BackgroundFBN1-related geleophysic dysplasia (GD2) is an ultrarare autosomal dominant disorder caused by dominant-negative missense variants in the TGFβ-binding protein-like domain 5 (TB5) of FBN1. It is characterized by severe short stature, brachydactyly, progressive joint stiffness, and cardiac valvular disease. Although hepatomegaly is known to occur in GD, progression to cirrhosis with portal hypertension in the elderly has never been documented.Case presentationA 76-year-old Chinese man presented with a 1-year history of abdominal distension and was found to have liver cirrhosis during routine examination. He had no history of viral hepatitis, alcohol abuse, or other conventional liver disease risk factors. Physical examination revealed short stature (128 cm), brachydactyly, and mild scleral icterus. His 39-year-old daughter shared a similar skeletal phenotype and had a history of cardiac valve replacement. Laboratory tests showed moderate hyperbilirubinemia and mild thrombocytopenia with normal liver enzymes. Serological screening markers for viral hepatitis and autoimmune liver disease were all unremarkable. Liver elastography (15.5 kPa) and contrast-enhanced MRI confirmed cirrhosis with portal hypertension. Whole-genome sequencing identified a heterozygous pathogenic FBN1 variant (c.5284G>A, p.Gly1762Ser) in both the proband and his daughter, confirming a diagnosis of GD. The patient was managed supportively and remained stable over 6 months of follow-up.ConclusionTo our knowledge, this is the first reported case of late-onset liver cirrhosis in an elderly GD patient caused by an FBN1 variant. This case raises the possibility that hepatic manifestations related to GD could be linked to late-onset cirrhosis, though a causal or progressive relationship cannot be confirmed due to absent serial hepatic assessments prior to cirrhosis diagnosis. For elderly patients with unexplained late-onset liver cirrhosis combined with short stature or multisystem malformations, FBN1 genetic testing may be considered. In addition, long-term hepatic monitoring may be considered for middle-aged and elderly patients or those with TB5 domain variants, although universal surveillance for all affected individuals is not supported by the current evidence.

BACKGROUND:Graves' disease (GD) is rare in children, and methimazole (MMI) is recommended as the first-line therapy. However, data on MMI-associated neutropenia and agranulocytosis in pediatric patients remain limited. In this study, we aimed to characterize the clinical features of these adverse events and to identify their associated risk factors. METHODS:A cohort study was conducted involving 432 pediatric patients with GD treated with MMI. Clinical and biochemical data were collected retrospectively and prospectively, with follow-up 0.5, 1, 2, 3, 4, 5, 6, 7-9, and 10-12 months after treatment initiation. Multivariable logistic regression analysis was performed to identify risk factors for MMI-associated neutropenia. RESULTS:During the 12-month follow-up period, 104 (24.1%) patients developed neutropenia, with 84.6% developing neutropenia within the first 3 months, 72.1% within 1 month, and 59.6% within 2 weeks. Among the affected patients, 83.7%, 13.5%, and 2.8% had mild, moderate, and severe neutropenia (agranulocytosis), respectively. All patients with moderate or severe neutropenia were asymptomatic and were identified through routine monitoring within the first month. Multivariable analysis revealed that a thyroid peroxidase antibody (TPOAb)-negative status (odds ratio [OR], 2.020; confidence interval [CI], 1.113-3.666) was associated with a higher prevalence of MMI-associated neutropenia, whereas older age (OR, 0.916; CI, 0.848-0.989) and higher baseline absolute neutrophil count (ANC; OR, 0.775; CI, 0.665-0.903) were protective factors. CONCLUSIONS:ANC monitoring is recommended every 1 to 2 weeks during the first month and monthly for the first 3 months after MMI initiation. Pediatric patients with GD younger than 3 years with TPOAb-negative status or a baseline ANC < 3 × 109/L may have a higher prevalence of MMI-associated neutropenia.

