Role of protein degradation in the growth of livers after a nutritional shift

Four patients with idiopathic pituitary dwarfism were shown to have growth hormone (GH), adrenocorticotropin (ACTH), and luteinizing hormone (LH) deficiencies. Basal levels of thyrotropin (TSH) were within normal range in three patients and slightly elevated in one. Exaggerated and delayed responses were obtained after TSH-releasing hormone (TRH) stimulation. Serum thyroxine (T4) values were low (2.3 +/- 0.4 mug/100 ml), while triiodothyronine (T3) levels were in the normal range (1.22 +/- 0.25 ng/ml), both rising substantially after exogenous TSH and consecutive TRH administration. Their hypothyroid state was, therefore, probably due to TRH deficiency. To examine the dose of L-T4 necessary to produce inhibition of the TSH response to TRH, 50 mug/m2/day of L-T4 was administered to these patients. At the end of 4 weeks of replacement, serum T4 rose to 5.2 +/- 0.5 mug/100 ml, whereas T3 was unchanged from the previous levels, after which TSH responses to TRH were completely suppressed in all patients. As a control group, six patients with primary hypothyroidism received gradually increasing doses of L-T4 for 4-week periods, and TSH response to TRH was tested at the end of each dosage of L-T4, until complete inhibition of TSH release was obtained. The primary hypothyroid patients required approximately 150 mug/m2/day of L-T4 for suppression of TSH response to TRH. At this dosage, serum T4 and T3 levels were 8.5 +/- 0.9 mug/100 ml and 2.34 +/- 0.5 ng/ml respectively, which were significantly higher than those levels in the pituitary dwarfs (P less than 0.001 for T4 and P less than 0.01 for T3). These observations indicate that the set point of TSH release in feedback inhibition by throxine is low in idiopathic hypopituitarism with TRH deficiency, and TRH seems to control the pituitary sensitivity to feedback regulation of thyroid hormones.     

Recurrent goiter, hyperthyroidism, galactorrhea and amenorrhea due to a thyrotropin and prolactin-producing pituitary tumor

A 22-year-old woman with recurrent goiter, hyperthyroidism, galactorrhea, and amenorrhea due to a pituitary tumor is described. She had been treated surgically twice for recurrent goiter with tracheal compression. Despite clinical signs of hyperthyroidism and slightly elevated plasma thyroid hormone levels (T4: 11 mug/dl; T3: 189 ng/dl), without thyroid hormone replacement therapy the basal TSH level was elevated up to 23 muU/ml and could not be suppressed by exogenous thyroid hormones: even when the serum thyroid hormone levels were raised into the thyrotoxic range (T4: 16.2 mug/dl T3: 392 ng/dl), the basal TSH fluctuated between 12 and 29 muU/ml. The basal PRL level was elevated up to 6000 muU/ml. The administration of TRH (200 mug iv) led only to small increments of TSH and PRL levels. Bromocriptin (5 mg p.o.) or l-dopa (0.5 g p.o.) suppressed TSH and PRL values significantly. After transsphenoidal hypophysectomy, TSH and PRL were below normal and the patient development panhypopituitarism. The adenoma showed two cell types which could be identified as lactotrophs and thyrotrophs by electronmicroscopy and immunofluorescence. From these data we conclude that the patient had a pituitary tumor with an overproduction of thyrotropin and prolactin.     

Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism

Pseudotumor cerebri is generally a benign disorder. It has been reported to occur in hypothyroidism, particularly after the initiation of L-thyroxine replacement therapy. Previous case reports have involved children primarily in the peripubertal age range (approximately 8 to 13 years). We report here the development of pseudotumor cerebri in an infant who required treatment with L-thyroxine for transient neonatal hypothyroidism as a result of maternal thyroid-stimulating hormone receptor-blocking antibodies.     

An analysis of fine-needle aspiration biopsy of the thyroid in children and adolescents

Fine-needle aspiration biopsy (FNAB) has proven safe and efficacious in the evaluation nodular thyroid disease in adults. Only one study has evaluated FNAB exclusively in children, for whom the prevalence of thyroid nodules and the probability of malignancy are different. In addition, no study has compared the accuracy of FNAB with that of other diagnostic procedures in the evaluation of thyroid nodules in children. The authors report the results of FNAB in 18 children evaluated for thyroid nodules between 1985 and 1994. The overall accuracy of FNAB was similar to that of other diagnostic procedures, including thyroid scintiscan and ultrasonography, but none of these was sufficiently accurate to be used as the sole predictor of malignancy. There were three false-negative biopsy results; this limited the overall accuracy and suggests that children with negative FNAB results should be monitored cautiously.     

Thyroxine, thyrotropin, and age in a euthyroid hospital patient population

The diagnosis of thyroid disease now often can be achieved reliably by measuring thyrotropin (TSH) alone. Thyroxine (T4), triiodothyronine, and other analytes are only needed if TSH and the accompanying clinical condition are discordant. We describe here work that confirms the age independence of TSH in both inpatient and outpatient euthyroid hospital populations between ages 20 and at least 80 years, and demonstrates that although free T4 does vary with age, the range of variation remains within the T4 reference interval. On this basis, TSH-based thyroid diagnostic algorithms can be used reliably in adults without reference to age-related reference intervals.     

Evaluation and management of the solid thyroid nodule

A tremendous effort has been applied to the determination of optimum management strategies in patients with solid thyroid nodules. The systematic acquisition of experience with historical and physical examination features suggestive of malignancy and the careful crafting of noninvasive techniques to assist in this determination have each contributed to improvements in the safety and cost-effectiveness of management in these patients. Despite this progress, significant difficulties await resolution, including the preponderance of patients still subjected to thyroidectomy for benign follicular lesions and the reluctance of clinicians to abandon the use of diagnostic techniques that offer little useful information, such as routine scintillation scanning and diagnostic trials of suppressive therapy. An exciting area now in its infancy is the identification of useful molecular markers for the selection of the few malignant thyroid nodules from among the multitudes of benign lesions. As is true in diagnostic evaluation, uncertainty continues to be experienced by clinicians charged with proper nonsurgical management of the solid thyroid nodule. The use of thyroid hormone suppressive therapy, once considered a cornerstone of conservative management, has been cast in a new light revealing both the limited utility and potential harm associated with this approach. These uncertainties should not be viewed as impediments, but rather, as opportunities for growth, as it is controversy rather than complacency that stimulates new investigation and fresh approaches to old problems.     

Thyroid cancer in pregnant women: diagnostic and therapeutic management

There is considerable literature on the effect of pregnancy on established thyroid cancer. In contrast, there are only isolated case reports of management of thyroid cancer diagnosed de novo during pregnancy. We describe four such patients. We recommend fine-needle aspiration biopsy (FNA) of solitary thyroid nodules found early in pregnancy. When the cytopathology is diagnostic of thyroid cancer, thyroidectomy under local or general anesthesia is advised. The patient should be given levothyroxine in a dose sufficient to keep serum thyroid-stimulating hormone (TSH) low. Serum thyroglobulin is a valuable noninvasive method of evaluating completeness of this therapy. The work-up of a nodule found late in pregnancy is best deferred until after delivery.     

Transient elevation of serum thyroid hormone concentration after initiation of replacement therapy in myxedema

Measurements of thyroid hormone concentrations in serum are commonly used to determine the proper dose of hormone replacement. We have noted that early in the course of thyroxine (T4) replacement in myxedema, serum T4 concentrations may be transiently elevated before reaching a lower "steady-state" level. This observation is illustrated in a study of six patients. Serum T4, free thyroxine index, and triiodothyronine (T3) rose to peak concentrations at 2 to 6 weeks, 35% to 120% above the values achieved 4 to 8 months later. Values were transiently in the thyrotoxic range in five of the six patients. This phenomenon is most likely due to a decrease in the metabolic clearance rate of the absorbed hormone associated with hypometabolism. Thus, serum T4 and T3 concentrations during the first 6 months of therapy do not reflect the optimal dose of T4 replacement on a long-term basis.     

Thyroxine suppressive therapy in patients with nodular thyroid disease

PURPOSE: To review evidence about thyroxine suppressive therapy in patients with thyroid nodules, including the clinical importance and natural history of nodules and the effects and potential side effects of thyroxine therapy. DATA SOURCES: English-language articles published from 1986 to December 1996 were identified through searches of the MEDLINE database, selected bibliographies, and personal files. DATA EXTRACTION: Randomized, controlled trials and nonrandomized trials of thyroxine suppressive therapy for solitary and predominantly solid thyroid nodules were reviewed. In most studies, nodule cytology was evaluated by fine-needle aspiration biopsy. Therapy was considered suppressive if suppression was documented by thyroid-stimulating hormone-releasing hormone tests or sensitive thyroid-stimulating hormone assays. Response was defined as a decrease of 50% or more in nodule size or volume; most recent studies measured nodule size by ultrasonography. DATA SYNTHESIS: The evidence suggests that thyroxine suppressive therapy fails to shrink most nodules: Only 10% to 20% of nodules responded to this treatment. Fine-needle aspiration biopsy is more reliable in distinguishing benign from malignant nodules. Recent studies suggest that spontaneous decrease in size with complete disappearance of thyroid nodules is not uncommon. No data show that thyroxine therapy arrests further growth in most existing nodules or prevents the emergence of new nodules. Postoperative thyroxine therapy does not seem to prevent recurrence of thyroid nodules except in patients with a history of radiation therapy. Potential adverse effects of long-term suppressive therapy include osteoporosis and heart disease. CONCLUSIONS: Patients with cytologically benign nodules are best followed without thyroxine treatment. Most benign nodules remain stable in size and remain benign when monitored for a long time. For nodules that increase in size, biopsy should be done again or surgery should be performed.     

Influence of clinical characteristics and parameters associated with thyroid hormone therapy on the bone mineral density of women treated with thyroid hormone

Reports of reduced bone mineral density (BMD) in patients receiving long-term replacement and suppression therapy with L-thyroxine have generated considerable interest and controversy. A substantial literature has evolved, with interpretation of conflicting results obscured by a variety of confounding factors. We examined the BMD measurements of 202 white women who were taking thyroid hormone to determine the contribution to BMD of a number of clinical characteristics and parameters associated with thyroid hormone therapy. Measurements of BMD (N = 335 over 2.6 +/- 1.6 years) of the spine (L2-L4) were performed in 195 subjects. The BMD of three sites of the hip was measured (N = 247 over 1.8 +/- 1.1 years) in 157 subjects. The BMD of the proximal radius was also measured (N = 172 over 1.8 +/- 1.2 years) in 124 subjects. Increasing age and a history of previous thyrotoxicosis had a deleterious effect on spine BMD. Body mass index (BMI) was positively correlated with spine BMD. Dose of thyroid hormone, duration of therapy, type of underlying thyroid disease, history of thyroidectomy, or serum-free thyroxine index did not influence either the initial BMD or the change in spine BMD over time. In the hip, age correlated with a decrease, and BMI with an increase in BMD. A history of previous thyrotoxicosis was associated with a decrease in hip BMD at all three sites (0.05 < p < 0.10). No other clinical parameters significantly influenced either the initial BMD or the change in hip BMD over time. Increasing age and dose of thyroid hormone, and a prior history of thyrotoxicosis had a deleterious effect on the BMD at the proximal radius. In summary, thyroid hormone therapy was not associated with a significant effect on BMD of the spine or hip, but a decreased BMD of the proximal radius was related to both previous thyrotoxicosis and to dose of thyroid hormone.     

Association of primary hypothyroidism with preconcious puberty. Presentation of clinical case and the effect of acute inhibition of thyrotropin on the gonadal activity

An 8 2/12 year-old girl with acquired primary hypothyroidism and precociuos puberty is described. Thyroid hormone treatment resulted in the regression of the sexual development, but moderate asymptomatic papilledema appeared as a result of therapy. Serial vaginal smears and measurements of urinary estrogen excretion during acute thyrotropin (TSH) inhibition with 75 mug/day of triiodthyronine (T3), showed a rapid drop in ovaric estrogen production up to prepubertal stage at 17 days of T3 administration. Moreover, a group of children with untreated hypothyroidism was followed through the first 3 to 12 months of thyroid therapy and none developed signs of increased intracranial pressure. These findings as well as the possible pathophysiology involved in this association are discussed.     

Altered patterns of thyroid hormones in serum and urine in pregnancy and during oral contraceptive therapy

Serum total, percentage free fraction and absolute serum free hormone concentration of thyroxine and triiodothyronine were measured in control, pregnant and oral contraceptive users, together with the daily urinary losses of unconjugated thyroid hormones. Increased urinary losses of both hormones, in particular thyroxine, were apparent in pregnancy and these could not be explained in terms either of an increased filtered load of hormone or the presence of proteinuria. The possible existence of filterable small-molecular weight hormone-binding substances in the urine of pregnant patients is discussed. It is concluded that assay of urinary thyroid hormones during pregnancy is of limited diagnostic value because of overlap with thyrotoxic values.     

Advice for the ''90s traveler

There are controversial reports on the potential role of L-thyroxine administration as a risk factor for osteoporosis. We studied bone mass and metabolism in a homogeneous series of 50 Caucasian women, 25 premenopausal and 25 postmenopausal, having nontoxic goitre treated with slightly suppressive L-thyroxine doses (50-200 micrograms/day) with subnormal serum TSH and normal thyroid hormone levels. These patients were matched with 50 controls for age, sex, body mass index, menopausal and thyroid disease. Patients and controls were also investigated for minor determinants of bone loss, such as hereditary and life-style factors. Patients and controls filled in a questionnaire and underwent physical examination, routine laboratory tests and calciotropic and thyroid hormone assay. Bone mineral turnover was evaluated by determining serum osteocalcin, alkaline phosphatase, tartrate-resistant acid phosphatase, calcium, phosphate, urine hydroxyproline/creatinine and calcium/ creatinine ratio. Bone mineral density was measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, trochanter and Ward's triangle. No difference in bone mineral density or biochemical markers was found between patients and controls; bone density and turnover were significantly affected by menopausal status. No relationship between bone density or turnover values and L-thyroxine administration was found. A significant positive correlation was found between osteocalcin and the hydroxyproline/creatinine ratio in premenopausal and postmenopausal patients, but not in controls. Our study suggests that slightly suppressive L-thyroxine administration in nontoxic goitre can activate bone turnover but constitutes neither an actual risk factor for bone loss nor, consequently, for osteoporotic fractures.     

Studies on the mechanism by which thyroid hormones enhance alpha-lactalbumin activity in explants from mouse mammary glands

Addition of 3,5,3'-triiodo-L-thyronine to cultures of mammary gland explants in serumfree medium containing insulin, hydrocortisone and prolactin results in a 3 to 5-fold increase in the activity of the milk-protein alpha-lactalbumin over that seen in the presence of the latter three hormones alone. The thyroid hormone does not act by substituting for any of the other hormones. It need not be present throughout the culture period but can act if added along with prolactin after insulin and hydrocortisone have induced formation of the rough endoplasmic reticulum. Delayed addition of the thyroid hormone also results in further stimulation of cells already responding maximally to insulin, hydrocortisone and prolactin. These effects of triiodothyronine are not blocked by progesterone at 1 microng per ml. They are, however, blocked by the addition of inhibitors of RNA (actinomycin D) or protein (cycloheximide or puromycin) synthesis, suggesting that the thyroid hormone increases the synthesis of the alpha-lactalbumin molecule itself. The thyroid hormone appears to act by altering the responsiveness of the mammary gland explants to prolactin, but not to insulin or hydrocortisone. In the presence of 10-9M triiodothyronine, enhanced alpha-lactalbumin activity is consistently obtained at prolactin concentrations as low as 4.5 x 10(-12)M whereas, in the absence of the thyroid hormone, ten times more prolactin (4.5 x 10(-11)M) is needed to obtain an increase in alpha-lactalbumin activity.     

Sucralfate causes malabsorption of L-thyroxine

PURPOSE: To determine if sucralfate causes malabsorption of L-thyroxine. PATIENTS AND METHODS: Five healthy volunteers ingested L-thyroxine, 1,000 micrograms, administered orally (1) without sucralfate, (2) with sucralfate, 1 g, and (3) 8 hours after sucralfate, 2 g. The amount of L-thyroxine absorbed was calculated from the peak increase in serum T4 levels within 6 hours of hormone ingestion multiplied by the volume of distribution for the hormone. RESULTS: Peak absorption of L-thyroxine in the absence of sucralfate was 796 micrograms (95% confidence interval (CI): 515-1,074 micrograms). Coadministration of sucralfate, 1 g, with L-thyroxine reduced thyroid hormone absorption to 225 micrograms (95% CI: 151-299 micrograms) (P = 0.0029 compared with control). Peak hormone absorption was delayed 2 hours by simultaneous sucralfate ingestion. Separation of administered L-thyroxine and sucralfate doses by 8 hours returned hormone absorption to control values. Maximum T3 levels did not differ, regardless of drug regimen, but suppression of thyroid-stimulating hormone (TSH) by L-thyroxine was reduced by coadministration of sucralfate. CONCLUSIONS: Sucralfate causes malabsorption of L-thyroxine, presumably by intraluminal binding of hormone.     

Solitary thyroid nodules. Separating benign from malignant conditions

Although features found on history taking, physical examination, thyroid function tests, and imaging studies help categorize solitary thyroid nodules as benign or malignant, fine-needle aspiration biopsy is the diagnostic test of choice. Nodules found to be malignant on cytologic examination should be treated with surgery. Benign nodules may be followed clinically or treated with levothyroxine to suppress their growth. Intermediate nodules should be excised if there is clinical suspicion of malignancy. In suspect nodules, levothyroxine therapy with follow-up ultrasound assessment for size is appropriate. Nodules that do not shrink significantly within 6 months should be excised.     

Distribution, abundance, and seasonal activities of ticks collected from rodents and vegetation in South Carolina

Perchlorate competitively blocks iodide from entering the thyroid by an effect on the Na+/I- symporter thus preventing the further synthesis of thyroid hormone but has no effect on the iodination process itself. It is concentrated by thyroid tissue in a manner similar to iodide but is not significantly metabolized in the gland or peripherally. What is not settled is whether there are additional perchlorate effects on iodide transport. Perchlorate has a fast turnover in the body and requires frequent daily doses for therapy of thyrotoxicosis. Perchlorate appears to be substantially more effective against large iodide loads than the thionamides, and, with long-term iodide contamination, combined therapy of perchlorate (with < or = 1 g/day) and thionamides is recommended for the more severe cases of thyrotoxicosis that may result from excess iodide or iodide-generating organic compounds, as for example with amiodarone. After approximately 30 days, the perchlorate dosage can be tapered or stopped, continuing with thionamides alone. This markedly increases its safe use. Despite serious side effects during its early use, lower dosages and shorter treatment periods appear to have prevented such reactions in its recent reintroduction, mostly for amiodarone-induced thyroid dysfunction. Perchlorate can also protect against inhibition of thyroid function and the resulting hypothyroidism caused by excess iodide, presumably by reducing the formation of an iodinated inhibitor. The reduction of the iodide pool by perchlorate thus has dual effects--reduction of excess hormone synthesis and hyperthyroidism, on the one hand, and reduction of thyroid inhibitor synthesis and hypothyroidism on the other. Perchlorate remains very useful also as a single dose application in tests measuring the discharge of radioiodide accumulated in the thyroid as a result of many different disruptions in the further metabolism of iodide in the thyroid gland.     

An insertion or deletion in the extramembrane loop connecting helices E and F of archaerhodopsin-1 affects in vitro refolding and slows the photocycle

A 34-year-old woman and a 54-year-old woman were treated with interferon-alpha (IFN-alpha) for chronic hepatitis C. Three months after the cessation of the IFN-alpha therapy, each patient developed hypothyroidism with the presence of thyroid-stimulation-blocking antibody (TSBAb) and TSH-binding inhibitor immunoglobulin (TBII). These two patients were treated with thyroxine, and both TSBAb and TBII activities gradually decreased. Although both TSBAb and TBII became negative several months after the start of the replacement therapy, the replacement dosage of L-thyroxine could not be reduced. Thyroid biopsies showed that the follicular epitheliums were flattened in both cases with lymphocytic infiltration. These findings suggest that IFN-alpha may induce hypothyroidism and the transient emergence of TSBAb and TBII.     

Morphological and functional polymorphism within clonal thyroid nodules

Thirty-nine thyroid nodules, removed because of recent growth, were analyzed morphologically by serial histological sections for the classical histomorphological hallmarks of follicular cell replication and for immunohistochemically demonstrable overexpression of the growth-associated ras-gene product p21ras. Clonal analysis was performed using the highly informative probe M27 beta that detects polymorphisms on the locus DXS255 of the X-chromosome. Twenty-four nodules were of clonal and 15 nodules were of poly-clonal origin. Only 3 out of the 24 clonal nodules were histomorphologically uniform. In all others, the structural hallmarks of active growth and the P21ras growth-marker expression were remarkably heterogeneous throughout the tumors. There were no histomorphological characteristics distinguishing these clonal tumors from polyclonal nodules. Even if a clonal thyroid tumor may be originally homogeneous in respect to the parameters studied here, mechanisms must exist that create wide heterogeneity of growth and of morphogenetic potential among the individual follicular cells during further expansion of the nodule. Thus, clonal nodules are much more common in nodular goiters than hitherto assumed on grounds of the classical morphological criteria. The diagnosis of a true monoclonal nodule can no longer rely on morphological and functional criteria alone but requires molecular or cytogenetic analysis of clonality.     

Utility of fine-needle aspiration cytology and frozen-section examination in the operative management of thyroid nodules

Fine-needle aspiration cytology has a high sensitivity for the diagnosis of solitary thyroid nodules. Certain diagnoses involving follicular histologies often cannot be made with needle biopsy alone. The utility of frozen-section examination of thyroid nodules, with particular regard to those lesions with follicular histologies, is also limited. We examined the correlation of fine-needle aspiration cytology and frozen-section examination in solitary thyroid nodules to determine the contribution of frozen-section examination to the operation. We reviewed the fine-needle aspiration cytology, frozen-section examination, and final pathology of 100 consecutive patients undergoing thyroidectomy for a solitary solid thyroid nodule in an 4-year period. The diagnoses were classified as indeterminant, benign, or malignant. The utility and impact of the diagnosis from fine-needle aspiration or frozen section on the operative procedure performed was analyzed. Fine-needle aspiration cytology as a diagnostic test for thyroid nodules demonstrated an indeterminant rate of 23 per cent, with a diagnostic accuracy of 77 and 92 per cent for benign and malignant disease, respectively. In all patients with inaccurate benign diagnosis on fine-needle aspiration cytology, follicular neoplasm was misinterpreted for follicular adenoma or multinodular goiter. In comparing frozen-section results, the indeterminant, benign, and malignant rates were 7, 96, and 64 per cent, respectively. Of the 23 patients with indeterminant results on fine-needle aspiration cytology, the intraoperative frozen-section diagnosis on 4 patients was deferred to permanent section; 18 received accurate cytological diagnosis; and in 1 patient, carcinoma was missed. Overall, the decision about the extent of surgical thyroid resection was changed in only 2 patients based on the frozen-section results. Preoperative evaluation with fine-needle aspiration cytology can accurately and appropriately define the extent of thyroid surgery in most patients with a diagnosis of malignant neoplasm or benign disease. Intraoperative frozen-section examination may be helpful if fine-needle aspiration cytology results are inderminant and in cases of follicular histology as an adjunct for evaluation of the thyroid nodule, but overall, frozen section does not contribute to the management of the thyroid lesion at the time of surgery.