3/48, 6%), or four (5/48, 10%) syn- or metachronously affected endocrine organs in a single patient, respectively.

Conclusion

MEN4 is an extremely rare disease, which most frequently affects women around 50 years of age. Primary hyperparathyroidism as a uniglandular disease is the leading pathology.

DOI:
https://doi.org/10.1530/EC-22-0411
Volume 12: Issue 2
Open access

Performance of contrast-enhanced ultrasound for lymph node metastasis in papillary thyroid carcinoma: a meta-analysis

Yong Yu, Lin-Lin Shi, Hua-Wei Zhang, and Qian Wang

Background

Papillary thyroid carcinoma is the most common thyroid carcinoma worldwide. Papillary thyroid carcinoma metastasis to the cervical region increases the probability of local or regional recurrence and the requirement for further surgery. Contrast-enhanced ultrasound has been suggested as a possible adjunct diagnostic technique for evaluating papillary thyroid carcinoma metastatic lymph nodes in several studies. This meta-analysis aims to evaluate the diagnostic accuracy of contrast-enhanced ultrasound for cervical lymph nodes metastatic in papillary thyroid carcinoma patients.

Methods

A search for studies evaluating the role of contrast-enhanced ultrasound for assessing cervical lymph nodes metastatic in papillary thyroid carcinoma patients from January 2000 to May 2022 was performed in PubMed, Embase, OVID, and Web of Science databases. The Quality Assessment of Diagnostic Accuracy Studies 2 evaluated the quality of the studies. All analyses were performed using Review Manager 5.3 and Stata 17.0.

Results

A total of seven articles were finally included in this study. Perfusion type, enhancement homogeneous, hilum absent, and perfusion defect were involved in the meta-analysis as the standard of contrast-enhanced ultrasound, among which, perfusion type showed the best diagnostic performance. The pooled estimated sensitivity, specificity, positive likelihood, negative likelihood ratio, and diagnostic odds ratio of perfusion type in contrast-enhanced ultrasound for detecting lymph node metastasis were 0.95 (0.91, 0.97), 0.87 (0.69, 0.96), 7.51 (2.80, 20.14), 0.06 (0.03, 0.10), and 124.17 (42.78, 360.46), respectively. Heterogeneity was moderate.

Conclusion

The perfusion type in contrast-enhanced ultrasound has good diagnostic performance for cervical lymph nodes metastasis in papillary thyroid carcinoma patients.

DOI:
https://doi.org/10.1530/EC-22-0341
Volume 12: Issue 2
Open access

Predictive value of highly sensitive basal versus stimulated thyroglobulin measurement in long-term follow-up of thyroid cancer

Kim Magaly Pabst, Robert Seifert, Nader Hirmas, Martina Broecker-Preuss, Manuel Weber, Wolfgang Peter Fendler, Timo Bartel, Sarah Theurer, Ken Herrmann, and Rainer Görges

Objective

Recurrence of differentiated thyroid cancer (DTC) is associated with reduced quality of life, and therefore, early identification of patients at risk is urgently needed.Here we investigated the predictive power of various cut-off values of single stimulated thyroglobulin (s-Tg) and single highly sensitive measured, unstimulated thyroglobulin (u-hsTg) measurements close to the end of primary therapy for recurrence-free survival (RFS) in long-term follow-up (>10 years) of patients with DTC.

Methods

In DTC patients with adjuvant radioiodine therapy, we assessed retrospectively u-hsTg (6 ± 3 months before s-Tg measurement) and s-Tg measurements (≤24 months after last radioiodine therapy). Positive predictive (PPV)/negative predictive values (NPV) of various cut-off values (s-Tg: 0.5/1.0 ng/mL; u-hsTg: 0.09/0.2 ng/mL) for patient outcomes as well as additional factors associated with disease development were analyzed.

Results

In total, 175 patients were retrospectively reviewed (tumor recurrence: n = 14/complete remission: n = 161). Examined cut-off values for s-Tg and u-hsTg showed significant predictive power for RFS (log-rank: all P < 0.001). NPV/PPV for s-Tg were 98.6%/36.4%, respectively (0.5 ng/mL cut-off) and 96.7%/42.9%, respectively (1.0 ng/mL cut-off); those for u-hsTg were 97.3%/35.7%, respectively (0.09 ng/mL cut-off) and 95.2%/85.7%, respectively (0.2 ng/mL cut-off). U-hsTg (P < 0.001) and patient age (P < 0.05) were significantly associated with tumor recurrence. One-third of patients with tumor recurrence in the course initially showed undetectable u-hsTg after completion of primary therapy.

Conclusion

With >10 years of follow-up, both s-Tg and u-hsTg have a comparably high predictive power for RFS, while only u-hsTg was significantly associated with a recurrence event.Serial u-hsTg measurements seem warranted since patients with tumor recurrence during follow-up may have an undetectable tumor marker at baseline.

DOI:
https://doi.org/10.1530/EC-22-0312
Volume 12: Issue 2