Efficacy of Anti-Thyroid Medications in Patients with Graves' Disease.

INTRODUCTION: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism due to increased thyroid-stimulating hormone receptor antibodies (TRAb).The treatment of GD often consists of radioactive iodine therapy, anti-thyroid drugs (ATD), or thyroidectomy. Since few studies have collected data on remission rates after treatment with ATD in Saudi Arabia, our study aimed to assess the efficacy and the clinical predictors of GD long-term remission with ATD use. METHOD: We conducted a retrospective chart review study of 189 patients with GD treated with ATD between July 2015 and December 2022 at the endocrine clinics in King Abdulaziz Medical City in Riyadh. All GD patients, adults, and adolescents aged 14 years and older who were treated with ATD during the study period and had at least 18 months of follow-up were included in the study. Patients with insufficient follow-up and those who underwent radioactive iodine (RAI) therapy or thyroidectomy as first-line therapy for GD were excluded from the study. RESULTS: The study sample consisted of 189 patients, 72% of whom were female. The patients' median age was 38years (33, 49). A total of 103 patients (54.5%) achieved remission. The median follow-up period for the patients was 22.0 months (9, 36). Patients who achieved remission had lower mean free T4 levels (25.8pmol/l ± 8.93 versus 28.8pmol/l ± 10.82) (P value = 0.038) and lower median TRAb titer (5.1IU/l (2.9, 10.7)) versus (10.5IU/l (4.2, 22.5)) (P value = 0.001) than patients who did not achieve remission. Thirty-five out of 103 patients who achieved remission (34%) relapsed after ATD discontinuation. The patients who relapsed showed higher median thyroid uptake on 99mTc-pertechnetate scan than patients who did not relapse: 10.3% (5.19, 16.81) versus 6.0% (3.09, 12.38), with a P value of 0.03. They also received ATD for a longer period, 40.0 months (29.00, 58.00) versus 25.0 months (19.00, 32.50), with a P value of < 0.0001. CONCLUSION: The remission of GD was achieved in approximately half of the patients treated with ATD; however, approximately one-third of them relapsed. Lower Free T4 and TRAb levels at diagnosis were associated with remission. Longer ATD use and higher thyroid uptake upon diagnosis were associated with relapse after ATD discontinuation. Future studies are necessary to ascertain the predictors of ATD success in patients with GD.

Triiodothyronine levels in athyreotic pediatric patients during levothyroxine therapy.

Objective: Levothyroxine (LT4) monotherapy is the current recommended approach for treating pediatric patients post-total thyroidectomy (TT) based on the assumption that peripheral conversion of thyroxine (T4) to triiodothyronine (T3) normalizes thyroid hormone levels. In adults, approximately 15% of post-TT patients on LT4 monotherapy have altered T4:T3 ratios with ongoing debate in regard to the clinical impact with respect to health-related quality of life (hrQOL). The ability to normalize T3 and T4 levels on LT4 monotherapy for pediatric patients' post-TT is important but not previously described. This study reports data on T3 levels in athyreotic pediatric patients to determine if a similar cohort of patients exists on LT4 monotherapy targeting normalization of TSH (LT4 replacement) or suppression (LT4 suppression). Methods: Thyroid function tests (TFTs) were retrospectively extracted from medical charts for patients <19 years old who underwent TT for definitive treatment of Graves' disease (GD) or differentiated thyroid cancer (DTC) between 2010-2021. LT4 dosing was selected to normalize the TSH in GD patients (LT4 replacement) or suppress TSH in DTC patients (LT4 suppression). Pre- and post-surgical TSH, T3 and T4 levels were compared. Results: Of 108 patients on LT4 replacement (n=53) or LT4 suppression (n=55) therapy, 94% (102/108) of patients demonstrated T3 levels in the normal range post-TT. However, the majority of patients on LT4 replacement (44/53; 83%) and LT4 suppression (31/55; 56%) displayed post-TT T3 levels in the lower half of the normal range despite 50% (22/44) and 48% (15/31) of these patients, respectively, having post-TT fT4 levels above the upper limit of the normal range. Conclusion: A significant number of pediatric patients do not achieve similar T3 and T4:T3 levels pre- and post-TT. Future multi-center, prospective studies evaluating LT4 monotherapy in comparison to combined LT4/LT3 therapy are warranted to determine the potential clinical impact of altered T3 levels in athyreotic pediatric patients.

