Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas.

CONTEXT: Changes in thyroglobulin (Tg) and/or Tg antibody (TgAb) methods can disrupt the serial monitoring of differentiated thyroid carcinoma (DTC) patients. OBJECTIVE: This study compared Tg measurements made in TgAb-negative and TgAb-positive sera using four RIA and 10 immunometric assay (IMA) methods. DESIGN: TgAb detection using a panel of 12 direct methods was contrasted with four Tg recovery tests. Sera from 110 normal euthyroid subjects (68 TgAb negative/42 TgAb positive) and 131 TgAb-negative DTC patients had Tg and/or TgAb analyses made by 10 laboratories in four countries. Euthyroid controls were used to compare Tg and TgAb ranges, sensitivities, and TgAb interference, whereas DTC patients were used to study Tg assay specificities, hook effects, and the influence of high Tg levels on TgAb measurements. RESULTS: Tg methods had high between-method variability [47 +/- 3% (+/-sem)] that was only marginally reduced by CRM-457 standardization (37 +/- 3%). All methods had suboptimal sensitivity, and some failed to detect Tg in some normal euthyroid controls. Although direct TgAb measurements were more reliable than exogenous recovery tests, TgAb status was only concordant in 65% of sera. Only four of 42 (9.5%) sera containing TgAb had antibody detected by all direct methods. All IMA methods reported paradoxically undetectable Tg for many TgAb-positive euthyroid controls, suggesting TgAb interference, whereas RIA methods reported appropriate normal range values for these same subjects. Some sera displaying interference had TgAb detected by only a minority of methods. CONCLUSIONS: Specificity differences, suboptimal sensitivity, hook effects, and an inability to reliably detect interfering TgAb compromise the clinical utility of current Tg and TgAb methods. All of the IMA methods were prone to underestimate serum Tg in the presence of TgAb, whereas the RIA methods appeared resistant to TgAb interference.

Follicular lesions of thyroid: a 5-year fine-needle aspiration experience.

BACKGROUND: Fine-needle aspiration (FNA) of the thyroid is of limited value in discriminating between nonneoplastic and neoplastic lesions in approximately 5-29% of patients. Indeterminate lesions are due primarily to the overlapping cytologic features found in follicular lesions. In this report, the authors describe their experience with FNA biopsy of the thyroid, concentrating on the analysis of those aspirates placed in the follicular lesion category. METHODS: A blinded, retrospective analysis of 92 patients who underwent FNA and were diagnosed with follicular lesions was performed by three of the authors (T.S.G., B.D.F., and M.O.) at a multihead microscope. A worksheet assessing a variety of cytologic and architectural features was filled out for each FNA patient. The reviewers then reached a consensus diagnosis. RESULTS: The reviewers agreed with the reported FNA diagnosis of follicular lesion in 63 of the 92 patients studied. No distinguishing cytologic features predictive of the histologic outcome were found in any of these 63 patients. Seven patients were judged by the reviewers to have insufficient cells for evaluation. In the remaining 22 patients, the reviewers' diagnoses were in agreement with the histologic diagnoses in 17 patients. CONCLUSIONS. The authors found that there is a gray area in the cytologic diagnosis of patients with thyroid lesions by FNA due to inherent similarities at the light microscopic level. However, increased specificity may be achieved by careful attention to cytologic features and morphologic detail. Skillful application of FNA techniques, with the recovery of an adequate sample, will further decrease both interpretive errors and the number of patients diagnosed with "follicular lesions."

Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement.

