Jens O L Jørgensen, Gudmundur Johannsson, and Ariel Barkan
Silvia Patricia Alonso, Sergio Valdés, Cristina Maldonado-Araque, Ana Lago, Pilar Ocon, Alfonso Calle, Luis Castaño, Elías Delgado, Edelmiro Menéndez, Josep Franch-Nadal, Sonia Gaztambide, Juan Girbés, Felipe Chaves, Sara Garcia-Serrano, Eva Garcia-Escobar, José Carlos Fernandez-García, Gabriel Olveira, Natalia Colomo, and Gemma Rojo-Martínez
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 of the study 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.
Longitudinal observational study including 3750 individuals, free of thyroid disease, TPO antibodies-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).
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).
A total of 231 deaths were recorded during an average follow-up of 7.3 years. Compared with the category with the highest sensitivity to free thyroxine (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).
A thyroid hormone resistance index focused on deviations of the average pituitary response to thyroid hormones may be associated with all-cause mortality independently of other conventional risk factors and comorbidities.
Maria Cristina Vigone, Rita Ortolano, Gaia Vincenzi, Clara Pozzi, Micol Ratti, Valentina Assirelli, Sofia Vissani, Paolo Cavarzere, Alessandro Mussa, Roberto Gastaldi, Raffaella Di Mase, Mariacarolina Salerno, Maria Elisabeth Street, Jessica Trombatore, Giovanna Weber, Alessandra Cassio, and the Congenital Hypothyroidism Group of ISPED/SIEDP Italian Society Pediatric Endocrinology and Diabetology
Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children.
The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age.
Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths’ Scale.
In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye–hand coordination at 36 months.
Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.
Jing Xiao, Yan Zhang, Lin Yan, Mingbo Zhang, Xinyang Li, Jie Tang, and Yukun Luo
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.
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 tumor progression (LTP), LTP-free survival, post-treatment complications, change in tumor volume, and RFA-related parameters were compared between the two groups.
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 tumor 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).
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.
Eliza B Geer, John L. Kilgallon, Karen J.p. Liebert, Allison Kimball, and Lisa B. Nachtigall
To assess the impact of virtual education programming for patients with acromegaly.
We conducted a mixed methods study to evaluate patient attitudes, examine if patient-centered educational forums change these attitudes, and determine the role of virtual education as a means to learn about patients’ unmet needs, self-reported outcomes, and educational priorities.
The study included 653 total virtual program registrants. Of these, 78 patients with acromegaly were included in the analysis. The programs consisted of patient-centered livestream education by a multidisciplinary team of pituitary experts and patient presenters. Multiple-choice questions were used to assess attitudes before and after the event, and short answer surveys were used to collect care goals and unmet needs related to treatment.
Attendance included participants from 37 countries. The number of patients who responded that they had no hope for improvement, had no choice in their treatment, and felt alone living with acromegaly each decreased significantly pre- to post-event (p<0.05). The number of patients who felt anxious about their acromegaly diagnosis remained unchanged. “Quality of Life/Mental Health” was the most common personal care goals concern followed by “Medical Therapies/Tumor Control.” Perceived acromegaly unmet needs were evenly distributed, with five of six categories reported by over 20% of patients.
Our findings indicate that virtual education may have a significant positive effect on acromegaly patients’ perceptions of their disease. The lessons learned from these virtual programs may be used to inform future virtual education programming for acromegaly and other rare diseases.
Rachel Fourneaux, Marie Vermalle, Frederique Albarel, Isabelle Morange, Thomas Graillon, Vincent Amodru, Thomas Cuny, Henry Dufour, Thierry Brue, and Frederic Castinetti
A relative can be an asset in dealing with chronic illnesses, such as acromegaly, where quality of life (QoL) is altered even after remission. However, it has been shown that quality of life of caregivers can also be impacted. Our main objective was to compare the perception of acromegaly in remission in the patient–relative dyad.