BACKGROUND:Chronic iodine excess is associated with increased serum thyrotropin (TSH) levels. We assessed the independent and interactive effects of iodine-excess transition outcomes and aging on TSH levels over 20-year follow-up. METHODS:The original prospective cohort study started in 1999 and focused on three communities in North China (n = 1176). Based on the iodine status transition over the 20-year period, the euthyroid participants were categorized into groups according to urinary iodine concentrations (UIC): continuous iodine sufficiency (UIC 100-299 μg/L) (SI-SI, n = 261), from iodine excess (UIC >299 μg/L) to iodine deficiency (UIC <100 μg/L) (EI-DI, n = 145), from iodine excess to iodine sufficiency (EI-SI, n = 530), and continuous iodine excess (EI-EI, n = 240), respectively. RESULTS:During 1999-2004, the baseline median TSH levels were positively associated with the initial UIC levels. After 20 years, for participants with negative thyroid antibodies, the three iodine-excess groups all exhibited elevated median TSH levels (SI-SI 1.81 mU/L vs. EI-DI 2.19 mU/L vs. EI-SI 2.08 mU/L vs. EI-EI 2.01 mU/L), an increased prevalence of mild subclinical hypothyroidism (SCH) with TSH <10.0 mU/L (SI-SI 5.3% vs. EI-DI 11.2% vs. EI-SI 12.3% vs. EI-EI 9.4%) and reduced central thyroid hormone sensitivity compared with the SI-SI group (p < 0.05). However, the EI-EI group had the lowest TSH rising degree (SI-SI 0.32 mU/L [24.57%] vs. EI-DI 0.47 mU/L [24.56%] vs. EI-SI 0.45 mU/L [37.52%] vs. EI-EI 0.21 mU/L [14.18%], p < 0.05). Repeated-measures analysis revealed that aging was primarily related to a stable increase in TSH. Iodine-excess transition outcomes were also associated. Furthermore, a significant interaction effect existed between aging and different iodine-excess transition outcomes, modulating the TSH rising degree. Alleviation of iodine excess promoted aging-related TSH elevation, whereas persistent iodine excess suppressed aging-related TSH elevation. However, among participants with positive thyroid antibodies, no significant interaction effect above was observed. By comparison, there was a greater prevalence of SCH, especially an obvious high prevalence of severe SCH under persistent iodine excess. CONCLUSIONS:Elevated TSH levels induced by chronic iodine excess cannot be downregulated by reducing iodine intake. In nonautoimmune contexts, an interaction effect between iodine status and aging synergistically modulates the TSH rising degree. Iodine excess contributes to mild SCH and is correlated with high baseline TSH levels.

It is estimated that by the year 2050, 16% of the world’s population will be 65 years old and above. As the global aging population continues to grow, there is an increasing focus on thyroid disorders among older individuals. Thyrotropin is widely used in diagnosing subclinical thyroid diseases due to its high sensitivity as an indicator of changes in thyroid function. However, thyrotropin levels change with age, and different reference intervals have been proposed in various studies. The variation in thyrotropin ranges among older adults is probably caused by the heterogeneity of the studied population. This review aims to provide an overview of the existing literature on thyrotropin reference intervals in older adults and their distinction as adaptive or pathologic. Recent research indicates that older individuals may have slightly elevated levels of thyrotropin and higher upper limits of reference intervals. Therefore, a higher thyrotropin threshold for diagnosing and treating subclinical hypothyroidism in the elderly seems reasonable.

BACKGROUND:In 2018, the Chinese Society of Endocrinology developed the "Chinese guideline for diagnosis and treatment of hyperuricemia and gout (2019)". Over the past 5 years, clinical and experimental research has expanded our knowledge of gout, resulting in novel diagnostic and therapeutic approaches. This update, prompted by new clinical challenges and gaps in evidence, aims to refine the 2019 guidelines. METHODS:The working group formulated clinical questions based on a nationwide questionnaire survey, and the expert panel evaluated new evidence addressing these questions from January 2019 to March 2025. The guideline development followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, adhering to internationally recognized protocols for clinical practice guideline development. RESULTS:The update includes 26 recommendations addressing 10 clinical questions related to urate-lowering therapy (ULT) for asymptomatic hyperuricemia and reproductive populations, anti-inflammatory treatments, urine alkalinization, dietary advice, and gout diagnosis in patients without a record of hyperuricemia and gout flare predictions in patients with asymptomatic hyperuricemia and intermittent gout. It recommends febuxostat as a first-line ULT for asymptomatic hyperuricemia and using it with caution during pregnancy and lactation. ULT should be customized according to the pathophysiologic type of hyperuricemia. Chronic gout management includes maintaining serum urate levels between 180 and 300 μmol/L and prolonged glucocorticoid tapering in combination with colchicine. Alkalinization with citrate is preferred over sodium bicarbonate for patients with urine pH < 6.0. Novel biomarkers for predicting gout flares are proposed for high-risk populations. CONCLUSIONS:These updated guidelines incorporate expert consensus and evidence to provide refined strategies for the diagnosis, prevention, and treatment of hyperuricemia and gout.