Thyroglobulin (Tg) measurement is primarily used to monitor patients with differentiated thyroid carcinoma (DTC) for tumor recurrence. Serum Tg levels principally integrate 3 variables: the mass of thyroid tissue present (benign or neoplastic); the degree of thyrotropin (TSH) receptor stimulation and tumor's intrinsic ability to synthesize and secrete Tg--a factor that needs to be assessed by a preoperative serum Tg determination. Serum Tg measurements should be interpreted relative to the TSH status of the patient. When TSH is low (on levothyroxine [LT4] therapy) basal serum Tg may be undetectable and recombinant human thyrotropin (rhTSH) administration may be needed to increase serum Tg into the measureable range. The Tg fold response to rhTSH (rhTSH-stimulated Tg/basal Tg) is an index of the tumor's sensitivity to TSH. Normal thyroid remnant and well-differentiated thyroid tumors display a greater (>10-fold) serum Tg response to TSH stimulation compared with less well-differentiated tumors (<3-fold). The factors influencing the response include the magnitude and chronicity of the serum TSH elevation, the mass of thyroid tissue and the TSH receptor status of the tumor. Technical problems still compromise the clinical utility of serum Tg measurement. Thyroglobulin autoantibodies are present in approximately 20% of all DTC patients and cause either underestimation or overestimation of serum Tg measurements made by immunometric assay (IMA) and radioimmunoassay (RIA) methods, respectively. Other technical problems include poor interassay precision, "hook" effects (IMA methods), intermethod standardization differences, and suboptimal sensitivity for detecting small amounts of tumor during TSH suppression. When TSH is suppressed, the basal serum Tg provides an integrated index of thyroid tissue mass and its capability to secrete Tg. Serial measurements of basal Tg concentrations can be used to monitor tumor progression or regression. The development of a low (<1 ng/mL) serum Tg (on LT4 therapy) by the second postoperative year signifies a low 5-year recurrence risk whereas a rising serum Tg in the face of TSH suppression is an abnormal response consistent with recurrence. The optimal degree of TSH suppression for a patient should be based on clinical judgment, relative to tumor staging and the risks from iatrogenic hyperthyroidism. Despite current technical limitations, serum Tg measurement is the cornerstone of long-term monitoring for most DTC patients. For optimal use of serum Tg, it is necessary to understand the pathophysiology of Tg secretion, the limitations of Tg methods and the use of rhTSH to overcome the insensitivity of current Tg methods.

Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma.

The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid peroxidase) was increased nearly 3-fold in patients with differentiated thyroid cancers (DTC) compared with the general population (40% vs. 14%, respectively). Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC patients and 10% of the general population. Serial postsurgical serum TgAb and serum Tg patterns correlated with the presence or absence of disease. Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two immunometric assay (IMA) methods to study TgAb interference. TgAb interference, defined as a significant intermethod discordance (>41.7% coefficient of variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera, was found in 69% of the TgAb-positive sera. TgAb interference was characterized by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in sera containing high TgAb concentrations. However, some sera displayed marked interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL) causing interference. Exogenous Tg recovery tests were an unreliable means for detecting TgAb interference. Specifically, the exogenous Tg recovered varied with the type and amount of Tg added and the duration of incubation employed. Further, recoveries of more than 80% were found for some sera displaying gross serum RIA/IMA discordances. The measurement of serum Tg in DTC patients with circulating TgAb is currently problematic. It is important to use a Tg method that provides measurements that are concordant with tumor status. IMA methods are prone to underestimate serum when TgAb is present, increasing the risk that persistent or metastatic DTC will be missed. The RIA method used in this study provided more clinically appropriate serum Tg values in the group of TgAb-positive patients with metastatic DTC. Furthermore, as serial serum TgAb measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may be an additional clinically useful tumor marker parameter for following TgAb-positive patients. Disparities between serial serum Tg and TgAb measurements might alert the physician to the possibility of TgAb interference with the serum Tg measurement and prompt a more cautious use of such data for clinical decision-making.

Influence of root anatomy on periodontal disease.

One of the essential elements of periodontal therapy is long-term maintenance. Anatomic factors that favor localized plaque accumulation may contribute to the progression of disease. The purpose of this investigation was to evaluate the influence of root concavities on the severity of furcation involvement. Measurements were recorded clinically at the time of surgical treatment. Statistical analysis revealed no significant association between the degree of root concavity and the severity of furcation involvement.

Laboratory tests for thyroid disorders.

