Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19.

INTRODUCTION: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and COVID-19. OBJECTIVE: To identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. METHODS: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. RESULTS: 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5 %. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (p = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥ 92 cm² exhibited the best survival rate. CONCLUSION: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

MTOR gene variants are associated with severe COVID-19 outcomes: A multicenter study.

BACKGROUND: The worst outcomes linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been attributed to the cytokine storm, which contributes significantly to the immunopathogenesis of the disease. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. The individual genetic background might play a role in the exacerbated immune response. OBJECTIVE: In this study, we aimed to investigate the association between MTOR genetic variants and COVID-19 outcomes. METHODS: This study enrolled groups of individuals with severe (n = 285) and mild (n = 207) COVID-19 from Brazilian states. The MTOR variants, rs1057079 and rs2536, were genotyped. A logistic regression analysis and Kaplan-Meier survival curves were performed. We applied a genotyping risk score to estimate the cumulative contribution of the risk alleles. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were also measured. RESULTS: The T allele of the MTOR rs1057079 variant was associated with a higher likelihood of developing the most severe form of COVID-19. In addition, higher levels of IL-6 and COVID-19 death was linked to the T allele of the rs2536 variant. These variants exhibited a cumulative risk when inherited collectively. CONCLUSIONS: These results show a potential pathogenetic role of MTOR gene variants and may be useful for predicting severe outcomes following COVID-19 infection, resulting in a more effective allocation of health resources.

Low muscle mass and high visceral fat mass predict mortality in patients hospitalized with moderate-to-severe COVID-19: a prospective study.

Introduction: The severity of coronavirus disease 2019 (COVID-19) has been positively correlated with several comorbidities. The primary outcome of the study was to assess the relationship between the mortality and severity of COVID-19 and obesity classes according to BMI, visceral adipose tissue (VAT) area, s.c. adipose tissue area, muscle area (MA), and leptin levels. Methods: In this prospective cohort study, 200 patients hospitalized with moderate-to-severe COVID-19 underwent an unenhanced CT of the thorax and laboratory tests, and leptin levels between June and August 2020 were obtained. Results: Our study included 200 patients (male 52%; mean age: 62 (49-74) years; obesity (BMI > 30): 51.5%)). Fifty-eight patients (23.5%) were admitted to the intensive care unit and 29 (14.5%) died. In multivariate logistic regression (corrected for leptin, sex, age, and serum biomarkers) and receiver operating characteristic curve analyses, high VAT > 150 cm2 (odds ratio (OR): 6.15; P < 0.002), MA < 92 cm2 (OR: 7.94; P < 0.005), and VAT/MA ratio > 2 (OR: 13.9; P < 0.0001) were independent risk factors for mortality. Indeed, the Kaplan-Meier curves showed that patients with MA < 92 cm2 and without obesity (BMI < 30) had a lower survival rate (hazard ratio between 3.89 and 9.66; P < 0.0006) than the other groups. Leptin levels were not related to mortality and severity. Conclusion: This prospective study reports data on the largest number of hospitalized severe COVID-19 patients and pinpoints VAT area and MA calculated by CT as predictors of COVID-19 mortality.

Nuclear score evaluation in follicular-patterned thyroid lesions using optical and digital environments.

INTRODUCTION: The subjective evaluation of nuclear features in follicular-patterned lesions of the thyroid is a reason for diagnosis discordance. The assessment of nuclear features also varies whether the observation is performed optically or digitally. Our objective was to study the concordance among pathologists regarding the nuclear score (NS) evaluation in a series of follicular-patterned lesions, using optical versus three digital scanning protocols. METHODS: Three pathologists evaluated the NS in a 3mm2 area randomly selected from 20 hematoxylin-eosin slides representative of the respective 20 follicular-patterned thyroid lesions. The NS evaluation was performed using optical and three different scanning protocols in two scanners: P1000_20x, P1000_40x and DP200_20x. Kappa statistic (κ) and intraclass correlation coefficient (ICC) were obtained for intra- and interpathologist concordance. RESULTS: We recorded a good agreement among pathologists in the optical evaluation of the NS (ICC of 0.73). The concordance between optical versus digital observation had an almost perfect agreement for P1000_20x [κ = 0.85 (0.67-1.02); p < 0.0001] and a substantial agreement for both P1000_40x [κ = 0.69 (0.43-0.95) p = 0.002] and DP200_20x [κ = 0.77 (0.57-0.97); p = 0.001]. The P1000_20x protocol had the best intrapathologist concordance with the optical method, classified as almost perfect agreement for pathologists A (80%) and B (85%), and substantial agreement for pathologist C (70%). CONCLUSION: Digital observation of the WSI is valid for the NS evaluation in follicular-patterned thyroid lesions, with good agreement among pathologists and between optical and scanning protocols. Performance studies and validation procedures cannot be avoided in this setting to prevent diagnostic discordance due to the scanning process.

Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19.

CONTEXT: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. OBJECTIVE: Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. METHODS: Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. RESULTS: In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (n = 79), Thr/Ala (n = 119), and Ala/Ala (n = 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. CONCLUSION: Here we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.

COVID-19 and thyroid function: What do we know so far?

Coronavirus disease 2019 (COVID-19) was characterized as a pandemic in March, 2020 by the World Health Organization. COVID-19 is a respiratory syndrome that can progress to acute respiratory distress syndrome, multiorgan dysfunction, and eventually death. Despite being considered a respiratory disease, it is known that other organs and systems can be affected in COVID-19, including the thyroid gland. Thyroid gland, as well as hypothalamus and pituitary, which regulate the functioning of most endocrine glands, express angiotensin-converting enzyme 2 (ACE2), the main protein that functions as a receptor to which SARS-CoV-2 binds to enter host cells. In addition, thyroid gland is extremely sensitive to changes in body homeostasis and metabolism. Immune system cells are targets for thyroid hormones and T3 and T4 modulate specific immune responses, including cell-mediated immunity, natural killer cell activity, the antiviral action of interferon (IFN) and proliferation of T- and B-lymphocytes. However, studies show that patients with controlled hypothyroidism and hyperthyroidism do not have a higher prevalence of COVID-19, nor do they have a worse prognosis when infected with the virus. On the other hand, retrospective observational studies, prospective studies, and case reports published in the last two years reported abnormal thyroid function related to acute SARS-CoV-2 infection or even several weeks after its resolution. Indeed, a variety of thyroid disorders have been documented in COVID-19 patients, including non-thyroidal illness syndrome (NTIS), subacute thyroiditis and thyrotoxicosis. In addition, thyroid disease has already been reported as a consequence of the administration of vaccines against SARS-CoV-2. Overall, the data revealed that abnormal thyroid function may occur during and in the convalescence post-COVID condition phase. Although the cellular and molecular mechanisms are not completely understood, the evidence suggests that the "cytokine storm" is an important mediator in this context. Thus, future studies are needed to better investigate the pathophysiology of thyroid dysfunction induced by COVID-19 at both molecular and clinical levels.

Thyroid Hormone Levels During Hospital Admission Inform Disease Severity and Mortality in COVID-19 Patients.

Background: Illness severity in patients infected with COVID-19 is variable. Methods: Here, we conducted an observational, longitudinal, and prospective cohort study to investigate serum thyroid hormone (TH) levels in adult COVID-19 patients, admitted between June and August 2020, and to determine whether they reflect the severity or mortality associated with the disease. Results: Two hundred forty-five patients [median age: 62 (49-75) years] were stratified into non-critical (181) and critically ill (64) groups. Fifty-eight patients (23.6%) were admitted to the intensive care unit, and 41 (16.7%) died. Sixteen (6.5%) exhibited isolated low levels of free triiodothyronine (fT3). fT3 levels were lower in critically ill compared with non-critical patients [fT3: 2.82 (2.46-3.29) pg/mL vs. 3.09 (2.67-3.63) pg/mL, p = 0.007]. Serum reverse triiodothyronine (rT3) was mostly elevated but less so in critically ill compared with non-critical patients [rT3: 0.36 (0.28-0.56) ng/mL vs. 0.51 (0.31-0.67) ng/mL, p = 0.001]. The univariate logistic regression revealed correlation between in-hospital mortality and serum fT3 levels (odds ratio [OR]: 0.47; 95% confidence interval [CI 0.29-0.74]; p = 0.0019), rT3 levels (OR: 0.09; [CI 0.01-0.49]; p = 0.006) and the product fT3 × rT3 (OR: 0.47; [CI 0.28-0.74]; p = 0.0026). Serum thyrotropin, free thyroxine, and fT3/rT3 values were not significantly associated with mortality and severity of the disease. A serum cutoff level of fT3 (≤2.6 pg/mL) and rT3 (≤0.38 ng/mL) was associated with 3.46 and 5.94 OR of mortality, respectively. We found three COVID-19 mortality predictors using the area under the receiver operating characteristic (ROC) curve (AUC score): serum fT3 (AUC = 0.66), rT3 (AUC = 0.64), and the product of serum fT3 × rT3 (AUC = 0.70). Non-thyroidal illness syndrome (fT3 < 2.0 pg/mL) was associated with a 7.05 OR of mortality ([CI 1.78-28.3], p = 0.005) and the product rT3 × fT3 ≤ 1.29 with an 8.08 OR of mortality ([CI 3.14-24.2], p < 0.0001). Conclusions: This prospective study reports data on the largest number of hospitalized moderate-to-severe COVID-19 patients and correlates serum TH levels with illness severity, mortality, and other biomarkers to critical illness. The data revealed the importance of early assessment of thyroid function in hospitalized patients with COVID-19, given the good prognostic value of serum fT3, rT3, and fT3 × rT3 product. Further studies are necessary to confirm these observations.

