Thyroid Associated Ophtalmopathy
Iodine DeficiencySodium-Iodide
SymporterMiscellaneous
Diekman et al., Amsterdam and Nijmegen, The Netherlands, tested the hypothesis that in hypothyroidism oxidation rate of LDL particles is increased versus euthyroidism. They tested oxidation kinetics of LDL and serum concentration of LDL in 10 patients with primary hypothyroidism (mean TSH 76 mU/l and mean T4 40 nmol/l) and retested when patients were at least 3 months euthyroid during T4 treatment (mean TSH 2.7 mU/l and mean T4 115 nmol/l). They found during primary hypothoidism that dienes in LDL particles was increased as compared to after T4 treatment (258 vs 187 nmol/mg). Resistance to oxidation of LDL was 43 vs 76 min, and oxidation rate was 15 vs 19 nmol/mg LDL/min respectively. It is concluded that hypothyroidism is associated with increased oxidizability of LDL promoting atherosclerosis.
Huber et al., Basel, Switzerland, studied 154 female patients with subclinical hypothyroidism (elevated serum TSH with normal free T4 and total T4 levels) over a mean period of 10 years. They found that after this period 34% of these patients developed overt hypothyroidism, 57% remained in the subclinical stage and 14% normalized their thyroid function. When patients were grouped according to TSH: gr.I TSH <6, gr. II TSH 6-12, and gr. III TSH>12 mU/l, overt hypothyroidism developed in 7.3%, 26% and 78% respectively. TSH reserve after TRH was more predictive in development of overt hypothyroidism than titers of circulating thyroid autoantibodies.
Krohn et al., Leipzig, Germany, argued that if a somatic mutation in one thyroid cell leads to the formation of autonomous nodules, these nodules should be of monoclonal characteristics. They investigated 27 toxic nodules and found in 13 somatic mutations in the TSHR and in 10 of these evidence was found for clonal expansion. In the 12 toxic nodules where no mutation was found in the TSHR or the G protein in 6 also monoclonal formation of the nodule was found. (Comment: It should be realized that not the whole gene of the TSHR and the G coupled protein have been investigated for mutations so far. It is thus not clear at the moment if all nodules are due to gene mutations or also due to other causes.)
Bennedbaek et al., Odense, Denmark, compared the efficacy of percutaneous ethanol injection therapy (PEIT) and T4 suppressive therapy (TST) on regression of solitary solid cold benign thyroid nodules. Patients were randomized to either (n = 25) TST or (n = 25) PEIT. PEIT resulted in a clinical response in 50% of patients while TST resulted in regression in only 30% of patients as evaluated 12 months after therapy.
Knudsen et al., Copenhagen, Denmark, investigated the prevalence of thyroid structural abnormalities and the natural history of solitary cold nodules (SCN) in an unselected population with borderline iodine deficiency (mean 24 hr iodine excretion 88 µg). People aged 41, 51, 61, and 71 years out of a population of 4.073 people were invited and 2.656 (65%) participated. Ultrasonography revealed that in 23% a multinodular thyroid structure was present. It was 3.1 times more frequent in women, 4.2 times in old age, and 1.44 times more frequent when anti TPO was present. In 65 participants (2.5%) solitary cold nodules (SCN) were found with Tc uptake. SCN was more frequent in heavy smokers, but no relation was found with sex, age, anti TPO or iodine excretion. After 2 years follow-up, 14 patients with SCN were operated but no cancers were found. Of the remaining SCN the diameter was generally unchanged after 2 years.
LoPresti et al., Messina, Italy, investigated retrospectively the relationship between thyroid nodules and parity in 393 women (age 18-43 years) from a moderate area of iodine deficiency. Patients were investigated with ultrasound and, if necessary, fine needle aspiration of the nodule. In cases of suspicion thryoidectomy was followed. 275/393 women (gr A) had 1 or more pregnancies and 118/393 (gr B) were nullipara. They found that multinodularity was age related but not parity related. Furthermore, cytological features were similar in both groups as was prevalence of differentiated thyroid carcinoma (5%).
Brix et al., Odense, Denmark, investigated the genetic contribution to the etiology of Graves' disease in a population of Danish twins. In 18 monozygotic twins they found a probandwise concordance rate of 0.36 and in 33 pairs of dizygotic twins this rate was 0 (p = 0.012). The authors conclude that as the pairwise concordance rate is significantly higher in monozygotic pairs, that genetic factors in the etiology of Graves' disease are important. Recently an association has been found between Graves' disease or autoimmune hypothyroidism and polymorphism in the CTLA- 4 gene that plays a central role in T cell activation and downregulation.
