David H. Sarne

Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state.

Hyperthyroidism has been reported to affect all of the major determinants of left ventricular performance in a manner that would augment ventricular shortening characteristics. The hypothesis tested in this study is that reduced afterload in conjunction with increased preload and heart rate, rather than augmented contractility, accounts for much of the increase in left ventricular performance noted previously in these patients. To investigate this hypothesis, 11 hyperthyroid patients were evaluated serially over 4 +/- 2 months. With therapy, serum total thyroxin (T4) decreased significantly (p less than 0.001). Ventricular hemodynamics were assessed by two-dimensional targeted M-mode echocardiograms and calibrated carotid pulse tracings. Ventricular preload was estimated by end-diastolic dimension, whereas afterload was measured as end-systolic wall stress. Overall left ventricular performance was quantitated by the extent and velocity of shortening, whereas myocardial work was assessed by ventricular systolic stress-length relations. With therapy, overall left ventricular performance declined (p less than 0.01). This change was associated with no change in end-diastolic dimension or end-systolic wall stress, and a 24% fall in heart rate (p less than 0.01). This latter finding has been shown previously to have no significant effect on left ventricular contractile state over the range of heart rates encountered in this study. In all cases, the end-systolic stress/rate-corrected shortening velocity relation fell with attainment of normal thyroid status, characteristic of a decline in contractility. There was a strong positive correlation between left ventricular contractility and serum thyroid hormone level (r = 0.83). In addition, ventricular minute work declined with therapy (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term risks for thyroid cancer and other neoplasms after exposure to radiation.

Radiation-related thyroid cancer continues to be a clinical concern for two reasons: the risks associated with the widespread use of radiation treatments for benign conditions in the middle of the last century persist for decades after exposure; and radiation continues to be an effective component of the treatment of several childhood malignancies. Patients who were irradiated in the head and neck area need to be evaluated for thyroid cancer, benign thyroid nodules, hyperparathyroidism, salivary-gland neoplasms and neural tumors, including acoustic neuromas. Radiation-related thyroid cancers appear to have the same clinical behavior as other thyroid cancers, but many irradiated patients are entering the age range when more aggressive neoplasms occur. In this paper, we review how to approach the clinical management of a patient with a history of radiation exposure in the thyroid area, and how to treat radiation-exposed patients who develop related neoplasms, especially thyroid cancer.

Variant thyroxine-binding globulin in serum of Australian Aborigines: its physical, chemical and biological properties

Low serum total thyroxine (TT4) and triiodothyronine (TT3) is found in approximately 40% of Australian Aborigines. Studies were carried out to characterize the properties of thyroxine-binding globulin (TBG) in these Australian Aborigines to explain the observed reduction of thyroid hormone concentration in their serum. TBG from Aborigines with low serum TT4 concentrations was compared to TBG fram Aborigines with normal TT4 concentration and Caucasians and American Blacks with normal or reduced serum TBG levels due to familial partial TBG deficiency. TBG from Aborigines with low serum TT4 concentrations had a reduced affinity for thyroid hormone (Ka). The Ka for T4 was 54% and for T3 30% of the Ka values for TBG from Aborigines with normal TT4 concentration or non-Aborigines. Maximal binding values were in agreement with TBG measurements by RIA for Aborigines with low or normal serum TT4 and for non-Aborigines. An increase in the rate of heat denaturation of TBG at temperatures from 54 to 60 C was also observed in sera from Aborigines with low TT4. The heat lability was lowered by 2 C. The low concentration of TT4 in serum of these Aborigines could not explain this higher heat lability of TBG since only addition of greater than 80-fold the physiologic T4 concentration obliterated the difference of heat inactivation by denaturation. Nevertheless, decreased T4 occupancy of this TBG with lower affinity for thyroid hormone may explain reduced stability at high temperatures. There were no differences in the microheterogeneity by isoelectric focusing between TBGs from Aborigines with low serum TT4 concentration and those with normal TT4 or non-Aborigines. From data on maximal binding capacity and TBG measurement by radioimmu-noassy it could be determined that TBG in these Aborigines as in non-Aborigines has a single thyroid hormone binding site. These results indicate that euthyroid Aborigines with low serum TT4 and TT3 concentrations have a variant TBG with reduced affinity for these hormones. The difference between this variant TBG as compared to the more common type of TBG in non-Aborigines appears to reside in the polypeptide chain rather than in the carbohydrate moiety. It fully accounts for the reduced serum total thyroid hormone concentration in the presence of clinical euthyroidism with normal serum free T4 and thyrotropin levels.