Pheochromocytomas and paragangliomas (PPGLs) exhibit the highest degree of heritability among all human tumors, yet the genetics of urinary bladder paragangliomas (UBPGLs) remains poorly understood. The present study aims to examine the characteristics of a cohort of Chinese patients with UBPGLs, focusing particularly on genetics. The study included 70 Chinese patients with UBPGLs from 15 centers in China, 240 patients with non-head and neck PGLs (non-HNPGLs) outside the urine bladder, and 16 Caucasian patients with UBPGLs. Tumor DNA samples were sequenced by next generation sequencing. All identified pathogenic variants (PVs) were confirmed by Sanger sequencing. Among the 70 Chinese patients, PVs were identified in 38 cases: 23 in cluster 1 A (13 SDHB, 1 SDHD, 1 SDHA, 4 IDH1, 2 SLC25A11, and 2 FH), 4 in cluster 1B (3 EPAS1 and 1 EGLN1), and 11 in cluster 2 genes (7 HRAS, 1 FGFR1, 2 NF1, and 1 H3F3A). Compared with other non-HNPGLs, UBPGLs had more PVs in cluster 1 A genes (32.9

Context Subclinical hypothyroidism is associated with metabolic diseases; however, it remains controversial in older individuals.Objective This work aimed to investigate the relationship between thyrotropin (TSH) levels and metabolic diseases.Methods In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of 6791 older (aged >= 65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters.Methods In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of 6791 older (aged >= 65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters.Results In contrast to young adults, there was no significant increase in the prevalence of any metabolic disorders assessed in the slightly elevated TSH group (TSH 4.21-8.86 mU/L) compared to the euthyroid group (TSH 0.27-4.2 mU/L) among older adults. After adjusting for interference factors, a TSH level higher than 8.86 mU/L was found to be an independent risk factor for low high-density lipoprotein cholesterol (OR, 1.84; 95% CI, 1.14-2.98) and dyslipidemia (OR, 1.49; 95% CI, 1.09-2.04) when compared to the euthyroid group in older adults.Conclusion Slightly elevated TSH levels are not associated with an increased risk of metabolic diseases in older adults. Therefore, we recommend raising the upper limit of the TSH range for individuals aged 65 years and older.

Subclinical hypothyroidism (SCH) is characterized by elevated levels of thyroid hormone (TSH) and normal levels of free thyroxine (FT4). The outcomes of SCH patients are crucial for determining treatment plans; therefore, our aim is to summarize the existing prospective studies to understand the changes in thyroid function over time in SCH patients and the factors influencing these changes, providing references for clinical diagnosis and treatment. We searched PubMed, Embase, Cochrane Library, and Web of Science for prospective follow-up studies on natural outcomes of SCH published until September 2024. Results are presented as the overall risk ratio (RR) and 95

Thyroid hormones mainly include thyroxine (T 4) and 3, 5, 3′-triiodothyronine (T 3). About 75% of T 4 and 70% of T 3 in circulating blood bind to serum thyroxine binding globulin (TBG). Hereditary TBG abnormalities is caused by SERPINA7 mutation, which are classified into three types according to serum TBG levels in male patients: complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD), and TBG excess (TBG-E). The decrease of serum TBG level often leads to decreased level of total T 4 and total T 3, while the serum free thyroid hormone are normal. If the diagnosis of hereditary TBG abnormalities can be confirmed in such patients, no treatment is required. When hereditary TBG abnormalities are combined with other thyroid diseases, the thyroid function test will become more complicated, which will easily lead to misdiagnosis, missed diagnosis, and even mistreatment. Therefore, enhancing the understanding of this disease can avoid misdiagnosis, mistreatment, reduce unnecessary laboratory tests, or inappropriate treatment.