Donner et al., Frankfurt/Main, Germany, and Watermann et al., Sheffield and Cardiff, UK, found that polymorphism of this gene represents an additional risk marker for Graves' disease but also for autoimmune hypothyroidism and postpartum thyroid disease.
Siegmund et al., Frankfurt/Main, Germany, also found that interferon-gamma polymorphism predisposes to development of Graves' disease. (Comment: Further studies are necessary to indicate if these and other genetic markers may be used to define subgroups that are at risk for development of autoimmune thyroid disease.) Inflammatory processes are often accompanied by increased serum levels of interleukin-6 (IL-6). These elevations have also been found in thyroiditis.
Salvi et al., Parma, Italy, and Moncayo et al., Innsbruck, Austria, investigated the presence of IL-6 in patients with Graves' disease with or without thyroid associated ophthalmopathy (TAO). They found increased levels of IL-6 when TAO was present, whereas normal levels were found in patients with Graves' disease without TAO. It was also found that decreases in IL-6 were associated with clinical improvement of symptoms after steroid therapy or external orbital radiation.
Glinoer et al., Brussels, Belgium, report a collaborative prospective investigation from 9 institutions in Belgium on the medical management of 140 newly diagnosed patients with a first episode of Graves' disease living in an area with marginally low iodine intake (50-75 µg/d). Patients were initially treated with a mean dose of 38 mg methimazole per day. Despite a 20% reduction in mean dosis after 2 months and co-administration of L-T4 in 63% of patients (mean dose 75 µg/d) free T4 was markedly reduced by 75% in average with 40% of cases below the lower normal limit. Also T3 was below normal in 34% of patients. After 4 months, despite a further reduction in MMI of 8% and all patients then receiving L-T4 substitution (mean 87 µg/d) free T4 and T3 were still below normal in 14 and 25% of cases respectively. Serum TSH rose >4mU/l in 25% of patients both at 2 and 4 months. The authors conclude that in an area of marginally low iodine intake, treatment of Graves' disease with MMI may rapidly induce frank elevations of serum TSH in a substantial number of patients. It is not known of this early rise in TSH will have an adverse effect on the longterm outcome of treatment.
Behr et al., Göttingen, Germany, and Belleville, NJ, USA, studied detectibility and therapy of occult and metastatic medullary thyroid carcinoma (MTC) using 131I labeled anti-CEA antibodies and labeled octreotide. The results from 44 patients indicate that detection of occult MTC is improved over conventional methods when using labeled CEA or octreotide for scintigraphy. In addition, treatment results with labeled anti-CEA showed that in 10 of 18 patients anti-tumor effects were induced lasting up to 26 months.
Frich et al., Oslo and Bergen, Norway, found that in women married to fishery workers the risk of developing thyroid carcinoma was increased by 1.91 (confidence interval 1.65-2.21). Especially between the age of 45-54 years the increased risk was high: 2.61. An increased risk was also associated with ship officers and pilots work. The authors suggest that seafood may play a role in this increased risk.
Angelini et al., Pisa, Italy, studied the effectiveness of radioablation with 131I in patients after operation for thyroid carcinoma. Patients were off L-T4 therapy and whole body scan was performed 24 hours after administration of 1 mCi 131I. Patients were divided in 3 groups (1) n = 180 treated with 1110 Mbq (30 mCi); (2) n = 200 who received between 1147 Mbq (31 mCi), and 2960 Mbq (80 MCi); (3) n = 226 who received doses > 2960 Mbq (80 mCi). It appeared that the effectiveness to ablate residual thyroid tissue was similar in the 3 groups: 44%, 47%, and 47.7% respectively. No relationship between effectiveness and age, serum TSH and Tg, urinary iodine excretion, and thyroid uptake was found. It is concluded that a dose of 30 mCi is as effective as higher doses 131I for thyroid ablation after surgery.
Beressi et al., Bobigny, France, report clinical characteristics and prognosis of 80 patients with sporadic medullary carcinoma (MTC) with a tumor less than 1 cm in diameter. The mean age at surgery was 51.8 years for 53 women and 27 men. Lymph node involvement was observed in 21% and another thyroid malignancy in 16%. Mean follow-up was 3.8 years. Specific survival rate was 95.7% after 10 years. Biological cure (normal basal serum calcitonin) was obtained in 71.3%.