In this observational study, 27 patients in remission and relatives were first asked to complete QoL, anxiety/depression and coping strategy questionnaires. Then, the patient’s body image and self-esteem were evaluated from both the patient’s and the relative’s point of view using the same questionnaires with modified instructions.
Relatives had overall an accurate estimation of patient body image using the Figure Rating Scale by Stunkard. However, there were wide variations between the patient’s and the relative’s responses regarding self-esteem and body perception. The QoL of relatives was not altered and was significantly higher in the social domain than for the patient.
Our results show that relatives require education concerning all the steps involved in the management of acromegaly, as they likely do not fully understand the sequelae of acromegaly.
Asuman Nur Karhan, Jamila Zammouri, Martine Auclair, Emilie Capel, Feramuz Demir Apaydin, Fehmi Ates, Marie-Christine Verpont, Jocelyne Magré, Bruno Fève, Olivier Lascols, Yusuf Usta, Isabelle Jéru, and Corinne Vigouroux
CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3.
In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3.
Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence.
The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.
Thomas I Hewat, Daphne Yau, Joseph C S Jerome, Thomas W Laver, Jayne A L Houghton, Beverley M Shields, Sarah E Flanagan, and Kashyap A Patel
Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis.
We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care.
We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and receiver operator characteristic (ROC) analysis to identify the features that predict KATP-hyperinsulinism.
Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted odds ratio: 4.5 (95% CI: 3.4–5.9), 0.09 (0.06–0.13) and 3.3 (2.0–5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI: 0.85–0.90). In this study, 86% born large for gestation and 78% born appropriate for gestation and who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism.
Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing of KATP channel genes.
Tim Verweij, Tessa N A Slagboom, Nadège C van Varsseveld, Aart-Jan van der Lely, Madeleine L Drent, and Christa C van Bunderen
Cardiovascular (CV) risk profile might differ between growth hormone-treated patients with craniopharyngioma and non-functioning pituitary adenoma (NFPA), since patients with craniopharyngioma more frequently suffer from hypothalamic metabolic disruption.
The aim of this study is to investigate the CV risk profile in adult patients with craniopharyngioma compared to NFPA before and after treatment with growth hormone (GH) replacement therapy due to severe GH deficiency.
A sub-analysis of the Dutch National Registry of Growth Hormone Treatment in Adults was performed, in which we compared 291 patients with craniopharyngioma to 778 patients with NFPA. CV risk profile and morbidity were evaluated at baseline and during long-term follow-up within and between both groups.
At baseline, patients with craniopharyngioma demonstrated higher BMI than patients with NFPA, and men with craniopharyngioma showed greater waist circumference and lower HDL compared to men with NFPA. During follow-up, BMI, as well as diastolic blood pressure among patients using antihypertensive drugs, deteriorated in the craniopharyngioma group compared to the NFPA group. Lipid profile improved similarly in both groups over time. No differences were found between groups in the occurrence of diabetes mellitus, cerebrovascular accidents, CV disease, or overall mortality.
This study suggests that overall CV risk profile is worse in craniopharyngioma patients with GH deficiency compared to patients with NFPA. During GH replacement therapy, patients with craniopharyngioma demonstrated an increase in BMI over time, where BMI remained stable in patients with NFPA. Also, diastolic blood pressure did not improve with antihypertensive drugs in craniopharyngioma patients as seen in patients with NFPA.
Nivedita Patni, Ra Hegele, and Abhimanyu Garg
Congenital generalized lipodystrophy (CGL) is a rare, heterogeneous, autosomal recessive disorder characterized by near total absence of body fat with increased muscularity noticed at birth or in early infancy. Four distinct genetic subtypes of CGL have been reported to date. Types 1 and 2 are caused by biallelic variants in the 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) genes, respectively, and are the most common subtypes (1). Types 3 and 4 are extremely rare and are caused by biallelic variants in the caveolin 1 (CAV1) (2), and Caveolae Associated Protein-1 (CAVIN1; also known as polymerase I and transcript release factor (PTRF)]) genes (3), respectively. Patients with all CGL subtypes are predisposed to metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis; however, each subtype presents with some unique clinical features.