The management of hyperthyroidism in pregnant patients has been a topic of raised clinical awareness for decades. It is a strong recommendation that overt hyperthyroidism of Graves’ disease in pregnant women should be treated to prevent complications. The consequences of hyperthyroidism in pregnancy are less studied than hypothyroidism, and a literature review illustrates that the main burden of evidence to support current clinical guidance emerges from early observations of severe complications in Graves’ disease patients suffering from untreated hyperthyroidism in the pregnancy. On the other hand, the more long-term consequences in children born to mothers with hyperthyroidism are less clear. A hypothesis of fetal programming by maternal hyperthyroidism implies that excessive levels of maternal thyroid hormones impair fetal growth and development. Evidence from experimental studies provides clues on such mechanisms and report adverse developmental abnormalities in the fetal brain and other organs. Only few human studies addressed developmental outcomes in children born to mothers with hyperthyroidism and did not consistently support an association. In contrast, large observational human studies performed within the last decade substantiate a risk of teratogenic side effects to the use of antithyroid drugs in early pregnancy. Thus, scientific and clinical practice are challenged by the distinct role of the various exposures associated with Graves’ disease including the hyperthyroidism per se, the treatment, and thyroid autoimmunity. More basic and clinical studies are needed to extend knowledge on the effects of each exposure, on the potential interaction between exposures and with other determinants, and on the underlying mechanisms.
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Stine Linding Andersen and Stig Andersen
Jia Liu, Min Liu, Zhe Chen, Yumei Jia, and Guang Wang
Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. Longitudinal relaxation time mapping (T1-mapping) measured by MRI is a new technique for assessing interstitial fibrosis of some organs, such as heart and liver. This study aimed to evaluate the relationship between T1-mapping value and thyroid function and determine the usefulness of T1-mapping in identifying thyroid destruction in AIT patients.
This case–control study recruited 57 drug-naïve AIT patients and 17 healthy controls. All participants were given thyroid MRI, and T1-mapping values were measured using a modified look-locker inversion-recovery sequence.
AIT patients had significantly higher thyroid T1-mapping values than the healthy controls (1.077 ± 177 vs 778 ± 82.9 ms; P < 0.01). A significant increase in thyroid T1-mapping values was presented along with the increased severity of thyroid dysfunction (P < 0.01). Correlation analyses showed that increased thyroid T1-mapping values were associated with higher TSH and lower FT3 and FT4 levels (TSH: r = 0.75; FT3: r = −0.47; FT4: r = −0.72; all P < 0.01). Receiver-operating characteristic curve analysis revealed a high diagnostic value of T1-mapping values for the degree of thyroid destruction (area under the curve was 0.95, 95% CI: 0.90–0.99, P < 0.01).
AIT patients have higher thyroid T1-mapping values than the healthy controls, and the T1-mapping values increased with the progression of thyroid dysfunction. Thyroid T1-mapping value might be a new index to quantitatively evaluate the degree of thyroid destruction in AIT patients.
Marcus Heldmann, Krishna Chatterjee, Carla Moran, Berenike Rogge, Julia Steinhardt, Tobias Wagner-Altendorf, Martin Göttlich, Hannes Schacht, Peter Schramm, Georg Brabant, Thomas F. Münte, and Anna Cirkel
Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α,β) with differential tissue distribution. Thyroid hormone receptor β (TRβ) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the β form of the receptor (pituitary, liver). This study seeks to identify effects of mutant TRβ on pituitary size.
Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHβ in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist).
Results: Patients with mutant TRβ (Resistance to Thyroid Hormone β,RΤΗβ) showed elevated fT3/4 levels with normal TSH levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHβ patients in comparison to healthy controls (F(1,35)=7.05, p=0.012, partial η2 =0.17).
Conclusion: RTHβ subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.
Susana Pastor, Abdelmounaim Akdi, Eddy R González, Juan Castell, Josefina Biarnés, Ricard Marcos, and Antonia Velázquez
Thyroid hormone receptors, THRA and THRB, together with the TSH receptor, TSHR, are key regulators of thyroid function. Alterations in the genes of these receptors (THRA, THRB and TSHR) have been related to thyroid diseases, including thyroid cancer. Moreover, there is evidence suggesting that predisposition to differentiated thyroid cancer (DTC) is related to common genetic variants with low penetrance that interact with each other and with environmental factors. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the THRA (one SNP), THRB (three SNPs) and TSHR (two SNPs) genes with DTC risk. A case–control association study was conducted with 398 patients with sporadic DTC and 479 healthy controls from a Spanish population. Among the polymorphisms studied, only THRA-rs939348 was found to be associated with an increased risk of DTC (recessive model, odds ratio=1.80, 95% confidence interval=1.03–3.14, P=0.037). Gene–gene interaction analysis using the genotype data of this study together with our previous genotype data on TG and TRHR indicated a combined effect of the pairwises: THRB-TG (P interaction=0.014, THRB-rs3752874 with TG-rs2076740; P interaction=0.099, THRB-rs844107 with TG-rs2076740) and THRB-TRHR (P interaction=0.0024, THRB-rs3752874 with TRHR-rs4129682) for DTC risk in a Spanish population. Our results confirm that THRA is a risk factor for DTC, and we show for the first time the combined effect of THRB and TG or TRHR on DTC susceptibility, supporting the importance of gene–gene interaction in thyroid cancer risk.
