Estimation of total body iodine content in normal young men.

Total body iodine content was estimated in six normal young men, who underwent 125I balance studies during 64-92 days of daily 125I administration. Total body retention of 125I was measured as the difference between total administered 125I and that collected in the urine and feces. Extrathyroidal 125I was the difference between total and thyroidal 125I content. The time-activity data for the ratio of extrathyroidal to total retained 125I were fitted to a growth (inverse exponential) function. Fits of this growth function to the individual data sets yielded asymptotes, the equilibrium extrathyroidal/total 125I ratios. The slopes of this function predicted the time that would have been required to achieve 125I/127I equilibration (approximately 10 months). Geometric mean for the asymptotic extrathyroidal/total 125I ratio was 0.34 (range, 0.19-0.63), if it was assumed that measured urine and feces represented all of the 125I lost to the body. If 90% measurement of 125I loss was assumed, the geometric mean ratio was 0.32 (range, 0.17-0.60). Assuming that 90% of total loss is reflected in measured excreta and that total iodine content of the thyroid gland is 10 mg, geometric mean for total body iodine in these subjects was 14.6 mg (range, 12.1-25.3 mg).

A mathematical model for the distribution of fluorodeoxyglucose in humans.

UNLABELLED: The goals of this study were to define the total body distribution kinetics of 18F-fluorodeoxyglucose (FDG), to contribute to its radiation dosimetry and to define a suitable proxy for arterial cannulation in human FDG studies. METHODS: Time-activity FDG heart, lung, liver and blood data from paired fasting and glucose-loaded sessions in five adult human volunteers, together with published brain parameters, were incorporated into a multicompartmental model for whole-body FDG kinetics. Tau values were calculated from this model. We also compared the usefulness of activity in the left ventricle (LV), right ventricle (RV), left lung and right lung as proxy for arterial blood FDG sampling. RESULTS: No systematic difference was found in model parameters between the fasting and glucose-fed sessions, even for the parameter for transfer of FDG into the myocardium. Myocardial PET data fitted well to a model in which there is very rapid exchange indistinguishable from blood kinetics and transfer into an intracellular "sink." The lung data fitted to a simple sink representing the lung cells. The liver data required an additional intermediate exchange compartment between the plasma and a hepatic sink. In terms of total body distribution kinetics, unmeasured organs and tissues (probably the skeletal muscle and gut) become increasingly important with time and account for a mean of 76% of the decay-corrected FDG activity at infinity. Right lung activity, corrected to venous blood, represents the whole arterial blood curve better than the LV or RV. The tau values for radiation dosimetry of FDG in the heart, lungs, liver and bladder calculated from our model do not differ significantly from published results using other methods. Bladder tau decreased with voiding frequency and was markedly decreased with early voiding. CONCLUSION: Glucose loading state is not a good predictor of myocardial FDG uptake. The majority of FDG distribution at 90 min is in tissues other than the blood, brain, heart and liver. Bladder radiation will be much reduced if the patient voids early after FDG administration. Summed large volume right lung activity, normalized to venous blood activity, is a good proxy for arterial blood FDG sampling. The model presented may be expanded to include other FDG kinetics as studies become available.

Improving informed consent in clinical trials: a duty to experiment.

Practitioners of clinical trials have a responsibility to ensure that patients' participation in research be informed and voluntary. This responsibility implies that we should strive continuously to improve the effectiveness of methods for informing prospective research volunteers about experimental studies, thereby enhancing the protection of their interests. We should test innovations in informed consent in realistic contexts (i.e., in clinical trials) and with randomization, when it is appropriate, at the first opportunity. In this study, we develop a preliminary proposal to improve the quality of informed consent, based on experimentation with informed consent in ongoing clinical trials. We discuss the conceptual, ethical, organizational, and technical bases for such an effort.

The MIRD perspective 1999. Medical Internal Radiation Dose Committee.

The MIRD schema is a general approach for medical internal radiation dosimetry. Although the schema has traditionally been used for organ dosimetry, it is also applicable to dosimetry at the suborgan, voxel, multicellular and cellular levels. The MIRD pamphlets that follow in this issue and in coming issues, as well as the recent monograph on cellular dosimetry, demonstrate the flexibility of this approach. Furthermore, these pamphlets provide new tools for radionuclide dosimetry applications, including the dynamic bladder model, S values for small structures within the brain (i.e., suborgan dosimetry), voxel S values for constructing three-dimensional dose distributions and dose-volume histograms and techniques for acquiring quantitative distribution and pharmacokinetic data.

MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee.