Lower proportion of intra-thyroidal B lymphocytes CD20+ associated to methimazole and lack of influence of iodide on lymphocyte subpopulations in Graves' disease.

Graves' disease (GD), an autoimmune thyroid disease, is one of the main autoimmune diseases in the general population. It is known that the pathophysiology of this disease may be related to immunological mechanisms dysregulation. These mechanisms can be influenced by GD therapies, such as iodide or antithyroid drugs (ATD). OBJECTIVE: Verify relation between clinical, biochemical and treatment modalities used prior to surgery and histopathological characteristics observed in total thyroidectomy products from patients previously diagnosed with Graves' disease. Furthermore, these data were related to composition of lymphocytic infiltrate in terms of proportions of lymphocytes CD4+, CD8+, CD25+ and CD20+. We aim to contribute to the understanding of the evolution pattern of GD, whose pathophysiology is not yet completely understood. METHODS: Cross-sectional study assessing thyroidectomy products for the presence of lymphocytic infiltrate, as well as the proportion and intensity of CD4+, CD8+, CD25+ and CD20+ markers. We selected 50 patients who underwent total or partial thyroidectomy in a tertiary service between 1996 and 2013 due to GD with histopathological confirmation. The control group (non-autoimmune disease group) consisted of 12 patients with histopathological data compatible with normal perilesional thyroid parenchyma. The intensity of lymphocytic infiltrate and immunohistochemical expression of the markers CD4+ (helper T lymphocytes), CD8+ (cytotoxic T lymphocytes), CD25+ (regulatory T lymphocytes) and CD20+ (B lymphocytes) were retrospectively evaluated and relationship with ultrasound, laboratory and clinical data was assessed. RESULTS: No differences were found in intensity, presence of lymphoid follicles, and expression of CD4+/CD8+/CD25+ in patients with GD who did or did not use ATD or iodide. In the group that did not use ATD, a higher proportion of CD20+ expression was found. The GD group was associated with hyperplastic epithelium and the control group was associated with simple epithelium. There was no difference in ultrasound thyroid volume between the groups. In GD patients with mild lymphocytic infiltrate, higher free thyroxin (FT4) levels were observed than those in patients with no infiltrate or moderate infiltrate. CONCLUSION: We found a lower proportion of intrathyroidal CD20+ B lymphocytes in patients under use of methimazole. However, no difference was observed in intrathyroidal lymphocyte subpopulations related to the short-term use of iodide. The understanding of thyroid autoimmunity, as well as identifying points of pharmacological modulation, are very important for advancement and improvement in treatments for these diseases.

Case report: Propylthiouracil-induced serious side effect: Perinuclear antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis?