Computerized physician order entry of medications and clinical decision support can improve problem list documentation compliance

OBJECTIVE The problem list is a key and required element of the electronic medical record (EMR). Problem lists may contribute substantially to patient safety and quality of care. Physician documentation of the problem list is often lower than desired. Methods are needed to improve accuracy and completeness of the problem list. DESIGN An automated clinical decision support (CDS) intervention was designed utilizing a commercially available EMR with computerized physician order entry (CPOE) and CDS. The system was based on alerts delivered during inpatient medication CPOE that prompted clinicians to add a diagnosis to the problem list. Each alert was studied for a 2-month period after implementation. MEASUREMENTS Measures included alert validity, alert yield, and accuracy of problem list additions. RESULTS At a 450 bed teaching hospital, the number of medication orders which triggered alerts during all 2-month study periods was 1011. For all the alerts, the likelihood of a valid alert (an alert that occurred in patients with one of the predefined diagnoses) was 96+/-1%. The alert yield, defined as occuring when an alert led to addition of a problem to the problem list, was 76+/-2%. Accurate problem list additions, defined as additions of problems when the problem was determined to be present by expert review, was 95+/-1%. CONCLUSION The CDS problem list mechanism was integrated into the process of medication order placement and promoted relatively accurate addition of problems to the EMR problem list.

EXTERNAL RADIATION AND THYROID NEOPLASIA

Radiation remains the only factor that has been shown unequivocally to cause (nonmedullary) thyroid cancer. Recent advances include the analysis of the dose-response relationship using data pooled from multiple studies. This analysis confirms that radiation-induced thyroid cancers continue to occur, with a maximum risk at approximately 30 years after exposure. Physicians asked to evaluate patients with a history of radiation exposure should attempt to estimate the dose from the history and should be familiar with the other risk factors. For some individuals, screening should include thyroid imaging, but the results of such imaging, especially with thyroid ultrasound, should be interpreted with caution. The treatment of radiation-induced thyroid cancers is based on the observation that they appear to be no more aggressive than thyroid cancers not associated with radiation. In the future, more information should emerge about the role of cancer genes and susceptibility factors in radiation-induced thyroid cancer.

Variant thyroxine-binding globulin in serum of Australian Aborigines: a comparison with familial TBG deficiency in Caucasians and American Blacks