[Unknown significance monoclonal gammopathy (USMG) and primary hyperparathyroidism (PH) on diferential diagnosis of hypercalcemia: case report]. / Associação entre gamopatia monoclonal de significado indeterminado e hiperparatireoidismo primário no diagnóstico diferencial das hipercalcemias - Relato de caso.

The monoclonal gammopathy of undetermined significance (USMG) is a pre-malignant rare asymptomatic disease, defined by a concentration of immunoglobulin in serum monoclonal more than 3 g/dL and a proportion of plasma cells in bone marrow more than 10% in the absence of lytic bone lesions, anemia, hypercalcemia and renal failure related to monoclonal cell proliferation. Primary hyperparathyroidism (PH) is a relatively frequent disease, affecting approximately one in 1,000 individuals. Some studies suggest that the frequency of PH is increased in cancer, broadening the spectrum of etiology of hypercalcemia in these patients. We report here a case of a 63 years-old patient admitted for investigation of anemia, paresthesias, pain in the lower limbs and kidney failure. During investigation, there was hypercalcemia, serum monoclonal peak of IgA/lambda without criteria for multiple myeloma and with parathyroid adenoma. Patient was submitted to parathyroidectomy, which anatomicopathological revealed parathyroid adenoma. After surgery, levels of calcium and kidney function returned to normal.

Associação entre gamopatia monoclonal de significado indeterminado e hiperparatireoidismo primário no diagnóstico diferencial das hipercalcemias - Relato de caso / Unknown significance monoclonal gammopathy (USMG) and primary hyperparathyroidism (PH) on diferential diagnosis of hypercalcemia - Case report

A gamopatia monoclonal de significado indeterminado (GMSI) é uma doença pré-maligna rara assintomática, definida por uma concentração de imunoglobulina monoclonal no soro menor que 3 g/dL e uma proporção de células plasmocitárias na medula óssea menor que 10%, na ausência de lesões líticas ósseas, anemia, hipercalcemia e insuficiência renal relacionadas com a proliferação de células plasmáticas monoclonais. O hiperparatireoidismo primário (HP) é uma doença relativamente frequente, afetando aproximadamente um em cada 1000 indivíduos. Alguns trabalhos sugerem que a frequência de HP está aumentada em neoplasias, ampliando o espectro da etiologia da hipercalcemia nesses pacientes. Relata-se, aqui, um caso de paciente de 63 anos admitido para investigação de anemia, parestesias e dores em membros inferiores, além de insuficiência renal. Durante investigação, verificou-se hipercalcemia, pico monoclonal sérico de IgA/lambda, sem critérios para mieloma múltiplo, e adenoma de paratireoide. O mesmo foi submetido à paratireoidectomia, cujo anatomopatológico revelou adenoma de paratireoide. Após a cirurgia, houve retorno dos níveis de cálcio e de função renal ao normal.

The monoclonal gammopathy of undetermined significance (USMG) is a pre-malignant rare asymptomatic disease, defined by a concentration of immunoglobulin in serum monoclonal more than 3 g/dL and a proportion of plasma cells in bone marrow more than 10% in the absence of lytic bone lesions, anemia, hypercalcemia and renal failure related to monoclonal cell proliferation. Primary hyperparathyroidism (PH) is a relatively frequent disease, affecting approximately one in 1,000 individuals. Some studies suggest that the frequency of PH is increased in cancer, broadening the spectrum of etiology of hypercalcemia in these patients. We report here a case of a 63 years-old patient admitted for investigation of anemia, paresthesias, pain in the lower limbs and kidney failure. During investigation, there was hypercalcemia, serum monoclonal peak of IgA/lambda without criteria for multiple myeloma and with parathyroid adenoma. Patient was submitted to parathyroidectomy, which anatomicopathological revealed parathyroid adenoma. After surgery, levels of calcium and kidney function returned to normal.