INTRODUCTION: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare disease characterized by the inflammation and destruction of small blood vessels and circulating ANCAs. Drugs such as antithyroid drugs (ATDs), especially propylthiouracil (PTU), have been used for the production of ANCAs and cause the development of drug-induced AAV. The pathogenesis of this disease is unclear but could be related to the physiological processes affecting the degradation of neutrophil extracellular traps (NETs). At present, PTU is widely used in patients with Graves' disease (GD) who are preparing for pregnancy and whose condition has not been controlled. Once drug-induced AAV has occurred with important organ damage, considering NETs have a significant role in the immune system, whether the cessation of drugs could stop the progression of organ damage is unclear, and a consensus regarding standard treatment has not been established. PATIENT CONCERNS: In this case report, a female patient who planned pregnancy was hospitalized with multiple joint pain, impaired renal function, and hematuria. Immunofluorescence of the renal biopsy demonstrated spherical and diffuse mesangial distribution of IgA (3+). Autoimmune serology demonstrated positivity for autoantibodies against p-ANCA and an anti-MPO titer 74.72 RU/mL. DIAGNOSIS: She was diagnosed with PTU-induced p-ANCA-associated and IgA-associated vasculitis (IgAV). INTERVENTIONS: The patient accepted low doses of glucocorticoid, immunosuppressive therapy and RAI treatment. OUTCOMES: Both her kidney function and thyroid function remained were on the mend. CONCLUSION: The authors believe that this type of patient needs to fully consider their pregnancy preparation needs, suspend pregnancy when a small chance of GD remission is indicated, and avoid the use of drugs with reproductive toxicity and other serious adverse events. The multidisciplinary combination therapy of low-dose glucocorticoids and immunosuppressants combined with iodine radiotherapy is one reasonable scheme. At the same time, it is necessary to eliminate the organ damage caused by other reasons. This report provides a clinical treatment basis for patients with drug-induced vasculitis manifestations who cannot receive an accurate diagnosis.

Block-and-replace regimen versus titration of antithyroid drugs: a recent meta-analysis.

INTRODUCTION: Drug therapy for Graves' disease (GD) is the first-line treatment in Europe. The use of a specific regimen for the administration of anti-thyroid drugs (ATDs) is still controversial. The objective was to compare block-and-replace therapy (BRT) with a titration (T) regimen in terms of incidence of overt hypothyroidism and development of Graves' orbitopathy (GO) over 18 months of treatment. MATERIAL AND METHODS: Two databases (PubMed, Cochrane Library) and reference lists were searched. Prospective and retrospective observational cohort studies were included. Data collection and analysis were performed independently by 2 authors. RESULTS: Two studies with 716 GD patients (40.36% treated with BRT, 59.64% with T regimen) were included. No statistically significant differences were observed between the ATDs regimens used in terms of incidence of overt hypothyroidism during 18 months of treatment [Mantel-Haenszel (M-H) odds ratio (OR): 1.54, 95% confidence interval (CI): 0.75-3.16, p-value = 0.24]. GD patients who followed BRT were less likely to achieve control of thyroid function than patients on T regimen (M-H OR: 0.55, 95% CI: 0.34-0.88, p = 0.01). One study reported fewer thyroid function tests (TFT) during BRT than during the T regimen. The other study included patients without GO at baseline and reported a lower incidence of GO during BRT than in the T regimen (9.1% versus 17.8%), with no statistical difference between the 2 regimens (M-H OR: 0.47, 95% CI: 0.19-1.14, p = 0.10). CONCLUSION: BRT may be more useful than the T regimen for patients with complicated GD or for those who required fewer TFTs.

Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease.

BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

Different Forms of Hypothyroidism in Infants with Maternal Graves' Disease: A Case Series.

Infants of mothers with Graves' disease (GD) may develop central hypothyroidism (CH) due to exposure of the foetal hypothalamic-pituitary-thyroid axis to higher-than-normal thyroid hormone concentrations, primary hypothyroidism (PH) due to transplacental passage of maternal thyroid stimulating hormone receptor antibody (TRAb), antithyroid drugs (ATD) or thyroid dysgenesis secondary to maternal uncontrolled hyperthyroidism. We describe two infants with PH and four infants with CH born to mothers with poorly controlled Graves' disease. All infants required levothyroxine and had normal developmental milestones. While national guideline consensus for high thyroid stimulating hormone (TSH) on neonatal screening is well-established, thyroid function tests (TFTs) should be serially monitored in infants with low TSH on screening, as not all mothers with Graves' disease are diagnosed antenatally.

Insulin Autoimmune Syndrome - An After-Meal Roller Coaster Ride.

Hypoglycemic disorders are rare in persons without diabetes, and clinical evaluation to identify its etiology can be challenging. We present a case of insulin autoimmune syndrome induced by carbimazole in a middle-aged Chinese man with underlying Graves' disease, which was managed conservatively with a combination of dietary modification and alpha-glucosidase inhibitor.

