Accuracy of fine-needle aspiration cytology in patients with radiation-induced thyroid neoplasms.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is useful for selecting patients with thyroid nodules for thyroidectomy. Its value in patients who have been exposed to low-dose therapeutic radiation is questionable because these patients have an increased risk of multifocal benign and malignant tumours, and thyroid cancer is common in such patients. METHODS: Between 1960 and 1999, 171 patients with one or more thyroid nodules who had a history of exposure to radiation underwent operation; 49 of these patients had preoperative FNAC. The cytology results in these 49 patients were compared with those of an age- and sex-matched control group of patients with thyroid nodules who did not have a history of radiation exposure. RESULTS: Of those who had been exposed to radiation, six of 20 patients with 'benign' cytology by FNAC and six of 16 patients with 'suspicious' cytology had thyroid cancer. All 13 specimens considered to be malignant on FNAC were indeed malignant. There was a higher rate of false-negative cytological examinations among patients with a history of irradiation that in those without. CONCLUSION: FNAC of thyroid nodules in patients with a history of irradiation is not as accurate as that in non-irradiated patients, primarily because of coexisting occult thyroid cancers.

Death from thyroid cancer of follicular cell origin.

BACKGROUND: Although patients with differentiated thyroid cancer (DTC) of follicular cell origin usually have an excellent prognosis, some patients die from progressive tumor. Numerous postoperative criteria have been used to predict prognosis in patients with DTC. The purpose of this investigation was to determine whether the TNM and metastases, age, completeness of resection, invasion, size (MACIS) classifications predicted survival time and why patients died from DTC. The extent of initial treatment and causes of death were also evaluated in these patients who died from thyroid cancer. STUDY DESIGN: Between 1965 and 1995, 102 of 1,224 patients with DTC treated at the University of California at San Francisco (UCSF) and UCSF/Mount Zion Medical Centers died from DTC. Risk factors including age at diagnosis, gender, histologic characteristics, TNM and MACIS classifications, the intervals among initial treatment, recurrence, and death, and the initial and subsequent treatments were documented in these 102 patients. RESULTS: Among the 102 patients who died of DTC 50% were men and 50% were women. The mean age of patients with DTC at diagnosis was 58 years at recurrence, 62 and 65 years at death. Thirty percent of these patients initially had unilateral thyroid operations and 70% had a bilateral operation. Tumors at presentation ranged from 0.6 to 13.0 cm (mean 4.4 cm); 46% of patients presented with late-stage tumors (TNM stage III, IV; MACIS score > 8). At presentation 46% of the patients had locally recurrent disease or regional metastases and 18% had distant metastases. Patients with persistent disease had a significantly shorter survival time than those with recurrent disease (p < 0.001). Both TNM and MACIS classifications were good predictors of survival time. Reoperations were performed in 51% of papillary, 26% of follicular, and 67% of Hürthle cell thyroid cancer patients. Fifty percent of patients with papillary thyroid cancer, 50% of patients with Hürthle cell thyroid cancer, and 11% of patients with follicular cell thyroid cancer died of locally advanced disease. CONCLUSIONS: As expected, patients with local or regional recurrence and those with TNM stage I or MACIS score < 6 survived longer than patients with distant metastasis and TNM stage III or IV, MACIS score > 6, but some patients thought to be at low risk (TNM stage I; MACIS < 6) also died from thyroid cancer.

Development of overt autoimmune hyperthyroidism in a patient therapeutically immunosuppressed after liver transplantation.

