If drugs cannot be given orally (e.g., in the unconscious patient), they can be administered by naso-gastric tube or enemas (1). In some European countries intravenous preparations have been used (10). If the thyrotoxic patient is untreated, an antithyroid drug should be given. PTU, 150-250 mg every 6 hours should be given, if possible, rather than methimazole, since PTU also prevents peripheral conversion of T4 to T3, thus more rapidly reduces circulating T3 levels. Methimazole (15-25 mg every 6 hours) can be given orally, or if necessary, the pure compound can be made up in a 10 mg/ml solution for parenteral administration. Methimazole is also absorbed when given rectally in a suppository. An hour after a thionamide has been given, iodide should be administered. A dosage of 100 mg twice daily is more than sufficient. Unless congestive heart failure contraindicates it, propranolol or other beta-blocking agents should be given at once, orally or parenterally in large doses, depending on the patient's clinical status. Permanent correction of thyrotoxicosis by either 131-I or immediate thyroidectomy should be postponed until euthyroidism is restored. Other supporting measures should fully be exploited, including sedation, oxygen, treatment for tachycardia or congestive heart failure, rehydration, multivitamins, occasionally supportive transfusions, and cooling the patient to lower body temperature down. Antibiotics may be given on the presumption of infection while results of culture are awaited.
The adrenal gland may be limited in its ability to increase steroid production during thyrotoxicosis. If there is any suspicion of hypoadrenalism, hydrocortisone (100-200 mg/day) or its equivalent should be given. The dose can rapidly be reduced when the acute process subsides. Pharmacological doses of glucocorticoids (2 mg dexamethasone every 6 h) acutely depress serum T3 levels by reducing T4 to T3 conversion. This effect of glucocorticoids is beneficial in thyroid storm and supports their routine use in this clinical setting. Propranolol controls tachycardia, restlessness, and other symptoms.
Usually rehydration, repletion of electrolytes, treatment of concomitant disease, such as infection, and specific agents (antithyroid drugs, iodine, propranolol, and corticosteroids) produce a marked improvement within 24 hours. A variety of additional approaches have been reported, but indications for their use are not well defined. For example, oral gallbladder contrast agents such as ipodate and iopanoic acid in doses of 1-2 g, which inhibit peripheral T4 to T3 conversion, might have value. Unfortunately, these agents are no longer available. Peritoneal dialysis can remove circulating thyroid hormone, and plasmapheresis can do likewise, but at the expense of serum protein loss. Orally administered ion-exchange resin (20-30g/day as Colestipol-HCl) can trap hormone in the intestine and prevent recirculation. These treatments are rarely needed.
Antithyroid treatment should be continued until euthyroidism is achieved, when a final decision regarding antithyroid drugs, surgery, or 131-I therapy can be made.
Graves’ orbitopathy (GO) is the main and most frequent extrathyroidal manifestation of Graves’ disease, although it may less frequently occur in patients with Hashimoto’s thyroiditis or apparently without thyroid abnormalities (so-called Euthyroid Graves’ disease) (11-15).
Fig. 1: Prevalence of GO in a series of 346 patients with newly diagnosed Graves’ hyperthyroidism. Moderate-to-severe GO includes one case of sight-threatening dysthyroid optic neuropathy (DON). Derived from Tanda ML et al. (17).
Data on the incidence of GO are limited (11, 14). In a population-based setting in USA, an adjusted rate of 16 cases per 100.000 per year in women and 2.9 cases per 100.000 in men was reported (16). In a recent study of a large cohort of newly diagnosed Graves’ patients, about 75% had no ocular involvement at diagnosis, only 6% had moderate-to-severe GO, and 0.3% showed sight-threatening GO due to dysthyroid optic neuropathy (DON) (17) (Figure 1). In a Danish population, moderate-to-severe GO showed an incidence of 16.1/million per year (women: 26.7; men: 5.4) (18). Ocular involvement is in most cases bilateral, although often asymmetrical, but it may be unilateral in up to 15% of cases (12, 14). As recently reviewed by the European Group on Graves’ Orbitopathy (EUGOGO), the overall prevalence of GO in Europe is about 10/10,000 patients, but the prevalence of its variants (hypothyroid GO, GO associated with dermopathy, GO associated with acropachy, asymmetrical or unilateral GO) is much lower, and recently euthyroid GO has been listed as a rare disease in Europe (19). The onset of GO apparently has a bimodal peak in the fifth and seventh decades of life, but eye disease may occur at any age (20). It is more frequent in women, but men tend to have a more severe disease (21-23), as suggested by a decrease in the female/male ratio from 9.3 in mild GO, to 3.2 in moderately severe GO, and 1.4 in severe GO (20). There is a close temporal relationship between the onset of GO and the onset of hyperthyroidism. In approximately 85% of cases GO and hyperthyroidism occur within 18 months of each other (20), although GO may both precede (about 20% of cases) or follow (about 40% of cases) the onset of hyperthyroidism (20).
The natural history of GO is poorly understood. However, in a longitudinal cohort study, spontaneous amelioration was observed in two thirds of cases, while ocular involvement did not change with time in 20% and progressed in 14% (22). The observation that mild GO rarely progresses and often spontaneously remits was recently confirmed by a large prospective study of patients with recent onset Graves’ hyperthyroidism (17) and summarized in a review of published studies (24). It is worth noting that GO seems to be less frequent than in the past. A review of the first 100 consecutive patients seen at the same joint thyroid-eye unit in 1960 and 1990 revealed a decrease in the proportion of Graves’ patients with clinical relevant GO from 57% to 32% (23); likewise, a reduction in the proportion of severe forms of GO compared to milder forms was observed (18), likely reflecting an earlier diagnosis and treatment of both hyperthyroidism and orbitopathy. It should be noted that a multicenter study carried out by the European Group on Graves’ Orbitopathy (EUGOGO) reported that 40% of GO patients had mild disease, 33% had moderate GO, and 28% had severe eye disease (25). It should be noted that these figures were clearly influenced by the fact that EUGOGO centers are all referral centers where it is likely to see more complicated cases of GO. Accordingly, a recent single-center study confirmed that most patients newly diagnosed with Graves’ disease have mild GO (26), although whether these forms are chronic remitting or a transient disease (27) or whether GO ever disappears completely (28) is unsettled. In summary, based on recent studies and reviews of the available literature, it can be concluded that GO is a rare disease, particularly in its severe expressions (19).
An important epidemiologic feature of GO is its relation with cigarette smoking (29,30). The prevalence of smokers among Graves’ women with orbitopathy is much higher than that in Graves’ women apparently without GO or in normal controls (Figure 2) (31). Smoking is a predictor of Graves’ hyperthyroidism, with a hazard ratio of 1.93 in current smokers, 1.27 in ex-smokers, and 2.65 in heavy smokers (32). In a case-control study, the odds ratio of cigarette smoking for Graves’ hyperthyroidism without GO was 1.7, but raised to 7.7 for Graves’ disease with GO (33). Whether passive smoking may have the same impact as active smoking is unsettled; however, in a recent European survey of GO in childhood, the highest prevalence of Graves’ children with GO was found in countries where the prevalence of smokers among teenagers was also highest: since >50% of children were <10 years of age, it is likely that passive smoking rather than active smoking influenced GO occurrence (34). Mechanisms whereby smoking may affect the development and course of GO are unclear. In addition to direct irritative effects and modulation of immune reactions in the orbit (35), smoking was associated with an increase in the orbital connective tissue volume as assessed by MRI (36), and with an increased adipogenesis and hyaluronic acid production in in vitro cultured orbital fibroblasts (37). Whatever the mechanism(s) involved, cigarette smoking is strong (probably the strongest) predictor of GO occurrence in patients with Graves’ hyperthyroidism (38).
Figure 2. Prevalence of smokers among women with Graves’ disease with (GO) or without (GD) associated orbitopathy. NTG: Non-toxic goiter; C: controls. Derived from Bartalena et al (31).
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