Graves-PCD: protocol for a randomised, dose-finding, adaptive trial of the plasma cell-depleting agent daratumumab in severe Graves' disease.

INTRODUCTION: Severe Graves' disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves' disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves' disease and will provide important data to inform a choice of dosing regimen for subsequent trials. METHODS AND ANALYSIS: The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves' disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks. ETHICS AND DISSEMINATION: The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events. TRIAL REGISTRATION NUMBER: ISRCTN81162400.

Predictive value of bone turnover markers and thyroid indicators for bone metabolism in GD patients after treatment.

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively. Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT3 and FT4 before and after treatment (FT3-P/FT3-A, FT4-P/FT4-A) on whether BTMs recovered. Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT3-P/FT3-A and FT4-P/FT4-A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05). Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT3 decreased more than 51% and FT4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD.

Dynamic Risk Model for the Medical Treatment of Graves' Hyperthyroidism according to Treatment Duration.

BACKGRUOUND: Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves' hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. METHODS: In this retrospective cohort study, 1,235 patients with Graves' hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12-24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. RESULTS: The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P<0.001). The patterns of TRAb changes were an independent risk factor for recurrence after adjusting for other confounding factors in all patients, except in group 1. Integrated discrimination improvement and net reclassification improvement analyses showed that model B performed better than model A in all patients, except in group 1. CONCLUSION: The dynamic risk model, including the patterns of TRAb changes, was more suitable for predicting prognosis in patients with Graves' hyperthyroidism who underwent longer ATD treatment duration.

Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Gut microbiome in the Graves' disease: Comparison before and after anti-thyroid drug treatment.

While several studies have proposed a connection between the gut microbiome and the pathogenesis of Graves's disease (GD), there has been a lack of reports on alteration in microbiome following using anti-thyroid drug treatment (ATD) to treat GD. Stool samples were collected from newly diagnosed GD patients provided at baseline and after 6 months of ATD treatment. The analysis focused on investigating the association between the changes in the gut microbiome and parameter including thyroid function, thyroid-related antibodies, and the symptom used to assess hyperthyroidism before and after treatment. A healthy control (HC) group consisting of data from 230 healthy subjects (110 males and 120 females) sourced from the open EMBL Nucleotide Sequence Database was included. Twenty-nine GD patients (14 males and 15 females) were enrolled. The analysis revealed a significant reduction of alpha diversity in GD patients. However, after ATD treatment, alpha diversity exhibited a significant increase, restored to levels comparable to the HC levels. Additionally, GD patients displayed lower levels of Firmicutes and higher levels of Bacteroidota. Following treatment, there was an increased in Firmicutes and a decrease in Bacteroidota, resembling levels found in the HC levels. The symptoms of hyperthyroidism were negatively associated with Firmicutes and positively associated with Bacteroidota. GD had significantly lower levels of Roseburia, Lachnospiraceaea, Sutterella, Escherichia-shigella, Parasuterella, Akkermansia, and Phascolarctobacterium compared to HC (all p < 0.05). Post-treatment, Subdoligranulum increased (p = 0.010), while Veillonella and Christensenellaceaea R-7 group decreased (p = 0.023, p = 0.029, respectively). Anaerostipes showed a significant association with both higher smoking pack years and TSHR-Ab levels, with greater abundantce observed in smokers among GD (p = 0.16). Although reduced ratio of Firmicutes/Bacteroidetes was evident in GD, this ratio recovered after treatment. This study postulates the involvement of the gut microbiome in the pathogenesis of GD, suggesting potential restoration after treatment.

Refractory hypothyroidism.