The availability of quantitative three-dimensional in vivo data on radionuclide distributions within the body makes it possible to calculate the corresponding nonuniform distribution of radiation absorbed dose in body organs and tissues. This pamphlet emphasizes the utility of the MIRD schema for such calculations through the use of radionuclide S values defined at the voxel level. The use of both dose point-kernels and Monte Carlo simulation methods is also discussed. PET and SPECT imaging can provide quantitative activity data in voxels of several millimeters on edge. For smaller voxel sizes, accurate data cannot be obtained using present imaging technology. For submillimeter dimensions, autoradiographic methods may be used when tissues are obtained through biopsy or autopsy. Sample S value tabulations for five radionuclides within cubical voxels of 3 mm and 6 mm on edge are given in the appendices to this pamphlet. These S values may be used to construct three-dimensional dose profiles for nonuniform distributions of radioactivity encountered in therapeutic and diagnostic nuclear medicine. Data are also tabulated for 131I in 0.1-mm voxels for use in autoradiography. Two examples illustrating the use of voxel S values are given, followed by a discussion of the use of three-dimensional dose distributions in understanding and predicting biologic response.

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Comparative stability and clearance of [Met30]transthyretin and [Met119]transthyretin.

[Met119]Transthyretin has been described as a non-amyloidogenic transthyretin variant. In Portugal, it has also been found in compound heterozygotic individual carriers of [Met30]transthyretin, the most prevalent variant associated with familial amyloidotic polyneuropathy. In these individuals, the evolution of the disease seems to be more benign than in typical [Met30]transthyretin carriers, suggesting a protective effect of [Met119]transthyretin on the pathogenic effects of [Met30]transthyretin. To study the mechanisms of this protective effect, we performed comparative in vivo clearance studies. Heterotetrameric [Met119]transthyretin showed a slower clearance, whereas homotetrameric [Met30]transthyretin presented a faster clearance. These data correlate with the relative TTR levels present in carriers of these mutations. Comparative analyses of the resistance to dissociation into monomers of serum transthyretin by 4M urea isoelectric focusing suggested a higher tetrameric stability of transthyretin in [Met119]transthyretin carriers, in contrast to a lower stability in [Met30]transthyretin carriers. The compound heterozygotes presented a pattern similar to the normal individuals. Our results suggest that the protective clinical effect of the Met119 mutation possibly involves the stabilisation of the tetrameric structure of transthyretin. Whether this behaviour correlates with the different metabolism found for the two variants is not known. The approaches reported here open some possibilities for the study and development of future therapeutic agents of familial amyloidotic polyneuropathy.

Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice.

As part of a study on tissue uptake of thyroxine (T4) in a transthyretin (TTR)-null mouse strain, kinetic parameters of thyroxine metabolism in wild-type mice under normal physiological conditions are presented. Kinetic analysis of injected [(125)I]T4 showed that TTR-null mutants have markedly increased [(125)I]T4 transfer rate constants from plasma to the fast-exchange compartments of liver and kidney and from fast to slow kidney compartments. Transfer rates from plasma to brain, testes, and fat were little affected. The T4 tissue content in the mutants was greatly reduced in brain but relatively normal in liver and kidney. No major changes were observed in brain 3,3',5-triiodothyronine concentrations, suggesting that availability of this hormone is not markedly altered in the mutant mice. The low T4 brain content probably reflects the absence of T4-TTR complexes in the mutant choroid plexus and cerebrospinal fluid. This study indicates that TTR is not essential for T4 tissue uptake or for T4 to reach the brain across the choroid plexus-cerebrospinal fluid and/or blood-brain barriers.

Psychological stress and myocardial perfusion in coronary disease patients and healthy controls.

This study examined the effect of two different psychological stressors on regional cardiac perfusion in six men with coronary heart disease (CHD) and nine healthy controls. Subjects recalled an anger experience and an anger plus helpless (i.e., Desperation Recall Task) experience during positron emission tomography (PET). Emotional reactivity, blood pressure, and heart rate were also assessed. Experimental manipulations generated significant emotional and cardiovascular reactivity. Cardiac perfusion to diseased myocardial segments failed to show any significant differences between CHD patients' diseased segments and controls' healthy segments for the Anger Recall task or the Desperation Recall Task. Results failed to confirm previous findings of coronary artery constriction while reliving an angry experience, yet are consistent with other studies utilizing mental arithmetic. Vasoactive medication use, sample size, and perfusion variability may have contributed to these findings.

Erythropoietin can be administered during dialysis. A kinetic analysis.