Immunosuppression is a therapeutic maneuver directed at preventing transplant rejection. When applied to autoimmunity, immunosuppression is intended to target similar immune processes. We report an unusual case of a 35-year-old woman who developed autoimmune hyperthyroidism of Graves' disease while on immunosuppressive therapy for liver transplantation. Signs and symptoms of hyperthyroidism were already present when, misled by the concomitant toxic hepatic syndrome, liver rejection was first suspected. Despite a therapeutic level of cyclosporine, elevated serum alanine and aspartate aminotransferase levels were noted. Consequently, a liver biopsy was performed to exclude an acute rejection. The findings were consistent with acute hepatitis without evidence of rejection. Then, the diagnosis of Graves' hyperthyroidism was considered and finally confirmed by finding a suppressed thyroid-stimulating hormone, elevated thyroid hormone levels, and a high and homogeneous thyroid uptake from radioactive iodine scan. Thyroid peroxidase antibody and thyroid-stimulating immunoglobulin were markedly elevated. The patient was treated with radioactive iodine, which resulted in improvement of symptoms and resolution of abnormal liver function tests. Although the mechanisms involved in transplant rejection and human autoimmunity are thought to be similar, the development of Graves' disease in this patient despite therapeutic immunosuppression suggests that the immunological processes may be different.

The effect of thyroid hormone on skeletal integrity.

BACKGROUND: Thyroid disease and osteoporosis are common problems often managed by primary care physicians. Despite many studies, confusion still exists about the effect of thyroid hormone on skeletal health. PURPOSE: To review evidence on the effect of thyroid hormone (from hyperthyroidism, exogenous or endogenous suppression of thyroid-stimulating hormone [TSH], and thyroid hormone replacement therapy) on skeletal integrity. DATA SOURCES: A MEDLINE search of papers published between 1966 and 1997. DATA SELECTION: Cross-sectional studies, longitudinal studies, and meta-analyses that had appropriate control groups (patients matched for age, sex, and menopausal status), made comparisons with established databases, or defined thyroid state by TSH level or thyroid hormone dose were reviewed. DATA EXTRACTION AND SYNTHESIS: Data synthesis was not straightforward because of changes in doses and types of thyroid hormone preparations; changes in definitions of thyroid hormone replacement therapy and suppressive therapies; problems with study design; differences in skeletal sites assessed (hip, spine, forearm, or heel) and techniques used to measure bone mineral density; and inclusion of heterogenous and changing thyroid disease states. Overall, hyperthyroidism and use of thyroid hormone to suppress TSH because of thyroid cancer, goiters, or nodules seem to have an adverse effect on bone, especially in postmenopausal women; the largest effect is on cortical bone. Thyroid hormone replacement seems to have a minimal clinical effect on bone. CONCLUSION: Women with a history of hyperthyroidism or TSH suppression by thyroid hormone should have skeletal status assessed by bone mineral densitometry, preferably at a site containing cortical bone, such as the hip or forearm.

Influence of lymphocytic thyroiditis on the prognostic outcome of patients with papillary thyroid carcinoma.

Both the association between lymphocytic thyroiditis (LT) and papillary thyroid carcinoma (PTC), and the prognostic significance of lymphocytic infiltrate in patients with thyroid malignancy, remain controversial. We examine the above relationships by retrospectively reviewing our series of patients treated for differentiated nonmedullary thyroid carcinoma at University of California-San Francisco over a 25-yr period (1970-1995). Of the 631 patients with complete data for analysis, 128 patients (20.3%) showed concomitant histologic evidence of LT and 503 patients (79.7%) had no evidence of LT. Prognostic outcome was assessed using Kaplan-Meier survival plots and analysis of risk factors by Cox's proportional-hazard modeling. The cohort with LT revealed a higher frequency of PTC (97.7% vs. 87.3%) and female patients (85.2% vs. 66.8%), a lower frequency of extrathyroidal invasion (7.8% vs. 23.3%) and nodal metastases (25.8% vs. 43.3%), and absence of distant metastases (0% vs. 4.8%), respectively, compared with those without LT. At initial surgery, a significantly greater proportion of patients with LT belonged to lower pathological tumor-node-metastasis stages, compared with those without LT (stage 1, 86.7% vs. 73%; stage 2, 4.7% vs. 8.3%; stage 3, 8.6% vs. 15.3%; and stage 4, 0% vs. 3.4%). Over a mean +/- SE follow-up period of 11.1 +/- 0.4 yr, patients with LT had significantly lower cancer recurrence rate (6.3% vs. 24.1%; P < 0.0001) and cancer mortality rate (0.8% vs. 8.0%; P = 0.001), respectively, compared with those without LT. In summary, our series showed a relatively common occurrence of LT in patients with PTC, and we believed that lymphocytic infiltration developed mainly in response to the tumor itself. We also found a more favorable course of PTC in the presence of LT; this supports the hypothesis that lymphocytic infiltration represents a form of immune reaction to control tumor growth and proliferation.