The evolution in thyroid function tests since the 1960s has improved the physician's proficiency in accurately identifying thyroid dysfunction in a patient with suspected thyroid disease. The mainstays of modern thyroid testing strategies are the serum TSH concentration and AMA (anti-TPO) titer. The TSH level serves as an endogenous indicator of the biologically active free T4 fraction and, as a result, is currently the best gauge of the thyroid status of an individual. In addition, the TSH level has other advantages over free T4 estimates in confirming the presence of thyroid disease. First, each individual has his or her own free T4-TSH setpoint, whereby any deviation from this genetically determined relationship changes the serum TSH level. Second, owing to the local nature of the T4 feedback at the pituitary, these alterations in serum TSH values amplify small changes in circulating free T4 values. The net result of these unique attributes of measuring TSH is the ability to detect thyroid dysfunction early in the course of thyroid disease. There are limitations to the use of a TSH determination as a single thyroid function test, however. They include the presence of hypothalamic or pituitary disease or concurrent nonthyroidal illness and the immediate treatment of either hyperthyroidism or hypothyroidism. Because the majority of thyroid diseases involves autoimmune processes of the thyroid gland, the inclusion of an AMA titer in any approach to thyroid testing enhances both the diagnostic and prognostic expertise of the physician. In conclusion, currently available thyroid function tests have enhanced the diagnostic skills of the physician, but their effectiveness relies on clinical judgment rather than guidance from protocol or random application.

Microleakage of CAD-CAM porcelain restorations.

PURPOSE: To evaluate the microleakage of CAD-CAM porcelain inlay restorations cemented with four different dual cure resin cements. MATERIALS AND METHODS: Thirty human extracted caries-free molar teeth were prepared with a Class II MOD cavity design. One proximal box ended on enamel and the other on root surface dentin. The teeth were divided into six groups of five samples each. Two groups were restored with a direct placement composite resin to serve as a control. The other four groups were restored with CAD/CAM-generated ceramic inlays that were cemented with four dual cure resin cements. All specimens were thermocycled. Microleakage of the restorations was assessed by dye penetration. RESULTS: Compared to direct placement resin composite which demonstrated an excellent enamel marginal seal, CAD/CAM-generated porcelain inlays produced excellent marginal seals at both the enamel and dentin interfaces.

Removal of enamel surface stains with at-home vital bleaching.

PURPOSE: To report the results obtained with an at-home bleaching product in the removal of enamel surface stains. MATERIALS AND METHODS: An individualized vacuum-formed mouthguard was fabricated and scalloped so that the terminal portion of the mouthguard ended approximately 1.0 mm from the gingiva. The patient was instructed to brush his teeth with Rembrandt Whitening Toothpaste prior to and after using the Rembrandt Gel Plus bleaching gel. In addition, the patient was informed as to the proper method of placing the gel in the mouthguard, and inserting the mouthguard into his mouth. The mouthguard was to be worn for 2-3 hours a day for a 2-week period. RESULTS: At the end of 2 weeks, the enamel surface stains were removed through the bleaching process.

Multiphasic thyrotropin responses to thyroid hormone administration in man.