The pharmacokinetics of intravenous recombinant erythropoietin administered during or after dialysis were studied by multicompartmental analysis in eight patients with end-stage renal disease to determine whether significant loss of the drug occurred during the hemodialysis procedure. Each patient had five studies, one in which the erythropoietin was given near the end of a dialysis session (baseline). In the other studies, erythropoietin was administered at the beginning of hemodialysis for 4 hrs using each of four different dialysis membranes. Both two compartment and three compartment models were used. In the two compartment solutions, the mass of the exchange compartment was significantly increased in the studies done during dialysis compared with the baseline. Clearance did not change significantly among the study sessions. When a third compartment, representing the dialysis system, was added, the kinetics of the internal exchange compartment and of the dialysis system could be determined separately. At the end of 4 hrs of dialysis after the erythropoietin dose, the dialysis systems contained an average of 7% of the administered dose. It was concluded that hemodialysis immediately after erythropoietin administration does not affect the rate of erythropoietin loss, except for small losses in the dialysis system itself when it is removed at the termination of the procedure.

Thyroid hormone metabolism. A comparative evaluation.

Knowledge of thyroid hormone and iodide metabolism is derived from a combination of in vivo and in vitro studies in a variety of mammalian species including cats, dogs, and humans. Each species provides a unique opportunity to investigate various aspects of normal or altered thyroid hormone physiology. Availability of sensitive and specific human TSH assays has allowed detailed studies of the human hypothalamic-pituitary-thyroid axis which have not been possible in cats and dogs to date. Similarities and differences of thyroid hormone metabolism in dogs, cats, and humans provide the basis for a better understanding of normal physiology as well as shedding light on the significance of changes induced by spontaneous or induced thyroidal and nonthyroidal disorders.

Changes in serum triiodothyronine kinetics and hepatic type I 5'-deiodinase activity of cold-exposed swine.

Swine exposed to cold air have elevated serum values of total triiodothyronine (TT3) and free T3 (FT3). To characterize the mechanism of these increases, we measured in vivo kinetic parameters after a bolus intravenous injection of 125I-labeled T3 by use of both multicompartmental (MC) and noncompartmental (NC) methods and in vitro hepatic type I iodothyronine 5'-deiodinase (5'D-I) activity. Ten ad libitum-fed 5-mo-old boars were divided into two groups, living for 25 days in either control (22 degrees C) or cold (4 degrees C) conditions. Cold-exposed animals consumed 50% more calories than control animals but showed no difference in total body weight, percent body fat, or plasma volume. Thyroid gland weight was increased 86% (P < 0.004), as was serum total thyroxine (TT4) (48%), free T4 (FT4) (61%), TT3 (103%), and FT3 (107%), whereas serum thyrotropin (TSH) was not different in cold-exposed compared with control animals. The T3 plasma clearance rate was similar between groups when both MC and NC techniques were used. However, T3 plasma appearance rate (PAR) was elevated in cold-treated animals 110% over controls by MC (P < 0.001) and 83% by NC methods (P < 0.001). The animal total hormone pool of T3 was increased 76% (MC) and 53% (NC) compared with control (P < 0.01). The Michaelis constant of hepatic 5'D-I was not different between groups, but the maximum enzyme velocity increased (106%; P < 0.02). Therefore cold exposure for 25 days is associated with increased energy intake, thyroid size, T3 PAR, and hepatic 5'D-I activity with little change in serum TSH.

Multicompartmental analysis of triiodothyronine kinetics in hypothyroid patients treated orally or intravenously with triiodothyronine.

Kinetic studies were performed with i.v. 125I T3 in four athyreotic women on two occasions each, once while they were taking oral T3 (30 micrograms T3 every 12 h) and again while on i.v. T3 replacement (same dosage schedule). The kinetic data were analyzed by a 7-compartment model, representing the plasma volume, the fast and slow peripheral exchange compartments, the iodide pool (as a delay compartment prior to appearance in the urine), the intestine (as a delay compartment before appearance in the feces), and the urine and feces. Modeling was done by the SAAM methodology. All data sets, and also the mean data treated as though they were data from a single subject, were fitted for the two limit solutions in which all metabolism was assumed to be in one or the other of the exchange compartments. The mean data set was also fitted to a solution in which limits were imposed on the excretion parameters and the partition of metabolism between the 2 peripheral exchange compartments was estimated. We found that steady-state parameters for removal of T3 from the circulation (the MCRs and DRs) were increased during the i.v. T3 replacement period compared with the oral replacement period, especially in the fast exchange compartment. Measured serum stable T3 levels (RIA) were lower in the i.v. than in the oral study, both at 8 and at 12 h after the most recent T3 dose. These values corresponded to similar differences in the circulating T3 levels projected from the model, although the T3 values projected from the model were greater than the measured T3 levels for unknown reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

Human thyroxine absorption: age effects and methodological analyses.