Riedel's thyroiditis presenting with hypothyroidism and hypoparathyroidism: dramatic response to glucocorticoid and thyroxine therapy.

Riedel's thyroiditis is a rare fibro-inflammatory process originating in the thyroid gland with progressive extension and invasion of surrounding tissues. Patients frequently present with a stony hard thyroid mass suggestive of anaplastic carcinoma. We report a striking case of Riedel's thyroiditis associated with hypothyroidism, hypoparathyroidism and bilateral vocal cord paralysis. A dramatic response to high dose prednisone and levothyroxine therapy was seen, with recovery of parathyroid and vocal cord function. Our case suggests that early initiation of combination therapy may be important, particularly in the presence of severe disease.

Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients.

The TNM classification (tumor-node-metastasis) was adopted by the American Joint Committee on Cancer and the International Union against Cancer a decade ago to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers. To date, however, clinical data based on this classification are lacking. We retrospectively evaluate the prognosis of 700 patients (208 men and 492 women) with papillary (89%) and follicular (11%) thyroid cancers according to the pathological TNM (pTNM) staging system, treated over a 25-yr period (1970-1995). Patients who received primary treatment at our center constituted 87.4% of the cases; the majority underwent total thyroidectomy, followed by 131I ablative therapy in high risk groups, as standard treatment. Clinical and follow-up data were obtained from the medical records and our cancer registry. Disease-free and cancer-specific survival data were analyzed by Kaplan-Meier product limit estimates and Cox proportional hazard models. Patient distribution by the pTNM system were: stage I, 516 patients; stage II, 57 patients; stage III, 104 patients; and stage IV, 23 patients. Over a mean +/- SE follow-up of 11.3 +/- 0.3 yr, the overall cancer recurrence and mortality rates were 20.5% and 8.4%, respectively. However, the respective cancer recurrence and mortality rates were distinctly different in the various pTNM stages: 15.4% and 1.7% in stage I, 22% and 15.8% in stage II, 46.4% and 30% in stage III, and 66.7% and 60.9% in stage IV tumors. Using actuarial survival plots, a clear separation in both disease-free survival and cancer-specific survival was noted among all the stages (P < 0.0001). Risk factors analyses showed a significant association between all the prognostic variables used in TNM staging (age, tumor size, extent of primary tumor, and presence of nodal or distant metastases) and the observed end points of recurrence or death from thyroid cancer. After correcting for TNM stages, the risk of cancer recurrence was halved in female compared to male patients, whereas this was 1.7-fold higher in multifocal than unifocal tumors. Conversely, cancer mortality was 3.4-fold higher in follicular than papillary thyroid cancer. In the analysis of effect of primary treatment among 492 patients with tumor more advanced than the T1N0M0 category, patients who underwent less extensive surgery (lobectomy or subtotal thyroidectomy) had a 2.5-fold risk of cancer recurrence (P < 0.0001) and a 2.2-fold risk of death (P < 0.01) compared to those who underwent total or near-total thyroidectomy. Patients not treated with 131I ablation had a 2.1-fold greater risk of cancer recurrence (P < 0.0001) than those given 131I ablation, although no difference was noted in deaths from thyroid cancer. Based on our data, the pTNM classification is useful in distinguishing patients with different prognostic outcomes. However, the small patient numbers in pTNM stages other than stages I precludes us from evaluating its usefulness as a guide for therapy. Until prospective data could be accrued from controlled treatment trials, we support the standard practice of total thyroidectomy followed by 131I ablative therapy (if focal iodide uptake was noted) in patients with papillary thyroid cancer more advanced than the T1N0M0 category or of multicentric nature and in the majority of patients with follicular thyroid cancer.