Olivieri et al., Rome, Italy, studied the prevalence of TPOAb in 62 pregnant women at risk for gestational diabetes mellitus (GDM). Risk factors were obesity, familial and personal history for GDM, and maternal age. Glucose tolerance was found to be abnormal in 15/62 women. Euthyroidism was found in all 62 women and TPOAb prevalence was similar to that observed in healthy pregnant controls (14.5% vs 12.5%). However, when 62 GDM risk women were grouped on the basis of family history of diabetes (IDDM or NIDDM) an increased prevalence of TPOAb was found (35%). When a positive family history for diabetes was combined with a positive history for thyroid dysfunction TPOAb prevalence was even higher (66%). The authors suggest screening for TPOAb especially in women who are at increased risk of GDM.
Mariotti et al., Cagliari, Italy and London, UK, studied the prevalence of thyroid autoantibodies (ATA), islet cell autoantibodies (ICA) and goiter rate in 7576 school children. They found that ATA and goiter prevalence did not show a sex difference in prepubertal children, while a clear age-dependent increase of both goiter and ATA prevalence was observed in females as compared to males beyond the age of 11-12 years. Between 12 and 14 years goiter rate increased from 30-35% in females and from 20-24% in males. In this age period ATA increased from 4.2-5% in females but did not vary significantly in males (2.0 ą 3%). The prevalence of ICA was not different in the age groups or between the sexes. (Comment: No information was given regarding the iodine intake in these children, but looking at the goiter rate, it seems that iodine intake was probably marginal.)
Beressi et al., Paris, Lille, Limoges, Bobigny, Kremlin-Bicźtre, France; Algiers, Algeria; Oxford, UK, studied vertical transmission of autoimmune thyroid diseases in multiplex families. Families were all caucasian but from different origin: France (n = 68), Algeria (n = 14), and Egypt (n = 10). Of these families 41% were Graves' disease only, 27% Hashimoto thyroiditis only, and 30% both. Vertical transmission (1 or 2 parents affected) of disease was observed in 59% of families. Horizontal transmission (at least 2 affected siblings) was observed in 50% of families. Among 260 affected subjects 82% were women. Presence of other autoimmune disease was rare (9 patients in 92 families). (Comment: This is an interesting study, showing clustering of autoimmune thyroid disease in caucasian families.)
Bocale et al., Rome, Italy, compared the diagnostic accuracy of autoimmune thyroiditis by ultrasonography and fine needle aspiration retrospectively in a group of 204 patients (177 females) in the age between 12 and 62 years. Four groups were delineated: group I: 6.9% of patients with an enlarged and diffusely hypoechogenic thyroid gland in all of whom chronic autoimmune thyroiditis (CAT) was confirmed by cytology; group II: 9.8% of patients with a sonographic pattern of multiple focal hypoechogenicities and positive cytology for CAT; group III: 72% of patients with hypoechogenic thyroid gland with single or multiple nodules and scattered hyperechogenic areas. In 57.1% CAT was cytologically confirmed; Group IV: 11.3% of patients with isoechogenic ultrasound but numerous hyperechogenic spots and strings in a small thyroid gland. In 45.5% CAT was cytologically confirmed while cytology was inadequate in 54.5%. The authors conclude that ultrasonography is a useful technique for the diagnosis of CAT, but can only serve as a complimentary test in addition to cytology and serum antithyroid antibody measurement. (Comment: I personally feel that the diagnosis of autoimmune thyroiditis should primarily be based on the presence of circulating thyroid antibodies and not on the echogenic pattern of ultrasound.)
Weissel et al., Vienna, Austria, investigated thyroid function and thyroid autoimmunity in 55 patients (42 females) suffering from myasthenia gravis (MG). They found in no instance thyroid dysfunction but in 5% of patients positive antibodies against Tg, in 16% against thyroid microsomes, and in 7% against TSH-receptor. The authors conclude that thyroid dysfunction in patients with MG is rare, however, that there is a relative increased frequency of thyroid autoantibodies, suggesting a link between autoimmune thyroid disease and MG. (Comment: Kiesling et al., Neurology 31:771-774, 1981, also found an increased frequency of thyroid dysfunction in 104 patients with MG. Thyrotoxicosis was found in 5.7%, thyroid autonomy in 10%, hypothyroidism in 1.9%, and subclinical hypothyroidism in 3.4%.)
