Subacute thyroiditis after Sars-COV-2 infection

Context: Subacute thyroiditis (SAT) is a thyroid disease of viral or postviral origin. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that began in Wuhan, China, has spread rapidly worldwide and Italy has been severely affected by this outbreak. Objectives: The objective of this work is to report the first case of SAT related to SARS-CoV-2 infection. Methods: We describe the clinical, laboratory, and imaging features of an 18-year-old woman who came to our attention for fever, neck pain radiated to the jaw, and palpitations occurring 15 days after a SARS-CoV-2-positive oropharyngeal swab. Coronavirus disease 2019 (COVID-19) had been mild and the patient had completely recovered in a few days. Results: At physical examination the patient presented with a slightly increased heart rate and a painful and enlarged thyroid on palpation. At laboratory exams free thyroxine and free triiodothyronine were high, thyrotropin undetectable, and inflammatory markers and white blood cell count elevated. Bilateral and diffuse hypoechoic areas were detected at neck ultrasound. One month earlier, thyroid function and imaging both were normal. We diagnosed SAT and the patient started prednisone. Neck pain and fever recovered within 2 days and the remaining symptoms within 1 week. Thyroid function and inflammatory markers normalized in 40 days. Conclusions: We report the first case of SAT after a SARS-CoV-2 infection. We alert clinicians to additional and unreported clinical manifestations associated with COVID-19

Is subacute thyroiditis an underestimated manifestation of SARS-CoV-2 infection? insights from a case series

Context: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 18 million people worldwide and the pandemic is still spreading. After the first case we reported, we observed 4 additional cases of subacute thyroiditis (SAT) related to SARS-CoV-2 infection. Objectives: The objective of this work is to describe additional cases of SAT associated with SARS-CoV-2 infection to alert physicians that SAT may be a manifestation of SARS-CoV-2 infection. Methods: We describe clinical, biochemical, and imaging features of 4 patients with SAT related to SARS-CoV-2 infection. Results: All patients were female (age, 29-46 years). SAT developed 16 to 36 days after the resolution of coronavirus disease 2019 (COVID-19). Neck pain radiated to the jaw and palpitations were the main presenting symptoms and were associated with fever and asthenia. One patient was hospitalized because of atrial fibrillation. Thyroid function tests (available for 3 individuals) were suggestive of destructive thyroiditis, and inflammatory markers were high. At neck ultrasound the thyroid was enlarged, with diffuse and bilateral hypoechoic areas and (in 3 patients) absent vascularization at color Doppler. Symptoms disappeared a few days after commencement of treatment (prednisone in 3 patients and ibuprofen in 1). Six weeks after the onset of SAT, all patients were asymptomatic and inflammatory markers had returned to normal range. Two patients were euthyroid, whereas 2 were diagnosed with subclinical hypothyroidism. Conclusions: SAT may be an underestimated manifestation of COVID-19. Clinicians should keep in mind the possible occurrence of SAT during and after SARS-CoV-2 infection

Activating antibodies to calcium-sensing receptor in immunotherapy-induced hypoparathyroidism

Context Immune checkpoint inhibitors (ICIs), as anti-programmed cell death protein-1 (PD-1), anti-programmed cell death protein-ligand 1 (PD-L1), and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immunerelated adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. Objectives The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. Methods Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, Ig subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. Results The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalised with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a nine-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. Conclusion The finding confirms that ICIs therapy can trigger, amongst other endocrinopathies, hypoparathyroidism which can be caused by pathogenic autoantibodies

TSH suppressive therapy and bone

Thyroid hormones stimulate bone turnover in adults by increasing osteoclastic bone resorption. TSH suppressive therapy is usually applied in patients with differentiated thyroid cancer (DTC) to improve the disease outcome. Over the last decades several authors have closely monitored the potential harm suffered by the skeletal system. Several studies and meta-analyses have shown that chronic TSH suppressive therapy is safe in premenopausal women and men. Conversely, in postmenopausal women TSH suppressive therapy is associated with a decrease of bone mineral density, deterioration of bone architecture (quantitative CT, QCT; trabecular bone score, TBS), and, possibly, an increased risk of fractures. The TSH receptor is expressed in bone cells and the results of experimental studies in TSH receptor knockout mice and humans on whether low TSH levels, as opposed to solely high thyroid hormone levels, might contribute to bone loss in endogenous or exogenous thyrotoxicosis remain controversial. Recent guidelines on the use of TSH suppressive therapy in patients with DTC give value not only to its benefit on the outcome of the disease, but also to the risks associated with exogenous thyrotoxicosis, namely menopause, osteopenia or osteoporosis, age >60 years, and history of atrial fibrillation. Bone health (BMD and/or preferably TBS) should be evaluated in postmenopausal women under chronic TSH suppressive therapy or in those patients planning to be treated for several years. Antiresorptive therapy could also be considered in selected cases (increased risk of fracture or significant decline of BMD/TBS during therapy) to prevent bone loss