The role of fine-needle aspiration biopsy in the management of palpable thyroid nodules.

FNAB is the most important advance in the management of thyroid nodules in the past two decades. Dr Mazzaferri has said that finding a thyroid cancer in a thyroid nodule is like finding a needle in a haystack. Fine-needle aspiration biopsy is like applying a strong electromagnet to find that needle. It should be available to all physicians who deal with thyroid disease.

Management of thyroid carcinosarcoma.

BACKGROUND: Thyroid carcinosarcoma is a rare and aggressive malignant thyroid tumor that has been described pathologically, but there is little clinical information regarding tumor behavior. METHODS: We retrospectively analyzed the course of our patient and 16 others reported in the literature to determine optimal management. We review the case history of our patient and the literature concerning patients with carcinosarcoma of the thyroid. RESULTS: Seventeen patients, 52 to 80 years of age (mean, 60 years), have had a thyroid carcinosarcoma of the thyroid. Five of seven patients for whom the information is available were treated by partial thyroidectomy and two by total thyroidectomy. Among these patients five (71%) died within the first 3 months and two (29%) survived more than 6 months. The mean survival was 5 months. At autopsy in seven patients, six had lymph node or distant metastases. CONCLUSIONS: Carcinosarcoma of the thyroid is a very aggressive tumor with a clinical course similar to anaplastic thyroid carcinoma. Like patients with anaplastic thyroid carcinoma, few survive more than 6 months despite aggressive multimodal treatment. Our patient's exposure to raw phosphorus, radiation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea may have predisposed her to this aggressive tumor.

Familial papillary thyroid cancer: a case report.

Familial occurrence of medullary thyroid cancer is well known in families as an isolated malignancy or in association with multiple endocrine neoplasia syndrome type II. Conversely, papillary thyroid cancer almost always presents sporadically except for reports of familial clustering in individuals with radiation exposure, inherited syndromes of colonic polyposis or multiple harmatomas, and rarely in monozygotic twins. We report a case of papillary thyroid cancer diagnosed incidentally in a 53-year-old woman who underwent surgery for excision of an adenomatous nodule. It was noted that her mother suffered from a similar thyroid malignancy some 33 years ago, and several of her maternal relatives had either Graves' disease or hypothyroidism. The possible existence of this familial entity and its likely genetic basis is discussed.

Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism.

OBJECTIVE: To compare relative bioavailability of Synthroid, Levoxine (Levoxine has been renamed Levoxyl), and 2 generic levothyroxine sodium preparations. DESIGN: Single-blind (primary investigators blinded), randomized, 4-way crossover trial. SETTING: Ambulatory care. PATIENTS: Twenty-two women with hypothyroidism who were clinically and chemically euthyroid and were receiving levothyroxine sodium, 0.1 or 0.15 mg. INTERVENTIONS: All patients received each of the 4 levothyroxine products for 6-week periods in the same dosage as their prestudy regimen with no washout period. The order of the drug sequences was randomly determined before study initiation. MAIN OUTCOME MEASURES: Area under the curve, time to peak serum concentrations, and peak serum concentrations of thyroxine, triiodothyronine, and free thyroxine index for all 4 products. RESULTS: All data analyses were completed prior to unblinding of the product codes. No significant differences between the 4 products were found in area under the curve or peak serum concentrations of total thyroxine, total triiodothyronine, or free thyroxine index. Although Synthroid produced a more rapid rise in total serum triiodothyronine concentration and a higher total peak serum triiodothyronine concentration than the other products, these differences were not statistically significant (P=.08). The Food and Drug Administration criterion for relative bioequivalence within 90% confidence intervals (0.8-1.25) was demonstrated (P<.05) for all pairs of products. Relative bioequivalence of 0.95 to 1.07 was demonstrated, tighter than the current bioequivalence criterion for oral formulations. CONCLUSIONS: The 4 generic and brand-name levothyroxine preparations studied are different but are bioequivalent by current Food and Drug Administration criteria and are interchangeable in the majority of patients receiving thyroxine replacement therapy. Further investigation is required to determine whether our results are equally applicable to all existing levothyroxine preparations.

Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature.

Three patients who developed symptomatic, autoimmune-mediated thyroid dysfunction during treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C with liver cirrhosis, age-related macular degeneration with foveal involvement, and chronic myelogenous leukemia, respectively, are described. The first two patients developed autoimmune hypothyroidism that required thyroxine replacement, and the third developed autoimmune thyroiditis with transient thyrotoxicosis. The clinical manifestations were protean, and required a high index of suspicion for diagnosis, the failure of which led to significant morbidity. A literature review revealed that the mean incidence of IFN-alpha induced thyroid dysfunction was 6%. Spontaneous resolution occurred in more than half with discontinuation of IFN-alpha treatment. Hypothyroidism was induced more frequently than hyperthyroidism. At least one positive thyroid autoantibody titer was found in 17% of patients receiving IFN-alpha. Risk factors for developing thyroid dysfunction with IFN-alpha treatment were female sex, underlying malignancy or hepatitis C, higher doses of IFN-alpha for longer durations, combination immunotherapy (especially with interleukin-2), and the presence of thyroid autoantibodies prior to or during treatment.

Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association.

A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee (the authors of the article) of the American Thyroid Association, New York, NY. The participants were selected by the committee chairman and by the president of the American Thyroid Association based on their clinical experience. The committee members represented different geographic areas within the United States, to reflect different practice patterns. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information. Each committee participant was initially assigned to write a section of the document and to submit it to the committee chairman, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. Several of the committee members further revised and refined the document, which was then submitted to the entire membership of the American Thyroid Association for written comments and suggestions, many of which were incorporated into a final draft document, which was reviewed and approved by the Executive Council of the American Thyroid Association.

Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentration as measured by equilibrium dialysis.

Heparin can cause an artifactual elevation in the concentration of unbound (free) thyroxine (T4) in the plasma, particularly when measured by equilibrium dialysis. The lipase released into the plasma by heparin acts on substrate (triglycerides; TG) in the plasma in vitro to release nonesterified (free) fatty acids (FFA), which, in high concentrations, inhibit the binding of T4 to its plasma binding proteins. This artifact occurs only in the presence of sufficient substrate (serum TG greater than approximately 180 mg/dL), and is most pronounced in methods requiring long incubation times. We observed this artifact in a patient receiving intralipid and subcutaneous (sc) heparin. Plasma-free T4, when measured by equilibrium dialysis, was elevated, but was normalized when the in vitro generation of FFA during equilibrium dialysis was prevented by prior treatment of the sample with protamine to inhibit lipoprotein lipase and with an antibody to hepatic triglyceride lipase. This observation caused us to investigate formally whether heparin, at standard sc doses or at iv doses even lower than those that are commonly used to flush iv lines (100-300 U), could also cause this artifact. We gave increasing doses of heparin at weekly intervals to each of three normal volunteers and measured FFA generation in their plasma (supplemented with 250 mg/dL triglycerides) under conditions simulating equilibrium dialysis. We found that, indeed, iv doses of heparin as low as 0.08 U/kg (5.6 U in a 70-kg subject) as well as a standard dose of sc heparin (5000 U) could release significant lipase activity into the plasma and, in the setting of sufficient substrate, cause enough in vitro generation of FFA to artifactually increase the serum-free T4 concentration when measured by equilibrium dialysis. These results indicate that equilibrium dialysis may not always be the best method for assessing serum-free T4 concentrations in hospitalized patients, and should be taken into account when interpreting previous studies demonstrating inhibitors of T4-serum protein binding in sera from hospitalized patients.

Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association.