IntroductionSubclinical hypothyroidism (SCH) is a common endocrine disorder characterized by elevated thyroid-stimulating hormone (TSH) levels and normal free thyroxine (FT4) levels. The overdiagnosis and overtreatment of SCH in elderly patients have become concerns as TSH levels naturally increase with age. Studies have shown that many elderly patients with SCH can recover without treatment, and the administration of levothyroxine (L-T4) does not improve their prognosis. Therefore, It is necessary to establish age-specific reference ranges for TSH in elderly individuals to aid in clinical decision-making and prevent overdiagnosis.MethodsThis is a multicenter prospective study that focuses on Chinese elderly patients with SCH who have TSH levels below 10 mU/L. After obtaining the informed consent of the patients, their initial diagnosis information will be registered, and they will be asked to fill out questionnaires such as the Montreal Cognitive Assessment-Basic (MoCA-B), Hamilton Depression Scale (HAMD), Hypothyroidism Symptom Questionnaire (SRQ), frail scale(FRAIL), fatigue scale, and EQ-5D. In addition, thyroid function tests, blood lipid analysis, carotid artery ultrasound, and thyroid ultrasound examinations will be conducted. Patients will also be grouped according to FT4 levels, the changes in FT4 and its relationship with TSH can also be described. For patients over 80 years old, a decrease in FT4 will be used as an endpoint event, while for patients between 60-80 years old, TSH levels greater than or equal to 10mIU/L or a decline in FT4 will be used as the endpoint event. The TSH reference intervals of the general and elderly populations will be used to calculate medical costs associated with multiple follow-ups of patients, and a social-economic analysis will also be conducted.DiscussionThis study will prospectively observe elderly patients with SCH who are screened using both age-specific and non-age-specific TSH reference ranges for the elderly population. We will compare the results of elderly patients diagnosed with SCH using different reference ranges and analyze their association with FT4 to identify meaningful SCH patients and reduce over diagnosis and over treatment of elderly SCH.EthicsThe Medical Science Research Ethics Committee of the First Affiliated Hospital of China Medical University approved this study (ID: AF-SOP-07-1.1-01). The results will be published in an open-access journal.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2300070831.

Supplementary Figure 7 from E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

BACKGROUND We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow up. METHODS The original prospective cohort study, started in 1999 (n=3,761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared to Zhangwu, which iodine status changed from more than adequate to adequate iodine (from 214μg/L to 167.2μg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UIC), serum thyroid hormone concentration, and thyroid antibodies were measured. RESULTS When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88μg/L to 141.9μg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody (TPOAb), positive thyroglobulin antibody (TgAb), and goiter decreased significantly (p<0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared to the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, p<0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634μg/L to 266.7μg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter (p<0.05 for all), were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, p<0.001) was seen. CONCLUSIONS The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders.

Supplementary Figure Legends 1-7 from E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

Supplementary Figure 6 from E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

Objectives To investigate the prevalence and risk factors of hypothyroidism after universal salt iodisation for 20 years in mainland China.Design Nationwide, cross-sectional survey.Setting and participants The Thyroid Disorders, Iodine Status and Diabetes epidemiological study included adults from 31 provinces of China. Data included demographic, physical characteristics, urine, serum thyroid-stimulating hormone (TSH), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb) and thyroid ultrasonography. Subclinical hypothyroidism (SCH) was classified into severe SCH (TSH >10 mU/L) and mild SCH (TSH 4.2–9.9 mU/L). A total of 78 470 (38 182 men and 40 288 women) participants were included in the final analysis.Results The prevalence of hypothyroidism was 13.95%. The prevalence rates of overt hypothyroidism (OH) and SCH were 1.02% and 13.93%, which mild SCH was significantly higher than severe SCH (12.18% vs 0.75%). Prevalence was higher in women than in men, and this gender difference was noted among all age groups. The prevalence of mild SCH, severe SCH and OH increases by 1.16%, 1.40% and 1.29% for every 10 years older. TPOAb or/and TgAb positive were significantly associated with OH and severe SCH (OR 15.9, p<0.001). However, SCH was positively correlated with increased urine iodine concentration, but this correlation was only in antibody-negative female patients. In non-autoimmune and male populations, there was a U-shaped relationship between severe SCH and OH and urine iodine concentration.Conclusions Mild SCH is the most common form of hypothyroidism, which is related to iodine intake. Severe SCH is more similar to OH which autoimmune is the main cause. The various effects of iodine on hypothyroidism depend on thyroid autoimmune and gender.

Supplementary Figure 6 from E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

Supplementary Figure 5 from E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

Context IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. Objective To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. Methods This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. Results The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. Conclusions The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.