Access, availability, and infrastructure deficiency: The current management of thyroid disease in the developing world.

Thyroid disease, a neglected tropical disease and the most common noncommunicable disease in the developing world, is overlooked, under-diagnosed, and inadequately managed. The spectrum of thyroid disorders in the developing world is qualitatively different from that found in industrialized countries. This qualitative difference has resulted in limited access to clinical, laboratory, and imaging resources that are necessary for the care of patients with thyroid disease. The management of thyroid disease in the developing world is comparable to the care provided for disorders of the thyroid in North America fifty years ago.This article reviews public health and clinical aspects of developing world medical and surgical thyroid disease. Topics covered include iodine deficiency disorders, congenital hypothyroidism, goiter, thyroid cancer, and hyper- and hypothyroidism. The review concludes with a description of programs based on smartphone technology to improve the availability, affordability, and quality of thyroid disease care.

Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status.

Background: Despite being the most performed laboratory endocrine investigation, the optimum use of thyroid tests (thyrotropin [TSH] and thyroid hormone [TH] measurement) is open to question and the interpretation of the results from these tests can be ambiguous. The American Thyroid Association (ATA) with its expertise support the endeavor of the U.S. Centers for Disease Control (CDC) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) to improve and maintain standardization and harmonization of thyroid testing. ATA mandated an international interdisciplinary working group panel to survey the status of thyroid testing by reviewing the recent literature to revise or update the criteria as needed in mutual agreement and to inform clinical care. Summary: This review represents the conclusions on the clinical use of current routine TSH and TH (thyroxine [T4] and triiodothyronine [T3]) assays, taking into account geographic differences in disease prevalence and clinical and laboratory practice among writing members. The interaction between physiological, pathophysiological, and pharmacological factors and thyroid assays can affect their measurements and confound result interpretation. These factors need to be considered in the clinical context of the patient for appropriate test ordering and result interpretation. Despite significant advances in laboratory methods over the past 50 years, routine thyroid assays remain susceptible to idiosyncratic analytical interference that may produce spurious results. Improved standardization needs to be demonstrated through ongoing international efforts before results from different assays can be considered equivalent. Emerging technology (e.g., mass spectrometry) shows promise for improved analytical performance, but more evidence of its clinical utility and improved throughput is required before it can be considered for routine use. Close clinical-laboratory collaboration is encouraged to overcome and avoid the pitfalls in thyroid testing as well as resolve clinically discrepant results. The evidence base supporting the conclusions of this review is summarized in four detailed online technical supplements. Conclusions: Over the past five decades, testing for TSH, T4, and T3 has evolved from manual radioisotopic immunoassays to nonisotopic multiplexed immunometric assays using highly automated equipment. Despite these technical advances, physicians and laboratorians performing these analyses must understand limitations of these methods to properly order tests and interpret results.

Bones and Joints: The Effects of Cannabinoids on the Skeleton.

CONTEXT: The endocannabinoid system uses tissue-specific lipid ligands and G protein‒coupled transmembrane receptors to regulate neurologic, metabolic, and immune responses. Recent studies demonstrate that the endocannabinoid system influences bone metabolism. With the increasing use of endocannabinoid mimetics (e.g., tetrahydrocannabinol and cannabidiol), the involvement of endocannabinoids in bone growth and remodeling has become clinically relevant. EVIDENCE ACQUISITION: This literature review is based on a search of PubMed and Google Scholar databases as of June 2019 for all English-language publications relating to cannabinoids and bone. We evaluated retrieved articles for relevance, experimental design, data acquisition, statistical analysis, and conclusions. EVIDENCE SYNTHESIS: Preclinical studies establish a role for endocannabinoids in bone metabolism. These studies yield complex and often contradictory results attributed to differences in the specific experimental model examined. Studies using human cells or subjects are limited. CONCLUSIONS: In vitro and animal models document that endocannabinoids are involved in bone biology. The relevance of these observations to humans is not clear. The increasing long-term use of medical and recreational cannabis underscores the need to better understand the role of endocannabinoids in human bone metabolism. Moreover, it is important to evaluate the role of endocannabinoids as a therapeutic target to prevent and treat disorders associated with bone loss.

