Chapter12-graves'disease: complications

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Chapter 12. Graves' Disease: Complications

Published in © 2018


Luigi Bartalena, MD, Professor of Endocrinology, University of Insubria, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy

Revised February 2018


Thyroid storm is an acute and life-threatening worsening of hyperthyroidism, characterized by an exacerbation of symptoms and signs of hyperthyroidism, with high fever, dehydration, marked tachycardia or tachyarrhytmias, heart failure, hepatomegaly, respiratory distress, abdominal pain, delirium, possibly seizures. It may occur in patients submitted to thyroidectomy or radioactive iodine treatment while hyperthyroid, or as a consequence of infections in unteated hyperthyroid patients. Treatment consists of antithyroid drug treatmnt, rest, sedation, fluid and electrolyte replacement, cardio-supportive therapy, oxygen therapy, antibiotics, cooling. Mortality is about 10%.

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease, found in about 25% of patients at diagnosis, often mild and self-remitting. Removal of risk factors (refrain from smoking, correction of thyroid dysfunction, oral steroid prophylaxis after radioactive iodine therapy, antioxidant therapy with seleniomethionine) are fundamental to prevent progression of mild GO to more severe forms. In moderate-to-severe and active GO, intravenous glucocorticoids are the first-line treatment, second line treatments include cyclosporine, orbital radiotherapy, rituximab (controversial). Novel biologicals, such as teprotumumab and tocilizumab are under investigation. Rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is often required. Thyroid dermopathy (pretibial myxedema) is a rare complication of Graves’ disease, usually observed in patients who also have severe GO. Topical glucocorticoids are usually effective. Thyroid acropachy (clubbing of fingers and toes, with swelling of hands and feet) is an extremely rare conditions, for which no treatment is available.

Hypertyroidism may be complicated by severe cardiovascular manifestations, such as tachyarrhythmias (most commonly atrial fibrillation), congestive heart failure, angina, particularly in the elderly or in patients with preexisting heart abnormalities. Prompt restoration of euthyroidism is, therefore, warranted, as well as specific treatments for the heart.


Thyroid (or thyrotoxic) storm is an acute, life-threatening syndrome due to an exacerbation of thyrotoxicosis. It is now an infrequent condition, because of earlier diagnosis and treatment of thyrotoxicosis, better pre- and postoperative medical management. However, acute exacerbation of thyrotoxicosis caused by intercurrent illness, especially infections, may still occur. Thyroid storm in the past most frequently occurred after surgery, but now it is usually a complication of untreated or partially treated thyrotoxicosis, rather than a postoperative complication.

Clinical pattern

Classic features of thyroid storm are indicative of a sudden and severe exacerbation of thyrotoxicosis, with fever, marked tachycardia, tremor, nausea and vomiting, diarrhea, dehydration, restlessness, extreme agitation, delirium or coma. Fever is typical and may be higher than 105.8 F (41 C). Patients may present with a true psychosis or a marked deterioration of previously abnormal behavior. Sometimes thyroid storm takes a strikingly different form, called apathetic storm, with extreme weakness, emotional apathy, confusion, absent or low fever

Signs and symptoms of multiple organ failure may be present. Delirium is one example. Congestive heart failure may also occur, with peripheral edema, congestive hepatomegaly, and respiratory distress. Marked sinus tachycardia or tachyarrhythmias, such as atrial fibrillation, are common. Liver damage and jaundice may derive from congestive heart failure or a direct action of thyroid hormone on the liver coupled with malnutrition (Chapter 10). Fever and vomiting may produce dehydration and prerenal azotemia. Abdominal pain may be a prominent feature. The clinical picture may be masked by a secondary infection such as pneumonia, a viral infection, or infection of the upper respiratory tract. Death may be caused by cardiac arrhythmia, congestive heart failure, hyperthermia, or other unidentified factors.

Storm is typically associated with Graves' disease, but it may occur in patients with toxic nodular goiter (1, 2). At present, although still life-threatening, death from thyroid storm is rarer if it is promptly recognized and aggressively treated in an intensive care unit. In recent nationwide studies from Japan mortality rate was >10% (3, 4).


In Nelson and Becker's series reported in 1969 (5), there were 21 cases of thyroid storm among 2,329 admissions due to thyrotoxicosis (about 1%). Other series, which included all cases with fever of 38.3 C or more in the postoperative period, reported an incidence of thyroid storm as high as 10% of patients operated on (6). Few patients are now seen with the classic pattern of thyroid storm, but patients are occasionally encountered with marked accentuation of symptoms of thyrotoxicosis in conjunction with infection. The incidence of thyroid storm currently may currently be as low as 0.2 cases/100,000 population (3).


Thyroid storm classically began a few hours after thyroidectomy performed on a patient prepared for surgery by potassium iodide alone. Many such patients were not euthyroid and would not be considered appropriately prepared for surgery by current standards. Exacerbation of thyrotoxicosis is still seen in patients sent too soon to surgery, but it is unusual in the antithyroid drug-controlled patient. Thyroid storm occasionally occurs in patients operated on for some other illness while severely thyrotoxic. Severe exacerbation of thyrotoxicosis is rarely seen following 131-I therapy for hyperthyroidism; some of these may be defined as thyroid storm (7). Thyroid storm appears most commonly following infection (1), which seems to induce an escape from control of thyrotoxicosis. Pneumonia, upper respiratory tract infection, enteric infections, or any other infection can cause this condition. The decreased incidence of thyroid storm can be largely attributed to improved diagnosis and therapy. In most cases, thyrotoxicosis is recognized early and treated by measures of predictable therapeutic value. Patients are routinely made euthyroid before thyroidectomy or 131-I therapy (8). Using thionamides preoperatively, thyroid glands have only minimal amounts of stored hormones, thus minimizing thyroid hormone release due to manipulation.


Diagnosis of thyroid storm is made on clinical grounds and involves the usual diagnostic measures for thyrotoxicosis. Semi-quantitative scales and related scores evaluating the presence and severity of clinical manifestations may be of some help in confirming the diagnosis (1, 3, 9). There are no peculiar laboratory abnormalities. Free T4 and, if possible, free T3 should be measured. Serum total T3 may be not particularly elevated or even normal, due to reduced T4 to T3 conversion as observed in nonthyroidal illness (1). Electrolytes, blood urea nitrogen (BUN), blood glucose, liver function tests, and plasma cortisol should be monitored.


Thyroid storm is an endocrine emergency that has to be treated in an intensive care unit (Table 12-1).

Table 1. Treatment of Thyroid Storm

Supportive Measures

1. Rest

2. Mild sedation, or anticonvulsant therapy if convulsions occur

3. Fluid and electrolyte replacement

4. Nutritional support and vitamins as needed

5. Oxygen therapy

6. Nonspecific therapy as indicated

7. Antibiotics

8. Cardio-supportive

9. Cooling
Specific therapy

1. Propranolol (20 to 200 mg orally every 6 hours, or 1 to 3 mg intravenously every 4 to 6 hours)

2. Antithyroid drugs (150 to 250 mg PTU or 15 to 25 mg methimazole, every 6 hours)

3. Potassium iodide (one hour after first dose of antithyroid drugs):

4. 100 mg KI every 12 hours

5. Dexamethasone (2 mg every 6 hours)
Possibly useful therapy

1. Ipodate (Oragrafin) or other iodinated contrast agents, if available

2. Plasmapheresis or exchange

3. Oral T4 and T3 binding resins

4. Dialysis

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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