INTRODUCTION: Persistently elevated thyroid stimulating hormone (TSH) despite levothyroxine (LT4) treatment that exceeds the standard weight-adjusted dose is a common clinical presentation. This may lead to additional testing for LT4 malabsorption or poor LT4 adherence, the latter of which is challenging to confirm because it is predicated on accurate patient accountability. CASE REPORT: A 35-year-old lady, post-radioactive iodine therapy for Graves' disease remained euthyroid for a year on oral LT4. Two years later, she was clinically and biochemically hypothyroid despite claiming LT4 compliance. As all laboratory investigations were within the reference range, pseudomalabsorption was suspected and a LT4 absorption test was done. During the test, her free thyroxine increased significantly at 4 hours, reaching a peak of more than 50% from baseline while TSH decreased appropriately from 0 minute to 360 minutes. This was followed by normalisation of TSH with LT4 treatment under direct observation. DISCUSSION: The LT4 absorption test is a prompt and economical means to rule out true malabsorption, decrease unwarranted subspecialty referrals and validate the weight-adjusted LT4 dose reduction.

Successful guselkumab treatment of a refractory psoriasis patient with Graves' disease: a case report.

Psoriasis is a chronic inflammatory skin disease. It is associated with many autoimmune diseases such as rheumatoid arthritis, Crohn's disease and thyroid diseases. Graves' disease (GD) is a common organ-specific autoimmune disease characterized by diffuse goitre and thyrotoxicosis. Management of psoriasis patients with GD is challenging. This current report presents the case of a 34-year-old female patient with refractory psoriasis with GD who was hospitalized for drug eruption and then experienced new-onset erythema and scaling following treatment with adalimumab and secukinumab. Despite the sequential move to phototherapy, tofacitinib and ustekinumab, the erythema and scaling continued unabated and exacerbated. Finally, switching to guselkumab resulted in the psoriasis lesions significantly improving. These findings suggest that guselkumab might be an effective treatment option for refractory psoriasis combined with GD.

Neutropenia Occurs More Often Under Carbimazole than Under Methimazole Treatment in Pediatric Graves' Disease Patients.

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.

Enhanced predictive validity of integrative models for refractory hyperthyroidism considering baseline and early therapy characteristics: a prospective cohort study.

BACKGROUND: A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. METHODS: A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. RESULTS: Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD. CONCLUSION: Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.

Apathetic Graves' disease with severe hepatic and renal dysfunction induced by COVID-19 infection: Case report and literature review.

RATIONALE: A rare and intractable case of apathetic Graves' disease (GD) with severe liver and kidney damage induced by coronavirus disease 2019 (COVID-19) carries a certain risk of missing diagnosis and delayed treatment during the COVID-19 pandemic. PATIENT CONCERN: A 60-year-old female patient developed anorexia, exhaustion, jaundice, nausea, and vomiting 10 days after COVID-19 infection. She was admitted to the Infectious Diseases Department because of recurring symptoms for more than a month. DIAGNOSIS: Based on the patient's epidemiological history, clinical symptoms, and prior history, she was preliminarily diagnosed with GD induced by COVID-19 with severe hyperthyroid-related liver injury and chronic kidney disease stage 4. Drug-induced and radiation-induced liver injuries occurred sequentially throughout the therapy. INTERVENTION: Methimazole (MMI) (10 mg/d) was administered for 1 week, and the patient's symptoms, thyroid function, and liver and kidney function improved. Nevertheless, the aforementioned symptoms and liver and kidney function deteriorated 20 days after increasing the MMI dose (20 mg/d). Therefore, in the presence of an artificial liver, hemodialysis, and other medical conditions, the treatment schedule was adjusted to individualized 131I anti-hyperthyroidism therapy. OUTCOME: After 131I treatment, the patient's liver function returned to almost normal levels after a month, but worsened when the hepatoprotective drugs were stopped. Renal function did not deteriorate significantly and returned to baseline after 3 months. Thyroid function was restored to normal approximately 4 months later. CONCLUSION: COVID-19 may induce GD. Multidisciplinary collaboration can be initiated as early as possible. Individualized 131I therapy or long-term low-dose MMI (10 mg/d) can be considered to manage hyperthyroidism in GD patients with liver and kidney dysfunction and to prolong liver protection therapy appropriately.