Experience with the use of simultaneous oral and iv radioiodine tracers of thyroxine (T4) to measure T4 absorption was reviewed to determine the effect of advanced age on T4 absorption and to search for acceptable simplifications in the measurement methodology. (1) Age effect: In control subjects, T4 absorption did not differ with age between 21 and 69 years; it averaged 62.8 +/- 13.5% (SD) in subjects over age 70 compared with 69.3 +/- 11.9% in subjects aged 21-69 (p < 0.001). We conclude that, because of this small but significant reduction in T4 absorption efficiency in the elderly, it is especially important to monitor individual response to replacement T4 doses in this age group. (2) Methodology studies: Intrasubject coefficient of variation for T4 absorption in triplicate studies averaged 8.9%, when an identical method was used at weekly intervals (n = 3). When the 3 studies were done by 3 separate methods (sequential po and i.v. 123I-labeled T4, sequential 125I-labeled T4 po and i.v., and simultaneous po and i.v. doses of different tracers), the intrasubject coefficient of variation averaged 9.8% (n = 8). When the absorption calculation used only one serum sample, taken after isotopic equilibrium was achieved at 24 h [the double isotope (eq) method], calculated T4 absorption differed little from that calculated in the same subjects using a full serum time-activity curve and a noncompartmental analysis [the double isotope (AUC) method]. Compared with a compartmental model solution, both methods slightly overestimated T4 absorption. In 4 subjects given i.v. radioiodide as a third tracer at the same time demonstrated that, as long as radioiodide contamination of the T4 tracers is measured and accounted for in the standards, contaminating radioiodide has no clinically significant effect on T4 absorption measurements. When an oral tracer of T4 was considered alone, without an i.v. tracer to correct for T4 metabolism, the estimates of T4 absorption correlated in a curvilinear fashion with T4 absorption as measured by the double isotope method. Except at very low absorption levels, the oral tracer alone is a poor predictor of T4 absorption. We conclude that, when using a double isotope method to measure T4 absorption, it is acceptable to rely on a single serum sample taken at 24 h, a time when isotopic equilibrium between the two tracers has been reached.(ABSTRACT TRUNCATED AT 400 WORDS)

Circulating 131I thyroxine and thyroid cancer.

We have developed a blood test to detect the presence of thyroactive tissues in patients being evaluated for ablative therapy of differentiated thyroid carcinomas. This test is based on the assumptions that if any thyroactive tissue is present, some radioactive T4 will be manufactured after administration of radioiodide, and that some of it will be released into the circulation. Twenty serum samples obtained from 19 patients at the time of total body 131I scanning to evaluate for the need of further 131I therapy were analyzed chromatographically, together with an internal 125I T4 marker, for the presence of 131I-labeled T4. Three patients also were studied 7 days after a treatment dose of 131I, when they returned for posttreatment scan. The chromatographic method used (Sep-Pak followed by HPLC) removes all radioiodide from the T4 fraction, so the results were interpreted as negative or positive based upon the absence or presence of detectable counts in the T4 fraction. Twelve patients (16 studies) with positive total body 131I scans all demonstrated circulating 131I T4. Seven patients with negative whole body scans were all negative for 131I T4. On the other hand, 2 patients with positive thyroglobulin assays had negative total body scans and 131I T4 tests. Both of them had independent evidence of the presence of thyroid cancer that did not concentrate radioiodine. Three patients had positive scans and 131I T4 tests but negative thyroglobulin assays. We conclude that measurement of circulating radioactive T4 is a sensitive test for the presence of normal or malignant thyroactive tissues which are likely to respond to 131I ablation.

Colonic excretion of iodide in normal human subjects.

Patterns of fecal radioiodine excretion were studied in seven normal young men with intact, unblocked thyroid glands, who received repeated oral daily doses of [125I]iodide in an attempt to achieve isotopic equilibrium. Fecal radioactivity was assumed to have originated either in the circulating inorganic radioiodine (radioiodide) compartment or in the circulating hormonal protein-bound iodine (PBI) compartment. Activity in the PBI compartment was measured directly in serum samples from which radioiodide had been removed by dialysis or resin treatment. Activity in the radioiodide compartment was measured by the difference between total and hormonal radioiodine, and also as a projection from the rate of urinary excretion of radioiodine. These compartments were fitted to the observed sequential fecal radioiodine data in each subject to identify the origins of the fecal radioactivity, using the SAAM modeling program. The fraction of fecal radioactivity attributable to iodide was 0.55 +/- 0.35 (mean +/- SD) (geometric mean 0.44, range 0.25-0.96). In all cases, at least some contribution from the iodide compartment was required for model fit to the observed pattern of fecal radioiodine excretion. These data demonstrate that, despite long-existing opinion to the contrary, iodide is an important component of intestinal iodine excretion in humans. This finding explains the presence of colonic activity in postradioiodide images of athyreotic patients.

