Background Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

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2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis

The brain of Homo habilis: A new level of organization in cerebral evolution☆

The microsurgical anatomy of the jugular foramen was studied in 10 fixed cadavers, each cadaver consisting of the whole head and neck. Five of the cadavers were injected with latex. The jugular foraminal region was exposed using the infratemporal fossa type A approach of Fisch and Pillsbury in five cadavers (10 sides) and the combined cervical dissection-mastoidectomy-suboccipital craniectomy approach in five cadavers (10 sides). The right foramen was larger than the left in seven cases (70%), equal in two cases (20%), and smaller in one case (10%). The dura covering the intracranial portal of the foramen had two perforations, a smaller anteromedial perforation through which passed the ninth cranial nerve (CN IX), and a larger posterolateral perforation, through which passed the 10th and 11th cranial nerves (CNs X and XI) and the distal sigmoid sinus. The perforations were separated by a fibrous septum in 16 specimens (80%). After exiting the posterior fossa, CNs IX, X, and XI all lay anteromedial to the superior jugular bulb (SJB) within the jugular foramen. The inferior petrosal sinus (IPS) entered the foramen between CNs IX and X in most cases; however, in 10% of our cases it entered the foramen between CNs X and XI, and in 10% it entered the foramen caudal to CN XI. The IPS terminated in the SJB in 90% of our cases; in 40%, the IPS termination consisted of multiple channels draining into both the SJB and internal jugular vein. This study shows that the arrangement of the neurovascular structures within the jugular foramen does not conform to the hitherto widely accepted notion of discrete compartmentalization into an anteromedial pars nervosa containing CN IX and the IPS and a posterolateral pars venosa containing the SJB, CNs X and XI, and the posterior meningeal artery.

The microsurgical anatomy of the jugular foramen

In 1967 Tobias noted that Australopithecus boisei cranium O.H.5 exhibited a cranial venous sinus pattern in which the occipital sinus and the marginal sinuses of the foramen magnum appeared to have replaced the transverse-sigmoid sinuses as the major venous outflow track. Specimens of A. robustus and several more recently recovered A. boisei crania also show evidence of enlarged occipital-marginal sinuses. In contrast, A. africanus and H. habilis retain a dominant transverse-sigmoid system that characterizes the great majority of extant apes and modern human cadaver samples. Pliocene A. afarensis exhibits a high frequency of occipital-marginal drainage systems. An examination of several series of precontact North American Indian crania shows that the frequency distribution of the occipital-marginal sinus pattern is spatiotemporally disjunct , ranging from 7.5% to 28%. The Late Pleistocene sample from P redmost , Czechoslovakia, also shows a very high incidence of occipital-marginal sinus patterns (approximately 45%). These observations suggest that occipital-marginal and transverse-sigmoid sinus patterns are adaptively equivalent character states. This conclusion is supported by the fact that enlarged occipital-marginal and transverse-sigmoid sinus systems often coexist on the same and/or contralateral sides of the head. It is well known that the frequencies of such adaptively neutral traits are often heavily influenced by population-specific epistatic interactions. The utilization of such traits in phylogenetic reconstruction entails a substantial risk of mistaking parallelism for synapomorphy . It is concluded that using functional-adaptive criteria in the definition of morphologic characters is a more reliable method to guide phylogeny reconstruction. In light of this, the distribution of venous sinus variants in Plio -Pleistocene hominids gives little or no basis for revising the phylogenetic scheme of Johanson and White (1979), or the functional-adaptive interpretation offered by White et al. (1981).

Variation in the pattern of cranial venous sinuses and hominid phylogeny.

The long-held concept of a proportional negative feedback control between the thyroid and pituitary gland requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic interrelationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4 and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with L-thyroxine (L-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3-FT4 dissociation, discernible FT3-TSH disjoint and conversion inefficiency have been recognised in L-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On L-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

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Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment

The authors have examined variations in shape and dimensions in the region of the terminal part of the sigmoid groove, venous portion of jugular foramen and jugular fossa with reference to age, sex, and body side. Examinations were carried out on 300 macerated skulls of both sexes within age limits of 11 up to 88 years. The specimens were divided into three age groups.

Variations in shape and dimensions of sigmoid groove, venous portion of jugular foramen, jugular fossa, condylar and mastoid foramina classified by age, sex and body side.

Despite some reports, the usefulness of levothyroxine ( LT4) and levotriiodothyronine (LT3) combination therapy in hypothyroidism remains controversial. The objective of this paper is to study a benefit of additional LT3 in athyreotic patients who failed to normalize TSH on LT4 alone even with hyperthyroid serum T4 values. In a survey of 200 athyreotic patients treated between 2006 and 2009, about 7% failed to normalize serum TSH levels following treatment with LT4, though serum T4 values in the hyperthyroid range were achieved. These patients (characterized by serum T4≥160 nmol/L and TSH≥5.0 mIU/L), were additionally treated with 10 μg b. i. d LT3. LT3 and LT4 combination therapy resulted in decreased serum TSH levels into the normal range (12.8 vs. 1.22 mIU/L; p Our results indicate a subpopulation of athyreotic patients that could significantly benefit from combined LT4 + LT3 therapy in restoring normal TSH and thyroid hormone patterns. Further research should be undertaken to provide a genetic basis for these findings.

Benefit of Combined Triiodothyronine (LT3) and Thyroxine (LT4) Treatment in Athyreotic Patients Unresponsive to LT4 Alone

Thyroid dysfunction is common in the population, especially in women, and thyroid diagnostic tests are among the most often used diagnostic procedures nowadays. Many thyroid societies developed guidelines for the detection of thyroid dysfunction. An interdisciplinary team of experts from the Croatian Thyroid Society studied guidelines of other thyroid societies and international publications, and according to our tradition and clinical practice developed guidelines for rational detection of thyroid dysfunction; hypothyroidism and hyperthyroidism. The aim of these guidelines is to recommend evidence-based and rational approach to the detection of thyroid dysfunction.

Croatian Thyroid Society guidelines for rational detection of thyroid dysfunction

The purpose of our study was to contribute to better understanding of cerebrospinal fluid (CSF) as a valuable biological material in the research of brain tumors within the "low T3 syndrome", and to discuss the role of thyroid hormones in the central nervous system in subjects with severe cerebral lesions We studied the levels of total triiodothyronine (tT3), total thyroxine (tT4), free triiodothyronine (fT3), free thyroxine (fT4), reverse triiodothyronine (rT3) and thyrotropin (TSH) in serum, and fT3, fT4, rT3 and TSH levels in CSF of patients with brain tumor, and compared the results with control group Study results indicated a statistically significantly higher level of rT3 in serum and CSF of brain tumor patients vs control group (p < 005) The rT3/fT3 ratio was highest in CSF and serum of brain tumor patients, yielding a statistically significant difference (p < 005) These results could suggest higher permeability of the blood-brain barrier in brain tumor patients We also assume that rT3, in the framework of"cerebral low T3 syndrome", is also generated through local intracerebral conversion Disruption of this process in severe cerebral lesion can lead to increased rT3 concentrations, ie development of the "low T3 syndrome"

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Brain tumor as a prototype of severe brain lesion in patients with "low T3 syndrome".

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Miljenko Solter

Papers

Variations in shape and dimensions of sigmoid groove, venous portion of jugular foramen, jugular fossa, condylar and mastoid foramina classified by age, sex and body side.

Benefit of Combined Triiodothyronine (LT3) and Thyroxine (LT4) Treatment in Athyreotic Patients Unresponsive to LT4 Alone

Croatian Thyroid Society guidelines for rational detection of thyroid dysfunction

Brain tumor as a prototype of severe brain lesion in patients with "low T3 syndrome".

Bone Remodeling and Thyroid Function