About 40% of clinically euthyroid Australian Aborigines have low concentrations of total thyroxine (TT4) and triiodothyronine (TT3) in serum. While the finding of normal concentrations of serum thyrotropin (TSH) in such individuals is compatible with their eumetabolic state, the reason for the finding of a low free T4 index (FT4I) has been unclear. A genetic variant of T4-binding globulin (TBG) with reduced affinity for T4 has been suggested but decrease in the absolute concentration of TBG has also been reported. In this study, we measured various parameters of thyroid function in 20 serum samples from euthyroid Australian Aborigines selected for their low TT4 levels. Results were compared to those obtained in serum samples from Caucasians and American Blacks with inherited partial TBG deficiency, 15 of which were matched to the Aborigines by their TBG and 20 by their TT4 concentrations. Results were also compared with those from another group of 20 samples from Caucasians and American Blacks with normal TBG concentration, matched to the Aborigines by their serum TT4 concentration. TBG in serum from these Australian Aborigines was immunologically identical to that in Caucasians and American Blacks in terms of parallelism of serially diluted samples in the TBG radioimmunoassay (RIA). Comparison of measurements of TBG concentration by RIA and by T4-binding capacity (CAP) gave identical results indicating that, in Aborigines as in non-Aborigines, TBG molecules have a single T4-binding site. Serum TBG concentration in this group of Aborigines with lowTT4was 1.1 ± 0.3 mg/dl (mean ± SD) and significantly lower (p< 0.001) than that in non-Aborigines of 1.6 ± 0.2 mg/dl. When the Aboriginal samples were matched to euthyroid Caucasians and American Blacks by their TBG concentration, their mean TT4 concentration was significantly lower (4.1 ± 0.8µg/dl vs. 5.6 ± 1.1 µg/dl, p < 0.001), as was their mean TT3 concentration (88 ± 17 ng/dl vs. 139 ± 27 ng/dl, p < 0.001). In contrast when matched by their TT4 concentration, the mean serum TBG level was significantly higher (1.1 ± 0.3 mg/dl vs. 0.7 ± 0.3 mg/dl, p < 0.001). TSH concentration was normal and not significantly different in the Aborigines and the two non-Aboriginal groups with familial partial TBG deficiency. All serum samples from non-Aborigines with normal TBG which were matched to the Aborigines by their TT4 concentration had high serum TSH values and thus belonged to patients with primary hypothyroidism. The mean FT4I value was significantly (p < 0.001) lower in the Aborigines (4.9 ± 1.0) as compared to the two euthyroid non-Aboriginal groups matched by their TBG or TT4 (7.4 ± 0.8 and 7.5 ± 1.3, respectively). In contrast, the free T4 (FT4) values measured by equilibrium dialysis in 5 Aboriginal samples spanned over the same normal range as that of 8 euthyroid non-Aborigines. There was an excellent correlation between the FT4I and FT4 in both Aborigines and non-Aborigines (r = 0.957 and 0.918 respectively). However, the slopes of the two regression lines were significantly different (p < 0.001). These results indicate that the degree of reduction of TT4 and TT3 concentration in euthyroid Australian Aborigines cannot be explained solely on the basis of diminished serum TBG level. They support the hypothesis that such individuals have a variant TBG with reduced affinity for T4 and T3.

Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions

Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormone in serum. In 1989, a variant TBG was reported with reduced binding affinity for thyroxine (T4) and triiodothyronine (T3) which results in low serum T4 and T3 levels. This variant, TBG-San Diego (TBG-SD), also displays reduced heat stability but has a normal isoelectric focusing pattern. We now report the sequence of the entire coding region of TBG-San Diego. It reveals two nucleotide substitutions: one located in exon 1 which results in the replacement of the normal Ser-23 (TCA) with threonine (ACA) and the other, located in exon 3, changes the normal codon 283 of TTG (leucine) with that of TTT, (phenylalanine). Allele specific amplification was used to search for both nucleotide substitutions in four affected members of the family. Results confirmed the co-segregation of these nucleotide substitutions with the TBG-SD phenotype. The substitution in codon 283 has been previously described and exists as a polymorphism in some ethnic groups or in combination with other TBG variants with different physical characteristics. Thus, it appears that the replacement of Ser-23 with threonine is responsible for the observed alterations in physical properties of TBG-San Diego.

A Piece of the Puzzle: What Does BRAF Status Mean in the Management of Patients with Papillary Thyroid Carcinoma?

This is a copy of an article published in the Journal of Clinical Endocrinology and Metabolism

Serum Thyrotropin and the Assessment of Thyroid Status

Excerpt Since their relatively recent introduction into clinical practice, sensitive immunoassays for serum thyrotropin have enhanced the ability of clinicians to firmly establish diagnoses which w...

Normal Cellular Uptake of Thyroxine (T4) from Serum of Patients with Familial Dysalbuminemic Hyperthyroxinemia (FDH) or Elevated Thyroxine-Binding Globulin (TBG): T4 Bound to Albumin is not Preferentially Transferred to Tissue

Only free thyroid hormone is thought to enter cells and be metabolically active while protein bound thyroid hormone, in equilibrium with the free fraction, remains in the intravascular compartment (1). Evidence that albumin-bound T4 preferentially enters hepatocytes (2) and that subjects with FDH have increased hepatic T4 delivery (3) have challenged this concept. We examined the in vitro cellular uptake of T4 by human hepatocytes, Hep G2 (4), from serum of subjects with FDH. Results were compared to those from sera matched to the FDH sera by total T4 concentrations and obtained from individuals with high TBG or thyrotoxicosis.