Subacute Thyroiditis during the SARS-CoV-2 Pandemic

Context: Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been related to subacute thyroiditis (SAT). Objective: We compared SAT cases during the SARS-CoV-2 pandemic to those observed in the previous years. Methods: A cross-sectional, retrospective study was conducted at the Endocrinology Unit of University Hospital of Pisa, Italy. We included all patients observed from January 2016 to December 2020 because of an untreated SAT, who had developed the disease within 15 days prior to the visit. SAT cases from 2016 to 2019 (N=152) are referred to as pre-SARS-CoV-2, while 2020 SAT patients are classified as pos-SARS-CoV-2 (N=18) or neg-SARS-CoV-2 (N=28), according to positive or negative SARS-CoV-2 testing performed up to 45 days from SAT onset. Results: While during 2016-2019, most SAT cases were observed in the third quarter, in 2020, 2 peaks were seen, superimposable to the SARS-CoV-2 outbreaks in the second and the fourth quarters. In the second and fourth quarters of 2020, we observed higher levels of free thyroxine (FT4), C-reactive protein (CRP), and thyroglobulin (Tg) compared with the same quarters of the years 2016-2019. Pos-SARS-CoV-2 patients had higher FT4 (28.4 vs 24.1 nmol/L), CRP (8.5 vs 3.6 mg/L), and Tg (155 vs 60 μg/L) (P0.05 for all) and more frequently had hypothyroidism (13/15 vs 30/152 at 3 months) (P0.001) than pre-SARS-CoV-2 patients. Neg-SARS-CoV-2 patients showed a clinical picture intermediate between the other 2 groups. Conclusion: The SARS-CoV-2 pandemic has caused a shift in the annual timing and severity of SAT cases

A severe inactivating PTH/PTHrP signaling disorder type 2 in a patient carrying a novel large deletion of the GNAS gene: a case report and review of the literature

Purpose: Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright’s hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as “inactivating PTH/PTHrP signaling disorder type 2” (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype–phenotype correlation of this disease. Methods: An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features. Results: The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband’s mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1–7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described. Conclusions: We report a kindred harboring a large GNAS deletion. A genotype–phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother

A Severe Inactivating PTH/PTHrP Signaling Disorder Type 2 in a Patient Carrying a Novel Large Deletion of the GNAS Gene : A Case Report and Review of the Literature

Purpose: Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright's hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as "inactivating PTH/PTHrP signaling disorder type 2" (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype-phenotype correlation of this disease. Methods: An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features. Results: The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband's mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1-7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described. Conclusions: We report a kindred harboring a large GNAS deletion. A genotype-phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother

Activating Antibodies to the Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism

Context: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. Objectives: The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. Methods: Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. Results: The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. Conclusion: The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies

The detection of serum IgMs to thyroglobulin in subacute thyroiditis suggests a protective role of IgMs in thyroid autoimmunity

Context: The role of serum immunoglobulin (Ig)Ms in autoimmune thyroid diseases isuncertain.Objective: We looked for IgMs to thyroglobulin (Tg) in patients with subacute thyroiditis (SAT),which is characterized by high serum Tg levels, the possible de novo appearance of IgGs to Tg(TgAb-IgGs), and no autoimmune sequelae.Main Outcome Measures: TgAb-IgMs and TgAb-IgGs were detected by binding to Tg using theenzyme-linked immunosorbent assay (ELISA). The upper reference limit of TgAb-IgMs and TgAbIgGs was established in 40 normal subjects. We looked for TgAb-IgMs in 16 patients with SAT,11 with Hashimoto's thyroiditis (HT), and 8 with Graves' disease (GD) who were all positive forTgAb-IgGs. IgM binding to bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), andglucagon in ELISA was measured. Inhibition of TgAb-IgMs binding to coated Tg was evaluatedby preincubating serum samples or IgG-depleted samples with soluble Tg.Results: TgAb-IgMs were positive in 10/16 patients with SAT, 2/11 with HT, and 1/8 with GD. TgAbIgMs were higher in SAT (0.95; 0.42-1.13) (median; 25th-75th percentiles) than in HT (0.47; 0.45-0.51) and GD patients (0.35; 0.33-0.40) (P <.005 for both). IgM binding of SAT sera to BSA, KLH, andglucagon was significantly lower than Tg. Preincubation with soluble Tg reduced the binding ofIgMs to coated Tg by 18.2% for serum samples and by 35.0% and 42.1% for 2 IgG-depleted samples.TgAb-IgM levels were inversely, although nonsignificantly, correlated with Tg concentrations.Conclusions: Tg leak associated with thyroid injury induces the production of specific TgAb-IgMs,which, in turn, increases the clearance of Tg and might prevent the establishment of a persistentthyroid autoimmune response