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Risk of over- and under- treatment with levothyroxine in primary care in Copenhagen, Denmark

Jeppe Lerche la Cour, Bjarke Røssner Medici, Mia Klinten Grand, Dagny Ros Nicolaisdottir, Bent Lind, Jens Faber, Christen Lykkegaard Andersen, and Birte Nygaard

Objective

A decrease over time in thyroid stimulating hormone (TSH) levels when initiating levothyroxine (L-T4) therapy for hypothyroidism has been reported, where treatment most often is initiated with TSH levels below 10 mIU/L. The primary objective of this study was to investigate whether this lower TSH threshold resulted in an increased number of overtreated patients.

Design and method

Retrospective cohort study comprising inhabitants in Copenhagen had TSH measurements requested by general practitioners which led to a new prescription of L-T4 between 2001 and 2012. Over- and under- treatment were defined as TSH <0.1 mIU/L or above 10 mIU/mL, respectively, in three consecutive measurements. Data were analyzed by Aalen–Johansen estimators and Cox proportional hazards models.

Results

In total, 14 533 initiations of L-T4 were included in the study. The cumulative risk of being over- or undertreated was 4.7 and 7.4% after 10 years. The hazard of overtreatment was higher among women, younger adults, and with lower initial TSH levels. The hazard of overtreatment decreased over the time period from 2001 to 2012. Among overtreated individuals, the chance of returning to a normal TSH was about 55% after 10 years. In 18% of the cases, L-T4 therapy was initiated on TSH levels less than 5 mIU/L.

Conclusion

Although a still decreasing threshold for initiating L-T4 therapy is known, the risk of overtreatment (and undertreatment) was low and lessened in the period 2001–2012 among Danish primary care patients. Nevertheless, as many as 18% were started on L-T4 with normal TSH levels.

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Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment

Silvia Molinari, Francesca Parissone, Veronica Evasi, Paola De Lorenzo, Maria Grazia Valsecchi, Simone Cesaro, Donatella Fraschini, Roberta Sangalli, Gianluca Cacace, Andrea Biondi, Adriana Balduzzi, and Alessandro Cattoni

Objective

Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH).

Design and methods

Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019.

Results

Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04).

Conclusions

In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.

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Thyroid autoimmunity and metabolic syndrome: a nationwide population-based study

Hye Jeong Kim, Sang Joon Park, Hyeong Kyu Park, Dong Won Byun, Kyoil Suh, and Myung Hi Yoo

Objective

Recent studies have reported that thyroid hormone levels are associated with metabolic syndrome (MetS) even in euthyroid subjects. However, the association between thyroid autoimmunity and MetS is uncertain. This study aimed to investigate the relationship between thyroid autoimmunity and MetS in a large cohort study of euthyroid subjects.

Methods

A total of 4775 participants aged ≥19 years from the Korea National Health and Nutrition Examination Survey VI (2013–2015) with anti-thyroid peroxidase antibody (TPOAb) results and normal thyroid functions were included in this study. Subjects were grouped according to thyroid autoimmunity (positivity of TPOAb). We estimated the odds ratios (ORs) for MetS according to TPOAb positivity using logistic regression models, adjusted for potential confounders.

Results

Of the study subjects, 25% (n = 1206) were diagnosed with MetS. Subjects with MetS showed higher median TPOAb levels (6.3 vs 6.8 IU/mL, P < 0.001) and higher positivity of TPOAb (5 vs 7%, P = 0.002) than those without MetS. There was a significant difference in prevalence of MetS depending on the TPOAb positivity (25% vs 33%, P = 0.002). Subjects with TPOAb positive had a significantly greater risk of abdominal obesity (OR 1.675, 95% CI: 1.302–2.154, P < 0.001), low high-density lipoprotein cholesterol (OR: 1.603, 95% CI: 1.244–2.066, P < 0.001) and elevated blood pressure (OR: 1.418, 95% CI: 1.099–1.829, P = 0.007) as compared to those with TPOAb negative. Positivity of TPOAb was a significant risk factor for MetS even after adjusting for confounding variables including age, sex, household income, education, smoking, alcohol consumption, walking activity, thyroid-stimulating hormone and free thyroxine (OR: 1.389, 95% CI: 1.048–1.841, P = 0.022).