OBJECTIVE: To develop a set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with hyperthyroidism and hypothyroidism. PARTICIPANTS: Guidelines were developed by a nine-member ad hoc Standards of Care Committee of the American Thyroid Association (the authors of this article). The participants were selected by the committee chair and the president of the American Thyroid Association on the basis of their clinical experience. The committee members represented different geographic areas within the United States, in order to take into account different practice styles. EVIDENCE: Guidelines were developed on the basis of expert opinion of the participants, as well as on available published information. CONSENSUS PROCESS: Input was obtained from all of the participants, each of whom wrote an initial section of the document. A complete draft document was then written by three participants (P.A.S., D.S.C., and E.G.L.) and resubmitted to the entire committee for revision. The revised document was then submitted to the entire membership of the American Thyroid Association for written comments, which were then reviewed (mainly by P.A.S., D.S.C., and E.G.L.). Many of the suggestions of the American Thyroid Association members were incorporated into the final draft, which was then approved by the Executive Council of the American Thyroid Association. The entire process, from initial drafts to final approval, took approximately 18 months. CONCLUSIONS: A set of minimum clinical guidelines for the diagnosis and treatment of hyperthyroidism and hypothyroidism were developed by consensus of a group of experienced thyroidologists. The guidelines are intended to be used by physicians in their care of patients with thyroid disorders, with the expectation that more effective care can be provided, and at a cost savings.

Octreotide therapy in advanced thyroid cancer.

Octreotide is a long-acting somatostatin analog that inhibits cell growth and hormone secretion. It has been successfully used in the management of a variety of endocrine tumors (i.e., acromegaly, carcinoid tumors, gastrinomas). In vitro, octreotide suppresses adenylate cyclase activity, DNA synthesis, and cell growth in cultured thyroid cell lines. Previous studies examining the use of octreotide in the treatment of medullary thyroid cancers, in vivo, report symptomatic improvement from tumor-related hormonal hypersecretion; however, octreotide's ability to suppress tumor growth was limited. In the present study, we examine the efficacy of long-term octreotide administration in six subjects with metastatic thyroid carcinoma, including Hurthle cell (one subject), medullary (one subject) and papillary or mixed papillary/follicular cancer (four subjects). All of the subjects had documented recurrences of their thyroid tumors despite appropriate therapy, and were considered to be untreatable by conventional therapeutic modalities (i.e., radioiodine or surgery). Subjects were monitored while receiving relatively high doses (4 mg daily) octreotide subcutaneously for up to 12 months. Octreotide therapy was very well tolerated; mild gastrointestinal symptoms persisted throughout treatment in one subject. Octreotide did not significantly decrease tumor markers (e.g., thyroglobulin, calcitonin, carcinoembryonic antigen). The carcinomas progressed during treatment, as evidenced by an increase in the size and/or number of metastatic lesions. In summary, in this small series subcutaneous octreotide administration did not appear to be efficacious in the management of advanced thyroid cancers.

Skeletal integrity in premenopausal and postmenopausal women receiving long-term L-thyroxine therapy.

PURPOSE: The impact of long-term L-thyroxine replacement therapy on skeletal integrity is a growing concern because of the large number of women receiving thyroid hormone therapy. The purpose of this study was to examine the hypothesis that long-term L-thyroxine therapy in which the free thyroxine index (FT4I) is maintained within a physiologic range has minimal impact on vertebral or femoral bone mineral density in both premenopausal and postmenopausal women. PATIENTS AND METHODS: We measured hip integral and spinal trabecular and integral bone densities in 28 premenopausal and 28 postmenopausal women who had been receiving L-thyroxine therapy for a median of 12 and 15 years, respectively, and in whom therapy was titrated to keep the FT4I within the normal range. The relationship between bone density parameters and thyroid hormone status was examined using univariate and multivariate statistical methods. RESULTS: Seventy-nine percent of the premenopausal women and 86% of the postmenopausal women had FT4I values in the normal range at the time of bone density determination. Moreover, throughout the study's duration, the majority of annually measured values were in the normal range for more than 80% of subjects. Premenopausal women had slightly lower bone density than would be expected for age: -6.7% (z = -0.39 +/- 0.74 [mean +/- SD], p less than 0.01), -3.1% (z = -0.22 +/- 0.78, p = 0.15), and -5.1% (z = -0.36 +/- 0.74, p less than 0.02) for spinal trabecular, spinal integral, and hip integral bone density, respectively. Postmenopausal women likewise had slightly lower bone density values that were significant only at the hip: -0.2% (z = -0.01 +/- 1.01, p = 0.95), -1.0% (z = -0.05 +/- 1.11, p = 0.80), and -6.2% (z = -0.39 +/- 0.80, p less than 0.02) for spinal trabecular, spinal integral, and hip integral bone density, respectively. When patients with previously treated Graves' disease (n = 4 in each group) were eliminated, the differences in bone density at the hip were no longer seen. Correlation analysis revealed only weak and generally nonsignificant relationships between parameters of thyroid hormone status and bone density at any site in either subgroup. Results of multiple regression analysis among the pooled data of all subjects showed that age provided a consistently significant contribution (R2 = 0.18 to 0.66) to the variability in bone density at the spine and the hip, but parameters of thyroid hormone status did not. CONCLUSION: These data provide the first supportive evidence that long-term L-thyroxine therapy that maintains the FT4I in the physiologic range is associated with a statistically significant, but clinically minimal, decrement in spinal and hip bone density in both premenopausal and postmenopausal women. The decrement at the hip was entirely due to the inclusion of patients with treated Graves' diseases. Thus, the changes in bone density in women receiving long-term L-thyroxine therapy are minimal at most and should not be a contraindication to therapy.