The magnitude and temporal pattern of serum TSH suppression after single or multiple doses of thyroid hormone (T3, T4, or triiodothyroacetic acid) were studied using third and fourth generation TSH assays (sensitivities, 0.01 and 0.001 mU/L, respectively). A constant T3 dose (263 micrograms i.v.) administered at a uniform clock time (1200 h) produced identical serum TSH suppression patterns, (percent of control TSH vs. hours) in euthyroid and hypothyroid subjects. The percent log TSH vs. log time plot revealed three temporally distinct linear suppression phases: phase 1, a rapid TSH suppression, onset 1 h and lasting for 10-20 h; phase 2, slower suppression, onset between 10 and 20 h and lasting for 6-8 weeks; and phase 3, an invariable low TSH level (< 0.01 mU/L) with chronic T3 suppression (100 micrograms four times a day). TSH escaped maximal suppression at a similar serum T3 level in both euthyroid and hypothyroid subjects (2.9 +/- 0.2 vs. 3.5 +/- 0.5 nmol/L, respectively; P > 0.9), despite different basal serum T3 values (2.0 +/- 0.1 vs. 0.6 +/- 0.1 nmol/L, respectively; P < 0.01). Two milligrams of triiodothyroacetic acid or 2 mg T4 given iv at 1200 h produced TSH suppression patterns similar to T3. The phase 1 suppression varied with the clock time of T3 administration, (steeper responses were seen at 2400 vs. 1200 h), whereas phase 2 responses were unaltered. This study shows that thyroid hormone suppression of TSH is a complex, biphasic, nonlinear process, which is reproducible and independent of thyroid status or the thyroid hormone analog used. It is hypothesized that phase 1 reflects inhibition of release of preformed hormone, whereas phase 2 likely reflects inhibition of de novo synthesis and/or thyrotroph storage of TSH. In contrast, phase 3 secretion seems to represent basal constitutive TSH release, which may have relevance to the role of thyroid hormone-suppressive therapy in the treatment of patients with benign or neoplastic thyroid disease.

New concepts in restorative dentistry. The CEREC CAD/CAM system.

The CEREC system offers the dentist a conservative means to esthetically restore posterior teeth in a single patient visit. It uses advanced restorative materials. It does not require traditional impression techniques, temporaries or outside laboratories. Seven-year recalls in Europe and five-year recalls in the United States establish a firm basis for predicting continued clinical success of these restorations. The technology is currently being taught in 13 dental schools in the United States. Four schools are continuing clinical research.

Tooth-colored posterior restorations using Cerec Method (CAD/CAM)-generated ceramic inlays.

The ability to provide patients with esthetic tooth-colored posterior restorations produced from "factory-standardized" ceramics in a single visit is a unique feature of CAD/CAM technology. Recent improvements in the hardware and computer software of the Siemens CEREC CAD/CAM System have improved its ease of use and the quality of the restoration produced. Attention to tooth preparation requirements and care in the cementing and finishing procedures remain requirements for the production of these restorations.

3,5,3'-Triiodothyronine (T3) sulfate: a major metabolite in T3 metabolism in man.

Previous studies have suggested that T3 metabolism relies more on nondeiodinative conjugation than on direct deiodinative degradation for its disposal in man. To better define this process, tracer T3 kinetic studies were performed in five euthyroid subjects before and after iopanoic acid (IA) administration to selectively impair T3 deiodinative disposal. Both a low IA (0.5-g load, followed by 0.5 g/day for 7 days) and a high IA (3.0-g load, followed by 3.0 g/day for 7 days) dosing schedule were employed to achieve varying levels of deiodinase inhibition. Additionally, the high IA dose was repeated with simultaneous oral T3 administration (100 micrograms daily) to normalize serum T3 levels that were reduced by IA-induced inhibition of T4 to T3 conversion. The results demonstrated that baseline serum T3 (2.3 +/- 0.1 nmol/L) and T3/T4 (1.9 +/- 0.1 x 10(-2)) values were significantly reduced by both the low IA (1.5 +/- 0.1 nmol/L and 1.2 +/- 0.1 x 10(-2), respectively) and the high IA (1.5 +/- 0.1 nmol/L and 0.9 +/- 0.2 x 10(-2), respectively) dosing schedule and that the addition of oral T3 to the high IA regimen restored both the T3 and T3/T4 levels to near-normal values (2.9 +/- 0.3 nmol/L and 1.7 +/- 0.2 x 10(-2), respectively). Low IA also significantly decreased T3 clearance (30 +/- 4 to 18 +/- 2 L/day; P < 0.005) and fractional urinary tracer recovery (70 +/- 3% to 37 +/- 4%; P < 0.005), whereas high IA produced only a minimal further reduction in clearance (16 +/- 2 L/day; P < 0.01) and urinary tracer recovery (32 +/- 3%; P < 0.05). Surprisingly, oral administration of T3 to the high IA regimen significantly increased T3 clearance (23 +/- 4 L/day; P < 0.01) without changing urinary tracer recovery (34 +/- 5%) compared to the effects of high IA alone. Evaluation of the urinary T3 metabolite pattern demonstrated that the major products of T3 metabolism were T3 sulfate and 3,3-diiodothyronine sulfate. These observations confirm previous results suggesting that the majority of nondeiodinative T3 disposal occurs via T3 sulfate formation. The additional finding that such nondeiodinative disposal may also be influenced by the circulating T3 level leads us to propose that sulfotransferase enzyme systems may play an important role in regulating the prereceptor availability of this ligand.

