Endomyocardial Fibrosis: Still a Mystery after 60 Years

The pathologist Jack N. P. Davies identified endomyocardial fibrosis in Uganda in 1947. Since that time, reports of this restrictive cardiomyopathy have come from other parts of tropical Africa, South Asia, and South America. In Kampala, the disease accounts for 20% of heart disease patients referred for echocardiography. We conducted a systematic review of research on the epidemiology and etiology of endomyocardial fibrosis. We relied primarily on articles in the MEDLINE database with either “endomyocardial fibrosis” or “endomyocardial sclerosis” in the title. The volume of publications on endomyocardial fibrosis has declined since the 1980s. Despite several hypotheses regarding cause, no account of the etiology of this disease has yet fully explained its unique geographical distribution

Thyroid hormone independent associations between serum TSH levels and indicators of bone turnover in cured patients with differentiated thyroid carcinoma

Objective: It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T-3), free thyroxine (FT4), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships. Design: We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma. Methods: We measured BMD of the femoral neck and lumbar spine. FT4, T-3, TSH, bone-specific alkaline phosphatase, procollagen type I aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727GIu polymorphism were determined by Taqman assay. Results: We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT4 and T-3 levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727GIu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index. Conclusion: We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed

Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts

Context: Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels. Objective: We examined the effects of L-thyroxine on human skeletal muscle transcriptome. Design: Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. Setting: The study was conducted in a university hospital laboratory. Patients: We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off L-thyroxine replacement. Mean Outcome Measures: Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods. Results: We detected 607 differentially expressed genes on L-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. L-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b. Conclusion: We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes. (J Clin Endocrinol Metab 94: 3487-3496, 2009

Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting

Context: The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T-3 production. Objective: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. Design: This was a prospective study. Setting: The study was conducted at a university hospital. Patients: We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T-4 replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. Mean Outcome Measures: D2 activity and D2 mRNA levels were measured in skeletal muscle samples. Results: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T-4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. Conclusion: Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle. (J Clin Endocrinol Metab 94: 2144-2150, 2009