Induction of HLA-DR expression on thyroid follicular cells by cytomegalovirus infection in vitro. Evidence for a dual mechanism of induction.

Cytomegalovirus (CMV) infection of primary cultures established from human thyroid nodular and normal (paranodular) tissues resulted in induction of human leukocyte antigen (HLA) DR expression on thyroid follicular cells (TFC), as detected by cell-surface immunofluorescence staining with monoclonal antibodies (MAb). Two distinct modalities of induction were observed. The first type occurred in cultures of normal tissue obtained from CMV-seropositive but not seronegative donors, was detected on 30% to 50% of the TFCs, even though the vast majority of these cells failed to show any morphologic or antigenic evidence of individual CMV infection, and was associated with production of gamma-interferon (gamma-IFN) in vitro. The induced molecules displayed the characteristic DR polypeptide profile on immunoprecipitation and electrophoretic analysis. These results demonstrate that CMV infection of normal thyroid cultures may induce DR expression on TFCs in the absence of pre-existing lymphoid infiltrates and suggest that the induction is the result of an in vitro response to CMV by previously sensitized immunocompetent cells present in these primary cultures. Such a response, associated with the release of gamma-IFN, would induce DR expression on neighboring uninfected cells. The second mode of induction occurred in all CMV-infected cultures, regardless of their tissue origin (nodular or normal) or the serologic status of the donors. Up to 50% of infected TFCs at a late stage of infection, having fully developed CMV antigen-positive intranuclear inclusions, also displayed the cell-surface DR-related determinant recognized by one of the four anti-DR MAbs used. This induction was restricted to TFCs, while CMV-infected fibroblastoid cells present in the monolayers were invariably negative. Induction by CMV of major histocompatibility class II antigens on human epithelial cells may have significant implications in the development of normal immune responses against local viral infection, the enhancement of alloimmune rejection of grafted organs, and the generation of organ-specific autoimmune responses.

The problem of the nodular goiter.

Nodular goiter is a worldwide problem involving millions of persons. Endemic goiter, and associated cretinism, is totally preventable by ensuring an adequate dietary iodine intake and eliminating malnutrition and dietary goitrogens. Therapy, on the other hand, is difficult in that the goiters often do not regress and the cretinoid changes are irreversible. Nonendemic goiter due to autoimmune thyroid disease, genetic defects in thyroid hormone biosynthesis, and environmental goitrogens or neoplasia is not usually preventable. The usual therapy, involving TSH suppression by administration of L-thyroxine orally, will frequently bring about regression of early, diffuse goiters but is often ineffective in bringing about regression of large, multinodular goiters. In these patients, surgical removal of the goiter may be necessary for alleviation of obstructive symptoms. Further research is needed to elucidate the factors involved in the development of these multinodular goiters and to control the autocrine and paracrine factors involved in nodule growth.