Conclusion

In euthyroid subjects, thyroid autoimmunity is associated with MetS. Further large longitudinal studies are needed to clarify causality.

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Thyroid hormone resistance index and mortality in euthyroid subjects: Di@bet.es study

Silvia Patricia Alonso, Sergio Valdés, Cristina Maldonado-Araque, Ana Lago, Pilar Ocon, Alfonso Calle, Luis Castaño, Elias Delgado, Edelmiro Menéndez, Josep Franch-Nadal, Sonia Gaztambide, Juan Girbés, Felipe Chaves, Sara García-Serrano, Eva García-Escobar, Jose Carlos Fernández-García, Gabriel Olveira, Natalia Colomo, and Gemma Rojo-Martínez

Objective: It has been proposed that a mild form of acquired resistance to thyroid hormone may occur in the general population. Its clinical significance remains largely unknown. The objective was to explore whether a newly described thyroid hormone resistance index is associated with the risk of mortality in a sample of community-dwelling euthyroid subjects representative of the adult population of Spain.

Design: Longitudinal observational study including 3750 individuals, free of thyroid disease, TPO Abs negative (<50 IU/mL) and with TSH levels within the euthyroid range (≥0.5 and ≤5.0 mUI/mL) participating in the nationwide study Di@bet.es (2008-2010).

Methods: We used the Thyroid Feedback Quantile-based Index (TFQI) as a marker of resistance to thyroid hormone. The study population was grouped into categories according to their TFQI values at baseline. Fatal events were ascertained from the national death registry (end of follow-up December 2016).

Results: 231 deaths were recorded during an average follow-up of 7.3 years. Compared with the category with the highest sensitivity to FT4 (TFQI≤p5) (reference), the Relative Risk of mortality in the categories with TFQI>p5 and ≤p25; >p25 and ≤p50; >p50 and ≤p75; >p75 and ≤p95; and >p95 were 1.01, (0.47-2.19), 1.42 (0.68-2.97), 1.54 (0.74-3.22), 1.47 (0.70-3.11) and 2.61 (1.16-5.89) respectively (p for trend 0.003). The association remained significant after multivariate adjustment of the data (p for trend 0.017).

Conclusions: A thyroid hormone resistance index focused on deviations of the average pituitary response to thyroid hormones may be associated to all-cause mortality independently of other conventional risk factors and comorbidities.

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Treatment of acromegaly has substantial effects on body composition. A long-term follow-up study.

Peter Wolf, Sylvie Salenave, Emmanuel Durand, Jacques Young, Peter Kamenicky, Philippe Chanson, and Luigi Maione

 

Background: Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated.

Methods: We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). To investigate specific effects of treatment vs ageing, changes in body composition were compared in a group of patients evaluated both at the time of active and controlled disease (A>C; n=31) and in another group of patients evaluated two times while the disease was controlled (C>C; n=32).

Results: In the whole cohort, IGF-I correlated with fat (r=-0.369;p<0.001) and lean mass (r=0.383;p<0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (p=n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39±34 vs +10±15%, p<0.001; lean mass: -8±8 vs -0.2±6%, p<0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r=-0.450; p=0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r=0.421;p=0.002) and insulin sensitivity index (r=-0.466;p<0.001).

Conclusions: Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with ageing.

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Ultrasonography-guided Radiofrequency Ablation for Solitary T1aN0M0 and T1bN0M0 Papillary Thyroid Carcinoma: A Retrospective Comparative Study

Jing Xiao, Yan Zhang, Lin Yan, Mingbo Zhang, Xinyang Li, Jie Tang, and Yukun Luo

Objective

Ultrasonography-guided radiofrequency ablation (RFA) is used to treat small low-risk papillary thyroid carcinoma (PTC), and has achieved favorable results. However, few studies have compared the outcomes of T1aN0M0 and T1bN0M0 PTC treated with ultrasonography-guided RFA. The objective of this study was to compare the outcomes of patients receiving RFA for solitary T1aN0M0 and T1bN0M0 PTC retrospectively.