M von Wolff, C T Nakas, M Tobler, T M Merz, M P Hilty, J D Veldhuis, A R Huber, and J Pichler Hefti
Humans cannot live at very high altitude for reasons, which are not completely understood. Since these reasons are not restricted to cardiorespiratory changes alone, changes in the endocrine system might also be involved. Therefore, hormonal changes during prolonged hypobaric hypoxia were comprehensively assessed to determine effects of altitude and hypoxia on stress, thyroid and gonadal hypothalamus–pituitary hormone axes. Twenty-one male and 19 female participants were examined repetitively during a high-altitude expedition. Cortisol, prolactin, thyroid-stimulating hormone (TSH), fT4 and fT3 and in males follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone were analysed as well as parameters of hypoxemia, such as SaO2 and paO2 at 550 m (baseline) (n = 40), during ascent at 4844 m (n = 38), 6022 m (n = 31) and 7050 m (n = 13), at 4844 m (n = 29) after acclimatization and after the expedition (n = 38). Correlation analysis of hormone concentrations with oxygen parameters and with altitude revealed statistical association in most cases only with altitude. Adrenal, thyroid and gonadal axes were affected by increasing altitude. Adrenal axis and prolactin were first supressed at 4844 m and then activated with increasing altitude; thyroid and gonadal axes were directly activated or suppressed respectively with increasing altitude. Acclimatisation at 4844 m led to normalization of adrenal and gonadal but not of thyroid axes. In conclusion, acclimatization partly leads to a normalization of the adrenal, thyroid and gonadal axes at around 5000 m. However, at higher altitude, endocrine dysregulation is pronounced and might contribute to the physical degradation found at high altitude.
Christin Krause, Martina Grohs, Alexander T El Gammal, Stefan Wolter, Hendrik Lehnert, Oliver Mann, Jens Mittag, and Henriette Kirchner
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.
Jakob Kirkegård, Dora Körmendiné Farkas, Jens Otto Lunde Jørgensen, and Deirdre P Cronin-Fenton
The association between thyroid dysfunction and gastrointestinal cancer is unclear.
We conducted a nationwide population-based cohort study to examine this potential association.
We used Danish medical registries to assemble a nationwide population-based cohort of patients diagnosed with hyperthyroid or hypothyroid disease from 1978 to 2013. We computed standardized incidence ratios (SIRs) with corresponding 95% CIs as measures of the relative risk of each cancer, comparing patients with thyroid dysfunction with that expected in the general population.
We included 163,972 patients, of which 92,783 had hyperthyroidism and 71,189 had hypothyroidism. In general, we found an increased risk of all gastrointestinal cancers within the first year after thyroid disease diagnosis. After more than 5 years of follow-up, patients with hyperthyroidism had a slightly increased risk of pancreatic and gallbladder and biliary tract cancer. Patients with hypothyroidism had a slightly increased risk of stomach, anal, liver, gallbladder and biliary tract, and pancreatic cancer after more than 5 years of follow-up, but the observed numbers of cancers were in general similar to the expected.
The increased risks of all gastrointestinal cancers in the first year following hyper- or hypothyroidism diagnosis are likely due to detection bias. After more than 5 years of follow-up, there does not seem to be a consistent causal association between thyroid disease and gastrointestinal cancer.
Xiaoya Zheng, Shanshan Yu, Jian Long, Qiang Wei, Liping Liu, Chun Liu, and Wei Ren
Objective: Both primary thyroid lymphoma (PTL) and diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) are two rare malignant tumours with different therapies and prognoses. This study compared their clinical features.
Methods: From a retrospective review of the pathologic database at our institute between January 2015 and August 2020, 52 PTL patients and 40 DSVPTC patients were included. Demographic, clinical, laboratory and ultrasound data were extracted from electronic medical records. Statistical analyses were performed using GraphPad Prism 5.0.
Results: Both PTL and DSVPTC were more likely to occur in women (83.7% and 67.5%), but DSVPTC patients were younger (median age: 36 vs 64.5), had fewer compressive symptoms, and more frequently had neck lymph node metastasis than PTL patients. The prevalence of Hashimoto’s thyroiditis (HT) and hypothyroidism was significantly higher in PTL patients than in DSVPTC patients (31% vs 17.5%). Hyperthyroidism could only be found in DSVPTC patients, which accounted for 7.5%. Heterogeneous echogenicity and irregular edges were frequently observed in both PTL and DSVPTC. However, compared with PTL, DSVPTC exhibited smaller lesion sizes, higher frequencies of diffuse sonographic patterns and calcification, and lower frequencies of hypoechoic features and internal blood flow signal. The overall survival rate with PTL was 77.23%, which was lower than that with DSVPTC (90.91%), but this difference was not significant (p=0.096).
Conclusion: Clinical characteristics such as age, compression symptoms, and sonographic features such as a large mass with heterogeneous echogenicity, hypoechoic, irregular edges, and calcification are helpful for impression diagnosis of PTL and DSVPTC before surgery.
Anna Olsson-Brown, Rosemary Lord, Joseph Sacco, Jonathan Wagg, Mark Coles, and Munir Pirmohamed
Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort.
Materials and methods
To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres.
Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies.
There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.
Jaafar Jaafar, Eugenio Fernandez, Heba Alwan, and Jacques Philippe
Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs).
We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm.
We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue.
In patients treated with PD-1 Ab, hypothyroidism occurred in 2–10.1% and hyperthyroidism occurred in 0.9–7.8%. When thyroiditis was reported separately, it occurred in 0.34–2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23–45 days and 2–3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0–10% and hyperthyroidism in 0.5–2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months.
Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.