Myxedema coma. A form of decompensated hypothyroidism.

This article describes the major pathophysiologic alterations that occur in patients with long-standing hypothyroidism and how these alterations may predispose them to the development of a decompensated state, commonly referred to as myxedema coma. Early recognition and the employment of appropriate interventions serve as the cornerstone for successful management of this condition. The use and limitations of thyroid hormone therapy for treatment of this condition are emphasized.

Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays.

TRH stimulation tests (n = 1109) were performed on 1061 ambulatory and 43 hospitalized patients with varying thyroid status, using a TSH immunochemiluminometric assay with third and fourth generation sensitivity characteristics (functional sensitivity, 0.01 and 0.001 mU/L, respectively). TRH test results were analyzed as both absolute (stimulated minus basal TSH) and fold (stimulated/basal TSH) responses. The absolute TRH response varied 8-fold across the physiological TSH range, whereas the mean fold response remained almost constant (mean +/- SEM, 8.5 +/- 0.2). The fold response became progressively attenuated as basal TSH values declined below physiological levels, becoming essentially absent in clinically thyrotoxic patients with markedly depressed basal serum TSH levels (0.007 +/- 0.002 mU/L). Progressive attenuation also occurred at hypothyroid TSH levels; a markedly impaired fold response (2.5 +/- 0.4) was characteristic of primary hypothyroid patients with basal TSH values greater than 50 mU/L. In untreated central hypothyroid patients with near-normal basal TSH levels, the TRH fold response was impaired (1.7 +/- 0.2), whereas in T4-replaced central hypothyroid patients, fold responses were near normal (5.6 +/- 1.2). Neither nonthyroidal illness, age, or sex appeared to influence the pattern of fold TRH response in the populations evaluated. When using third and fourth generation TSH methodology, the TRH-stimulated TSH fold response is more diagnostically useful than the absolute TRH response. However, if patients have an intact hypothalamic-pituitary axis, there appears to be no diagnostic advantage gained by TRH testing over an accurately measured basal TSH value.

Total quality management: doing things right.

Total quality management transforms quality assurance performance controls into a dynamic system for continuously improving healthcare services to internal and external "customers" in terms of outcomes. Success depends upon gaining and maintaining commitment of physicians, top management and key staff members through a working environment which values and rewards improvement efforts.

Bonding composite to glass ionomer with adhesive resin cements.

This study was to determine the bond strength of composite to glass ionomer using the following adhesive resin cements: Imperva Dual, CB Metabond, All-Bond, Geristore, and Panavia. All materials were mixed following the manufacturer's specifications. Bonded samples were thermocycled for 2000 x between 5 degrees C and 55 degrees C. Shear bond strengths were determined using an Instron Testing Machine. No statistical differences were noted between materials at the p < .05 level of significance. In addition, scanning electron micrographs were taken of the primed glass ionomer surfaces. These micrographs revealed varying amounts of matrix dissolution along with roughened surface topographies.

Characteristics of 3,5,3'-triiodothyronine sulfate metabolism in euthyroid man.