Smyth et al., Dublin, Ireland, investigated the prognostic significance of the presence of TPO antibodies in the outcome of breast cancer. They found positive antibodies in 41% of breast cancer patients versus 19.2% in controls. The presence of TPO antibodies was associated with improved outcome following therapy in breast cancer in 143 patients available for follow-up, only if thyroid volume varied between 9.4 and 18.8 ml. At 5 years disease, free survival was 65% compared to 36% in TPO negative breast cancer patients, and for the same period overall survival was respectively 93 and 54%. No such associations were found in TPO positive patients when thyroid volume was beyond the above mentioned range. (Comment: The mechanistic and clinical significance of these findings is not known, but further studies are welcome.)
Marino et al., Cagliari, Italy, investigated the prevalence of circulating anti-cardiolipin (aCL) with a recent more specific ELISA and compared the results to those obtained with a less specific first generation ELISA in 31 patients with Graves' disease and 31 patients with Hashimoto's disease. The first generation ELISA found an increased prevalence of aCL in Graves' disease but not in Hashimoto's disease. With the more specific ELISA no differences with controls were found in either patients groups.
Gerding et al., Amsterdam, The Netherlands, measured quality of life (using Medical Outcomes Study: MOS-24) in 70 consecutive euthyroid patients with different degrees of severity of TAO. Also disease-specific quality was assessed using a newly developed questionnaire (GO-QOL) containing 16 questions concerning two dimensions i.e. visual functioning and appearance. Also 844 patients with diabetes mellitus were tested. It was found that TAO has an important impact on quality of life, even when compared to patients with diabetes. Daroszewski et al., Wroclaw, Poland, studied 24-hour urine excretion of glycosaminoglycans (GAG). It is known that part of the eyesigns in TAO are caused by increased GAG production in the orbit. Eyesigns were assessed by NO SPECS, ultrasound of extraocular muscles and CT scanning of the orbit. GAG excretion during the active phase of TAO was 2052g/24h which was significantly higher than 603g/24h when patients were in remission. The authors conclude that GAG measurement in the urine is a useful marker of activity of TAO and of effectiveness of treatment. Kahaly et al., Mainz, Germany, performed octreoscanning in 20 consecutive patients with Graves' disease with active untreated TAO at 4 and 24hr after injection of tracer before and 3 months after starting antithyroid therapy combined with prednisone. Thyroid octreotide uptake decreased during methimazole: 253 counts vs 95 counts after 24hr. Thyroid uptake was positively correlated with free T3 and with TSH-receptor antibodies in untreated patients. Fourteen/twenty patients responded to prednisone/irradiation therapy with regard to TAO. In these patients orbital octreotide uptake decreased markedly after completion of therapy: 4hr 25 counts vs 6.2 counts before and after therapy respectively. A high pretreatment uptake correlated with a response to therapy with a predictive value of 90%. The authors conclude that octreoscanning in TAO has a high sensitivity with regard to prognosis of treatment and may be used as an semi-objective tool in the evaluation of Graves' TAO and Graves' hyperthyroidism.
Saito et al., Yamanashi, Japan, compared hmRNA of hNIS in normal human thyroid and in thyroids of patients with Graves' disease. They found 3.8-fold increased concentrations of the message in Graves' thyroid glands. They also found that incubation of human thyroid cells in culture with TSH or forskolin increased hNIS mRNA 2-3-fold.
Reinhardt et al., Essen and Hannover, Germany, investigated the TSH-secretion pattern in 6 male patients with severe sleepapneasyndrome before, during the first night with continuous positive airway pressure (cpap) and after 4 weeks of cpap. Cpap resulted in an increase of 15% in REM-sleep and 32% increase in sleep stages 2 and 3. There was a drecrease of about 50% in TSH secretion in the first night of cpap as compared to the night before, but after 4 weeks pretreatment values were again seen. As prolactin secretion pattern was unchanged during cpap it is suggested that the temporary decrease in TSH is caused by a dopaminergic independent mechanism.
Fliers et al., Amsterdam, The Netherlands, investigated the question why serum TSH is not elevated in NTI while serum T3 and sometimes also T4 are low. To this effect they measured TRH mRNA in 10 formalin-fixed, paraffin embedded hypothalamy of patients in whom plasma T3, T4 and TSH were measured 24hr before death. They found a positive correlation between total TRH mRNA in the paraventricular nucleus with serum T3, log TSH, but not with T4. They conclude that these findings suggest an important role of TRH in the absent rise of TSH in NTI.