Methods

Patients treated with RFA for solitary T1aN0M0 or T1bN0M0 PTC between April 2014 and December 2019 were retrospectively reviewed. All patients were ineligible for or refused surgery. Our institutional review board approved this study. A total of 262 patients were included after adjustment for propensity score matching between the T1a and T1b groups. Local tumour progression (LTP), LTP-free survival, post-treatment complications, change in tumor volume, and RFA-related parameters were compared between the two groups.

Results

The LTP rate was 3.82% in both groups, and the LTP and LTP-free survival rates did not significantly differ between the two groups. One patient in group T1b developed transient recurrent laryngeal nerve injury. Significant tumor shrinkage was observed during the follow-up. The rate of tumour disappearance rate was higher in group T1a than in group T1b (81.7% vs. 52.7%, P<0.001). During RFA, the output power and total energy were higher and the duration was significantly shorter in group T1b than in group T1a (P<0.001).

Conclusions

The outcomes of RFA for the treatment of T1aN0M0 and T1bN0M0 PTC were similar. Therefore, RFA may be an alternative to surgery for the treatment of T1bN0M0 and T1aN0M0 PTCs.

Free access

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

L Bartalena, G J Kahaly, L Baldeschi, C M Dayan, A Eckstein, C Marcocci, M Marinò, B Vaidya, W M Wiersinga, and EUGOGO

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

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Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network

Elisa Deflorenne, Michel Peuchmaur, Delphine Vezzosi, Christiane Ajzenberg, Laurent Brunaud, Nicolas Chevalier, Sophie Christin-Maitre, Bénédicte Decoudier, Natacha Driessens, Delphine D Drui, Olivier Gilly, Pierre Goudet, Frédéric Illouz, Christel Jublanc, Hervé Lefebvre, Antoine-Guy Lopez, Charlotte Lussey, Aurelien Morini, Marie-Laure Raffin-Sanson, Isabelle Raingeard, Peggy Renoult-Pierre, Caroline Storey, Antoine Tabarin, Marie Christine Vantyghem, Emmanuelle Vidal-Petiot, Eric Baudin, Jerome Bertherat, and Laurence Amar

Objective

Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management.

Methods

A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center.

Results

Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4–156)).

Conclusion

Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

Open access

Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C

Dilek Cicek, Nick Warr, Gozde Yesil, Hatice Kocak Eker, Firdevs Bas, Sukran Poyrazoglu, Feyza Darendeliler, Gul Direk, Nihal Hatipoglu, Mehmet Eltan, Zehra Yavas Abalı, Busra Gurpinar Tosun, Sare Betul Kaygusuz, Tuba Seven Menevse, Didem Helvacioglu, Serap Turan, Abdullah Bereket, Richard Reeves, Michelle Simon, Matthew Mackenzie, Lydia Teboul, Andy Greenfield, and Tulay Guran

Context: Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (MEGD syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD). 

Method: We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing.

Results: A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, 2 girls with 46,XY complete GD, and one undervirilized boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low AMH, and high FSH and LH concentrations. All patients manifested characteristic features of MEGD syndrome.

Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5 and 8.5 days post coitum revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.

Conclusion: Our data indicate essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Free access

Cabergoline should be attempted in progressing non-functioning pituitary macroadenoma

Yona Greenman and Marcello D Bronstein

Non-functioning pituitary adenomas (NFPA) usually present with symptoms of mass effect. Thus, the first-line treatment generally consists of transsphenoidal surgery. Since these tumors are usually large and invasive, post-surgical tumor remnants are common. Active surveillance is the follow-up strategy adopted by most pituitary centers, although the prevalence of residual tumor growth may reach 50% in 5–10 years, often leading to repeat surgery, radiation therapy, or both. NFPA remain the only pituitary tumor type for which no medical therapy has been approved. In this debate, we consider the evidence in favor and against using cabergoline to treat progressing NFPA.