The sulfated conjugate of T3 (T3S) has long been recognized as a normal product of peripheral thyroid hormone metabolism. In order to better understand the role that T3S may play in this process, the metabolic handling of T3S was studied in euthyroid man. After the iv administration of [125I]T3S in man, T3S was found to be rapidly metabolized with estimated mean MCR of 135 +/- 15 liters/day (L/D) after a bolus injection and 127 +/- 8 L/D employing a constant infusion. The primary route of T3S disposal was by deiodination with an efficiency of 92%. The administration of propylthiouracil (PTU, 300 mg every 6 h x 5 days) and iopanoic acid (IA, 500 mg every day x 5 days), both inhibitors of deiodination, decreased clearance compared to control (87 +/- 9 L/D, P less than 0.01 and 46 +/- 10 L/D, P less than 0.002, respectively). A 3-day fast also reduced the clearance of T3S (56 +/- 10 L/D, P less than 0.002). All three maneuvers decreased the total urinary deiodination fraction of tracer T3S (control 91 +/- 2%, PTU 70 +/- 9%, P less than 0.04, IA 26 +/- 3%, P less than 0.0001, and fasting 58 +/- 6%, P less than 0.01). A strong correlation between T3S clearance and deiodination was noted for fasting and IA only (r = 0.78, P less than 0.003). However, no relationship between clearance and deiodination was noted with PTU administration presumably as a result of a compensatory increase in biliary losses of T3S. The urinary thyronine excretion pattern demonstrated the presence of small amounts of labeled T3,3,3'-T2, and 3,3'-T2S with the major metabolite being T3S itself. TSH levels were not influenced by the infusion of stable T3S designed to achieve a serum value greater than 50 ng/dL. No absorption of intact T3S was detected after its oral ingestion. In conclusion, T3S is rapidly cleared from the serum, primarily by deiodination, may undergo nondeiodinative disposal when hepatic deiodination is inhibited by PTU but not with IA or fasting, and has no intrinsic biological activity. Thus, T3S may serve as a metabolite of T3 for its rapid deiodinative disposal. Although the precise role T3S plays in human thyroid hormone metabolism has not been defined, the metabolic characteristics of T3S appear similar to that of an unidentified alternate T4 metabolite formed in low T3 states of fasting and nonthyroidal illness.

Influence of fasting and refeeding on 3,3',5'-triiodothyronine metabolism in man.

To determine the influence of prolonged fasting and refeeding on rT3 metabolism in man, five euthyroid obese subjects underwent a 13-day fast, followed by a refeeding period. Each patient received an iv dose of 25 muCi [125I]rT3 during the fed control period, on days 7 and 13 of the fast, and on the fourth day after refeeding with a regular diet. Serial blood and urine samples were obtained to determine serum rT3 clearance and production rates and the urinary tracer rT3 deiodination fraction. Significant increases in serum rT3 values were noted by day 7 and remained elevated for the duration of the fast (P less than 0.01). Normalization of rT3 levels occurred after 4 days of refeeding. Both 7 and 13 days of fasting decreased rT3 clearance [132.6 +/- 8.3 L/day (P less than 0.001) and 132.2 +/- 9.5 L/day (P less than 0.001), respectively] without changing rT3 production (36.8 +/- 5.3 and 33.0 +/- 3.7 nmol/D, respectively) compared to control values (207.0 +/- 10.9 L/day and 31.8 +/- 3.8 nmol/day, respectively). Refeeding did not restore rT3 clearance (151.2 +/- 6.9 L/day; P less than 0.002), but significantly reduced blood rT3 production (18.4 +/- 3.8 nmol/day; P less than 0.003). The fractional deiodination of rT3 was significantly reduced on day 7 (42.5 +/- 4.6%; P less than 0.01) and day 13 (41.9 +/- 3.7%; P less than 0.01) of fasting compared to the control value (69.2 +/- 2.8%), while refeeding only partially restored deiodination to baseline (48.4 +/- 5.1%; P less than 0.04). The clearance of rT3 was highly dependent on the fractional deiodination rate (r = 0.83; P less than 0.001). Although rT3 production remained constant during fasting, reduced rT3 production was seen on the fourth day of refeeding. This unique observation explained the fall in serum rT3 to prefasting levels after 4 days of refeeding when rT3 clearance was still inhibited. This study, in context with previous investigations, indicates that T4 conversion to circulating T3 and rT3 in fasting is a highly complex and multifaceted process requiring further investigation to elucidate the mechanism responsible for these alterations.