Point-of-Care Endocrine Diagnostics.

Endocrinology relies on hormone and metabolite measurement for public health screening, diagnostics, and disease management. Advances in microfluidics, immunoassay technology, electronics, and software are moving in vitro endocrine diagnostics from the laboratory to the point of care. Point-of-care endocrine diagnostics provide results clinically equivalent to those produced by expensive laboratory instrumentation for a fraction of the cost and with a substantially more rapid turnaround time. Similar to the transformation of mainframe computers into laptops, tablets, and smartphones, clinical laboratories are evolving into point-of-care technologies.

Newborn Thyroid Screening: Influence of Pre-Analytic Variables on Dried Blood Spot Thyrotropin Measurement.

BACKGROUND: Measuring thyrotropin (TSH) eluted from a dried blood spot (DBS) is used to screen an estimated 30 million newborns annually for congenital hypothyroidism (CH). Newborn thyroid screening has eliminated cretinism from the industrialized world and decreased the adverse effects of unrecognized CH on neurocognitive development. Hematocrit, a pre-analytic variable that affects the measurement of TSH from a DBS, contributes to the imprecision of DBS TSH measurement and could account for false-negative and false-positive DBS newborn screening test results. To assess whether variations in hematocrit found in newborns have a clinical effect in DBS-based newborn thyroid screening, the effects of hematocrit variability on the measurement of DBS TSH were studied. METHODS: U.S. Centers for Disease Control and Prevention procedures for manufacturing DBS performance testing standards were used to generate DBSs from blood samples, with hematocrits of 35%, 40%, 45%, 50%, 55%, 60%, and 65% and serum TSH concentrations of 6.3 ± 0.4 and 26.6 ± 8.0 mIU/L. TSH was measured in the eluates of four replicate DBS 3 mm punches at each hematocrit using the Thailand Ministry of Public Health Newborn Screening Operation Center enzyme-linked immunosorbent assay. Data were analyzed using a linear mixed-effects model. RESULTS: Based on the mixed-effects model, hematocrit significantly affected DBS TSH measurement (p < 0.001). A 1% increase in hematocrit resulted in a 0.06 mIU/L decrease in eluate TSH when TSH was 6.3 + 0.4 mIU/L, and a 0.21 mIU/L decrease in eluate TSH when TSH was 26.6 + 8.0 mIU/L. CONCLUSIONS: DBS TSH is significantly affected by the blood sample hematocrit. The pre-analytic variability due to hematocrit is independent of TSH assay sensitivity, specificity, precision, repeatability, and reference intervals. The effect of hematocrit on DBS TSH measurement is clinically relevant, could account for geographic and ethnic variation in the incidence of CH, and may result in both false-positive and false-negative CH screening results. Individual newborn and population-specific hematocrit correction factors may improve the precision of DBS TSH measurement.

3,5,3'-Triiodo-L-Thyronine- and 3,5-Diiodo-L-Thyronine- Affected Metabolic Pathways in Liver of LDL Receptor Deficient Mice.

3,5,3'-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e., low density lipoprotein receptor (LDLr)-knockout (Ldlr-/-) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr-/- mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α) and peroxisome proliferator-activated receptor α (PPARα), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα) nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr-/- mice.

Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex.

BACKGROUND: Establishing the reference interval for thyrotropin (TSH) and free thyroxine (T4) is clinically important because a number of disease states have been linked to alterations in TSH and free T4 concentrations that are within the 95% confidence interval for normal thyroid hormone values. Age, sex, time of day, and ethnicity are known to affect circulating levels of TSH and free T4 but have not been used to establish reference intervals. The purpose of this study was to define the reference interval for TSH and free T4 taking into account age, sex, ethnicity, and circadian and circannual variability. METHODS: We performed a retrospective analysis of 465,593 TSH and 112,994 free T4 measurements from subjects ages 1-104 years with no thyroid disease using a single TSH and free T4 immunoassay method. Boundaries for the central 95% of patient values, taking into account hour of day, day of year, sex, and age were calculated. RESULTS: Females had significantly higher TSH and free T4 levels than males; the magnitude of these differences did not exceed 0.1 mIU/L or 0.1 ng/dL respectively. Although the 2.5% TSH reference interval remains constant through the day, date, and age ranges, the upper limit (97.5%) of the TSH reference interval increases from 6.45 to 7.55 mIU/L with age, due primarily to a progressive increase in the amplitude of the nocturnal TSH surge. Additionally, significant ethnic differences in TSH circadian periodicity occur between African American, Pacific Island, and Caucasian populations. CONCLUSIONS: The reference interval for TSH varies significantly by age, sex, hour of day, and ethnicity. Time of year does not affect the TSH reference interval, and age, sex, hour of day and time of year do not affect the free T4 reference interval.

Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway.

Although studies in vitro and in hypothyroid animals show that thyroid hormone can, under some circumstances, modulate the actions of low-density lipoprotein (LDL) receptors, the mechanisms responsible for thyroid hormone's lipid-lowering effects are not completely understood. We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T(3) and 3,5-diiodo-l-thyronine. High doses of both 3,5-diiodo-l-thyronine and T(3) dramatically reduced circulating total and very low-density lipoprotein/LDL cholesterol (∼70%) and were associated with reduced plasma T(4) level. The cholesterol reduction was especially evident in the LDLR-knockout mice. Circulating levels of both apolipoprotein B (apo)B48 and apoB100 were decreased. Surprisingly, this reduction was not associated with increased protein or mRNA expression of the hepatic lipoprotein receptors LDLR-related protein 1 or scavenger receptor-B1. Liver production of apoB was markedly reduced, whereas triglyceride production was increased. Thus, thyroid hormones reduce apoB lipoproteins via a non-LDLR pathway that leads to decreased liver apoB production. This suggests that drugs that operate in a similar manner could be a new therapy for patients with genetic defects in the LDLR.

A perforated diverticulum in Cushing's disease.

We report a case of perforated colonic diverticulum in Cushing's disease. Although perforated diverticuli have been described in patients with Cushing's syndrome secondary to exogenous glucocorticoids, this complication has not been described in patients with Cushing's disease. Patients with hypercortisolism, from either exogenous or endogenous sources, should be monitored for diverticular perforation.

Neonatal age and point of careTSH testing in the monitoring of iodine deficiency disorders: findings from western Uganda.

BACKGROUND: Iodine deficiency is a major public health problem throughout Africa. Although salt for human consumption is said to contain adequate amounts of iodine in Uganda, iodine intake may not be optimal. We undertook a field study to assess the adequacy of iodine nutrition in western Uganda using on-site measurement methods of neonatal thyroid stimulating hormone (TSH) levels as recommended by the World Health Organization (WHO) for monitoring the degree of iodine deficiency during pregnancy. METHODS: The study design consisted of a prevalence study using the percentage of newborns between the ages of 3 and 7 days with TSH >5 mIU/L, measured with a point-of-care immunochromatographic TSH assay, as a surrogate marker of iodine deficiency. Five districts in western Uganda were selected for study on the basis of a past history of iodine deficiency. One thousand seventy-eight newborns from the five districts were sequentially enrolled in each separate district and tested between July 2007 and January 2008. RESULTS: The prevalence of TSH levels >5 mlU/L ranged from 20% to 32%. Neonates tested on or before the age of 3 days were more likely to have a TSH level >5 mlU/L than those tested beyond the age of three days (28.2% vs. 18.7%, p < 0.001). CONCLUSIONS: Assessing neonatal TSH levels in developing countries with a TSH assay method suitable for field use can be successfully used to screen for congenital hypothyroidism and to indirectly assess a population's iodine status. Based on the percentage of neonates with TSH values >5 mIU/L, presumptive iodine deficiency persists in western Uganda. This finding suggests that continued monitoring of iodine nutrition in the area surrounding the Rwenzori Mountains in Uganda and Congo is needed. Due to the progressive fall in the percent of TSH values >5 mIU/L from day three to day five of life, we conclude that TSH measurement earlier than day five of life in newborns at risk for iodine deficiency may be misleading. Guidelines for the use of neonatal TSH to monitor iodine nutrition should specify that TSH measurement take place no earlier than day five of life.

Phlorizin: a review.

The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia.