[Choice of time of surgery in the surgical rehabilitation of Graves' ophthalmopathy].
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Female↗
Biomedical subjects
W M Wiersinga
Publications and source records attributed to W M Wiersinga.
Immunosuppressive treatment of Graves' ophthalmopathy.
Glucocorticoids and retrobulbar irradiation are the most employed immunosuppressive treatment modalities in Graves' ophthalmopathy. The response rate is approximately 60%. Efficacy is good for improvement of appearance and visual acuity, moderate for correction of extraocular muscle dysfunction, and poor for reduction of proptosis. Immunosuppression seldom cures the eye disease. Its main advantage is to stabilize the eye disease by inactivating the inflammation of orbital tissues, thereby permitting corrective eye surgery to be performed at an earlier time. Future developments in immunosuppression aim at reduction of side effects and enhancement of efficacy. Alternative treatment schedules (e.g., methylprednisolone pulses, intravenous immunoglobulin) may have equal efficacy but less side effects than classic high-dose oral steroids. Efficacy can be improved by restriction of immunosuppression to patients with active eye disease who are more likely to respond. Disease activity might well be the main determinant of therapeutic outcome of immunosuppression in Graves' ophthalmopathy.
Cyclosporine↗
Soluble IL-2 receptor levels in patients with Graves' ophthalmopathy.
In various autoimmune diseases circulating levels of soluble IL-2 receptor (sIL-2R) seem to be related to disease activity. Because reliable parameters of disease activity in Graves' ophthalmopathy are lacking, we measured sIL-2R levels in 47 patients with this disorder. The patients had Graves' disease, but no other immune-mediated diseases, had not yet received specific treatment for their ophthalmopathy and were euthyroid during the entire study period. Twenty-one of the 47 patients (45%) had sIL-2R values above the upper normal limit of 650 U/ml, as established in 20 healthy controls. There were no differences between patients with normal (median 469, range 280-644 U/ml) and elevated (median 946, range 678-1588 U/ml) sIL-2R levels regarding duration or severity of the eye disease (as assessed clinically from the total eye score). However, patients with severely enlarged eye muscles had higher sIL-2R values than patients with less severely enlarged eye muscles on CT scan. Patients with elevated sIL-2R tended to have a higher response rate (71%) to a 3-month course of prednisone, than those with normal levels (46%; P = 0.081). Since a successful outcome of prednisone treatment might be representative for disease activity, the elevated sIL-2R levels seem to reflect active inflammation. Although the practical relevance of this finding in individual patients is limited, it underscores the importance of cell-mediated immune responses in this thyroid-related eye disease.
Adult↗
Circadian changes in pulsatile TSH release in primary hypothyroidism.
OBJECTIVE: We evaluated pulsatile and circadian TSH secretion in primary hypothyroidism. DESIGN: In a prospective study, blood was sampled every 10 minutes during 24 hours for assay of TSH (IRMA). Thyroid hormones and TSH responsiveness to TRH were then measured. SUBJECTS: Nine patients with overt primary hypothyroidism, seven patients with subclinical hypothyroidism and 16 healthy controls. MEASUREMENTS: Computer-assisted analysis by the Desade and Cluster programs. RESULTS: Both computer-assisted programs revealed an increased TSH pulse amplitude in both overt and subclinical hypothyroidism versus controls (Desade: 36.9 +/- 31.4 (mean +/- SD) (P < 0.001) and 2.8 +/- 1.9 (P < 0.001) vs 0.4 +/- 0.2 mU/l; Cluster: 25.6 +/- 25.1 (P < 0.001) and 2.4 +/- 1.4 (P < 0.001) vs 0.4 +/- 0.2 mU/l). TSH pulse frequency remained unchanged with approximately 10 pulses/24 hours. A highly significant correlation was found between the mean 24-hour TSH concentration and the TSH pulse amplitude in all controls and patients but not to TSH pulse frequency. The nocturnal TSH surge was absent in six out of nine patients with overt primary hypothyroidism. The deficient nocturnal rise of TSH in primary hypothyroidism vs controls (22 +/- 51 vs 82 +/- 41%, P < 0.001), was associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency. CONCLUSIONS: Mean 24-hour TSH pulse amplitude is increased in primary hypothyroidism, but TSH pulse frequency remains unchanged. The decrease of the nocturnal TSH increase in primary hypothyroidism is associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency.
Adult↗
The nocturnal thyroid-stimulating hormone surge is absent in overt, present in mild primary and equivocal in central hypothyroidism.
UNLABELLED: The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%, NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3 +/- 0.4 vs 0.9 +/- 1.0 mU/l, p less than 0.05) and relative (24 +/- 31 vs 63 +/- 51%, p less than 0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight of ten patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54 +/- 33%) and subclinical (92 +/- 69%), but decreased in overt hypothyroidism (2 +/- 10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. IN CONCLUSION: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.
Circadian Rhythm↗
Distribution of the nuclear thyroid-hormone receptor in extraocular and skeletal muscles.
The correlation between the occurrence of Graves' ophthalmopathy and Graves' hyperthyroidism may indicate a role for tri-iodothyronine (T3) hormone in the pathogenesis of Graves' ophthalmopathy. In Graves' ophthalmopathy the recti eye muscles are greatly enlarged whereas skeletal muscles seem unaffected. The distribution of the nuclear T3 receptor was studied in normal human and rat eye and skeletal muscles with immunohistochemistry using mouse (monoclonal) antibodies, and by in-situ hybridization for the detection of mRNA encoding the T3-receptor protein. Nuclear staining with T3-receptor antibodies was found in all types of tissues studied. Cytoplasmic staining occurred predominantly in the muscle fibres of the orbital layer of the eye muscles and was generally absent or very low in skeletal muscle fibres and hepatocytes. Immunostaining could be inhibited by preabsorbing the antibodies with bacterially expressed T3-receptor protein, implying specificity. The presence of nuclear and cytoplasmic hormone-free T3 receptor sites was indicated after preincubation of sections with T3 hormone; T3-receptor immunostaining decreased and T3-hormone staining increased. In-situ hybridization clearly revealed the presence of alpha-1 and beta-1 forms of the T3-receptor mRNA in liver, skeletal muscles, and orbital and intermediate layers of the eye muscles. The data demonstrate the presence of T3 hormone-receptor molecules in the extraocular and skeletal muscles. The different susceptibilities of these muscles to Graves' hyperthyroidism may relate to the quantitative differences in T3 hormone-receptor distribution.
Adolescent↗
Site-dependent effects of experimental hypo- and hyperthyroidism on resident macrophages in extraocular muscles of rats: a quantitative immunohistochemical study.
It has been suggested that the effects of dysthyroidism on resident immunocompetent cells of the extraocular muscles may play a role in the pathogenesis of Graves' ophthalmopathy. The distribution of such cells was therefore studied in extraocular muscles of rats that were made hyper- or hypothyroid by the oral administration of thyroxine or propylthiouracil respectively. Skeletal muscles were studied for comparison. The cell distributions were analysed in cryostat cross-sections subjected to a two-step immunoperoxidase method using well-characterized monoclonal antibodies against T cells, B cells, macrophages and MHC class II antigens. The extraocular muscles of control (euthyroid) rats contained numerous macrophages, fewer MHC-II positive cells and T cells and no B cells. Differences in the distribution of immunocompetent cells were found in control rats, between skeletal and extraocular muscles as well as within the various recti eye muscles. This particular tissue distribution resembles that previously reported for human extraocular and skeletal muscles. Quantitative analysis showed that experimental dysthyroidism only affected cell populations in the extraocular muscles. Significant effects on the number of macrophages were observed in the inferior rectus muscle of both hypo- and hyperthyroid rats, this was most pronounced in the orbital layer of the muscles. Both hyper- and hypothyroidism appear to affect local cell distributions in a tissue-specific manner. The presently observed site-dependent effects of dysthyroidism on local immunocompetent cell populations may have relevance for the differential involvement of muscular tissues in Graves' ophthalmopathy.
Animals↗
Determinants of outcome in sporadic nontoxic goiter.
The author points out that natural history of sporadic nontoxic goiter (SNG) is characterized by increasing thyroid volume, nodularity and autonomy of function leading to hyperthyroidism in 13-16% of the patients after a medium follow-up of circa 12 years. Successively, the author reports and discusses the effectiveness and the outcome of the therapeutical modalities used for SNG: thyroidectomy, thyroid hormones and radioactive iodine.
Goiter↗
A rare case of Riedel's thyroiditis, 6 years after retroperitoneal fibrosis: two diseases with one pathogenesis?
We describe a 70-yr-old female patient in whom both a retroperitoneal fibrosis and 6 years later a Riedel's thyroiditis were diagnosed. Both diseases belong to the group of fibrotic diseases called "multifocal fibrosis". Retroperitoneal fibrosis is now known to be an auto-allergic reaction to lipid components of the atherosclerotic process in the abdominal aorta, resulting in a fibrotic reaction around it. We hypothesize that similarly Riedel's thyroiditis is in fact a periarteritis of the carotid artery, resulting in cervical fibrosis, secondarily involving the thyroid. This hypothesis would account for the occurrence of these two rare diseases in one patient.
Aged↗
Competitive inhibition of T3 binding to alpha 1 and beta 1 thyroid hormone receptors by fatty acids.
This study was undertaken to investigate whether fatty acids inhibit the binding of T3 to the alpha 1 and beta 1 form of the thyroid hormone receptor. Fatty acids inhibited the binding of T3 to both receptor proteins isolated from a bacterial expression system. The effectiveness of inhibition depends on the chain length and degree of saturation of the fatty acids. The inhibition of T3 binding to the alpha 1 and beta 1 receptor by oleic acid is competitive in nature; the Ki value was 5.4 10(-6) M for the c-erbA alpha 1 protein and 3.3 10(-6) M for the c-erb beta 1 protein. The findings indicate a direct interaction of fatty acids with T3 receptor proteins.
Animals↗
[Radioactive iodine; a useful alternative in the treatment of non-toxic goiter?].
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Adult↗
An increase in plasma cholesterol independent of thyroid function during long-term amiodarone therapy. A dose-dependent relationship.
OBJECTIVE: To determine whether long-term amiodarone treatment is associated with a rise in plasma cholesterol, and, if so, to analyze its relation with thyroid function. DESIGN: Consecutive entry trial, including cardiac patients who initiated amiodarone medication but excluding those with abnormal thyroid function (defined as peak thyroid-stimulating hormone [TSH] response to thyrotropin-releasing hormone [TRH] less than 2.8 or greater than 22.0 mU/L) either before or during amiodarone treatment. PATIENTS: Twenty-three patients who remained euthyroid were studied. INTERVENTION: Oral administration of amiodarone (mean duration of treatment, 17 months; range, 6 to 30 months). MEASUREMENTS: Fasting plasma lipids, thyroid hormones, and peak TSH to TRH values were recorded before and every 6 months during amiodarone treatment. RESULTS: Plasma cholesterol gradually increased from 5.1 +/- 0.2 mmol/L before treatment to 6.9 +/- 0.8 mmol/L after 30 months of amiodarone medication (P less than 0.001); the peak TSH response to TRH did not change. When age- and sex-specific reference values were applied, 30% of the patients had cholesterol values above the 75th percentile before treatment; this number rose to 69% after 2 years of treatment. The rise in plasma cholesterol was associated with an equal increase in apoprotein B. Plasma cholesterol was not related to the daily dose of amiodarone or to plasma concentrations of amiodarone, desethylamiodarone, thyroxine (T4), triiodothyronine (T3), or reverse triiodothyronine (rT3). Linear regression analysis indicated a positive relation between plasma cholesterol and the cumulative dose of amiodarone (r = 0.25, P less than 0.05). CONCLUSION: Long-term amiodarone treatment is associated with a dose-dependent increase in plasma cholesterol that is independent of thyroid function.
Adult↗
Inhibition of nuclear T3 binding by fatty acids liberated from nuclear membranes via phospholipase C.
1. We have investigated whether phospholipase C (PLC) might act on phospholipids in the nuclear membrane of rat liver, resulting in inhibition of nuclear T3 binding (INB activity). 2. Incubation of intact nuclei with PLC caused a time- and dose-dependent increase of INB activity; this was correlated with a rise of the free fatty acid concentration in the nuclear ether extract. 3. Removal of the nuclear membrane resulted in a loss of INB activity of the nuclei. 4. Other compounds liberated by the action of PLC (such as diacylglycerols, IP3 and phosphoalcohols), had no INB activity. 5. We conclude that PLC can liberate fatty acids from the rat liver-nuclear membrane via further degradation of the direct product diacylglycerol. 6. These fatty acids display inhibition of nuclear T3 binding in vitro.
Animals↗
Amiodarone induces a dose-dependent increase of plasma cholesterol in the rat.
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Amiodarone↗
Propranolol and thyroid hormone metabolism.
Propranolol decreases plasma T3 and increases plasma rT3 in a dose-dependent manner due to a decreased production rate of T3 and a decreased metabolic clearance rate of rT3, respectively, caused by inhibition of the conversion of T4 into T3 and of rT3 into 3,3'-T2. This inhibition of 5'-deiodination is not secondary to inhibition of thyroid hormone transport across the plasma membrane. Propranolol and its major metabolite, 4-hydroxypropranolol, are not directly responsible for these effects, but an unidentified metabolite of propranolol might be involved. beta-blockers ameliorate clinical symptoms and signs of thyrotoxicosis independent of the decrease of plasma 13, that is confined to beta-blockers with membrane-stabilizing activity, such as propranolol and alprenolol. The decrease of plasma T3, however, appears responsible for some of the metabolic responses to beta-blockers.
Adrenergic beta-Antagonists↗
Classification of the eye changes of Graves' disease.
Classification of the eye changes of Graves' disease may have clinical use in the description of the present eye state, in the assessment of treatment results, and in the choice of therapy. Requirements for any classification system should include simplicity, clinical nature (i.e., easily carried out by any physician equipped with ordinary noninvasive techniques), reproducibility and meaningfulness (i.e., objective and of clinical relevance to the patient). The NOSPECS system (although it can be improved) is suitable for pure description. It is not very helpful in the assessment of treatment results. Therapeutic outcome probably is best described by measuring quantitatively changes in visual acuity, eye muscle motility, and proptosis. Such an approach, however, does not solve the problem of whether or not the overall outcome is a success in the patient with improvement in one aspect but worsening in another item. A recently developed clinical activity score may be helpful in the selection of therapy, especially for deciding whether or not immunosuppressive therapy should be instituted.
Graves Disease↗
The course of biochemical parameters of bone turnover during treatment with corticosteroids.
The mechanisms by which glucocorticoids cause osteopenia are incompletely understood. It is generally accepted that bone formation is depressed during corticosteroid treatment, but the cause of the ongoing bone resorption is less clear. Secondary hyperparathyroidism and changes in vitamin D metabolism are thought to play a role. This is based mostly on data from cross-sectional studies in heterogeneous patient groups. We, therefore, studied longitudinally the course of biochemical parameters and the hormones influencing bone turnover in a homogeneous group of 10 euthyroid patients with Graves' ophthalmopathy, all euthyroid for at least 1 yr before, during, and after a 12-week course of prednisone. Bone formation was depressed as reflected by a fall in serum osteocalcin (3.0 +/- 2.1, 1.7 +/- 1.1, and 2.4 +/- 1.9 micrograms/L at weeks 0, 4, and 12, respectively; P = 0.02) and in total alkaline phosphatase (1.15 +/- 0.33, 0.83 +/- 0.22, and 0.88 +/- 0.40 mukat/L; P = 0.001). Parameters of bone resorption (urinary hydroxyproline/creatinine ratio, serum acid phosphatase) and the levels of vitamin D metabolites remained unchanged. Serum intact PTH seemed to decrease slightly. Our findings suggest that glucocorticoid induced osteopenia is caused by a depressed bone formation in the presence of an unaltered but ongoing bone resorption. Secondary hyperparathyroidism and changes in vitamin D metabolism are apparently not involved.
Acid Phosphatase↗
Inhibition of nuclear T3 binding via PLA2-induced release of fatty acids from nuclear membranes.
This study was undertaken to explore putative regulatory mechanisms involved in the inhibition of nuclear T3 binding (INB) by fatty acids. Ether extracts of intact rat liver nuclei contained INB-activity. Removement of the nuclear membrane resulted in the loss of INB-activity of the nuclei. Incubation of intact nuclei with phospholipase A2 increased nuclear INB-activity in a time- and dose-dependent manner; this was correlated with a rise of free fatty acid concentration in the ether extract. We conclude that fatty acids present in the nuclear membrane can be released by phospholipase A2, and are capable of inhibiting nuclear T3 binding.
Animals↗