Deiodination and deconjugation of the glucuronide conjugates of the thyroid hormones by rat liver and brain microsomes.

Radioiodinated thyroxine (T4) glucuronide (T4G) and triiodothyronine (T3) glucuronide (T3G), paired with T4 or T3, were incubated at 37 degrees C for 2 hours in the presence of dithiothreitol and microsomes that had been prepared from euthyroid rat liver or hypothyroid rat brain tissues, as sources of type I and type II iodothyronine 5'-deiodinases, respectively. Incubations with boiled microsomes served as controls. The incubated supernatant was analyzed by high-pressure liquid chromatography (HPLC) for content of T4, T4G, T3, T3G, and combined T2 and T2G. The deiodination of T4G resulted from incubation with both liver and brain microsomes, but was somewhat less active than the deiodination of simultaneously incubated T4. All batches of microsomes studied also caused deconjugation of both T4G and T3G. The data are compatible with the hypothesis that T4G can serve as an alternate pathway for conversion of T4 to T3 in these tissues.

Transport of the thyroid hormones across the feline gut wall.

Intestinal absorption of radioiothyroxine (T4*) and of radiotriiodothyronine (T3*) was studied in normal cats (n = 5 for T4* and n = 6 for T3*). Absorption was localized by a series of studies comparing the time-activity data for plasma and fecal T4* or T3* radioactivity after i.v. administration with data obtained in the same cats after administration by the oral, jejunal, midileal, and cecal routes. Data were analyzed using a multicompartmental model to account for longitudinal gut transit, metabolic loss, and reversible and irreversible binding, as well as absorption. The relative importance of the gut as a site for T4* or T3* residence at steady state was determined from T4* (n = 6) and T3* (n = 3) content of gut wall and contents at the end of tracer infusion to steady state. Secretion of T4* and T3* from the general pool into the various parts of the gut was calculated from the steady-state data by fitting them to the model using its steady-state parameters. Secretion parameters were adjusted in this fitting process, which established the rate and sites of T4* and T3* secretion into the gut. Overall, feline absorption of T4* and T3* is low compared with absorption in human subjects. Gentamicin treatment enhanced T3* absorption, but general wasting (weight loss associated with time under study) had no effect on either T4* or T3* absorption. The most important site for absorption of both T4* and T3* is the jejunum-upper ileum bowel segment. However, when the mass of gut wall in each segment is taken into account, absorption rate is highest at the duodenum and decreases distally. Secretion of both T4* and T3* is most active into the duodenum, presumably largely through the bile. In addition, there is active secretion of both T4* and T3* into the ileum and of T4* into the colon. These studies indicate that T4* and T3* absorption and secretion balance to make the gut an important locale for both hormones. Because of the cat's relatively low T4 and T3 absorption rates, much of the gut contents are destined for excretion. However, an active secretion-reabsorption loop for both T4* and T3* is present.

Localization of human thyroxine absorption.

The distribution of intestinal absorption of 131I-labeled thyroxine (T4*) was studied in 4 normal subjects after oral and i.v. T4*, given in separate experimental sessions. In addition to collection of time-activity curves for plasma T4* from the two sessions, distribution and transport of T4* through the gut was quantified by external imaging. Time-activity curves were obtained for the stomach, duodenum, and upper jejunoileum. A multicompartmental model for systemic T4, with three distribution compartments and a single exit route, was employed. Additional, gastrointestinal, compartments were introduced. The stomach data were fitted to a model with three compartments, two for transport and a small sink of gastric activity that does not interact with the absorptive sites. Transfer from the duodenum to the upper jejunoileum and from the upper to the lower jejunoileum was modeled from fits to the peak T4* activities in the images of the duodenum and upper jejunoileum. The rate of transfer from the lower jejunoileum into more distal intestinal sites was fixed, but the impact on the results of using various values for this parameter was analyzed. The model calculations of absorption (mean +/- SD for 3 of the subjects) are duodenum, 15 +/- 5%, upper jejunoileum, 29 +/- 14%, and lower jejunoileum, 24 +/- 11%. The fourth subject, whose global absorption was abnormally low for uncertain reasons, had 17% absorption from the duodenum, 9% from the upper jejunoileum and none from the lower jejunoileum. Model projections mimicking clinical gut abnormalities known to affect T4 absorption were compatible with the results of published studies.