Hyperthyroidism in Graves’ Disease☆

Danila Covelli and Mario Salvi, University of Milan, Milan, Italy

© 2018 Elsevier Inc. All rights reserved.

Introduction 1
Clinical Manifestations 1
Diagnosis 3
Management 3
References 5
Further Reading 5

Glossary
Hyperthyroidism Overproduction of thyroxine and triiodothyronine by an overactive thyroid gland.
Orbitopathy Inflammatory condition of the orbital tissues causing protrusion of the eye globe and diplopia. Most frequent
extrathyroidal manifestation of Graves’ disease.
Pretibial myxedema and acropachy Other more rare extrathyroidal manifestations of Graves’ disease characterized by
remodeling of the dermis and of the bone-connective tissue of the extremities.
T3 receptor Receptor for triiodothyronine (T3) present in the cytoplasm and nucleus of most human cells; after T3 binding, this
T3 receptor complex influences gene transcription.
Thyrotoxicosis Elevated thyroxine (T4) and triiodothyronine (T3) levels, regardless of their cause; may result from an
overactive thyroid gland, but also may result from exogenous T4 and/or T3 use or from destruction of the thyroid gland.
Thyroxine (T4) Inactive prohormone produced by the thyroid gland and containing four iodine atoms.
Triiodothyronine (T3) The active thyroid hormone mainly produced locally in the tissues by deiodination of thyroxine;
approximately 20% of circulating T3 is produced by the thyroid gland itself.
TSH—receptor The target of TSH in a physiological state and of autoreactive immunoglobulins in Graves’ hyperthyroidism.
Thionamides Antithyroid drugs such as methimazole, carbimazole and propylthiouracil.

Introduction

Hyperthyroidism is the main clinical feature of Graves’ disease (GD) and is due to the excess of thyroid hormones produced by
follicular cells, as a result of stimulation by autoantibodies against the thyroid-stimulating hormone (TSH) receptor.
Manifestations of hyperthyroidism in Graves’ patients were first described by Caleb Perry in the first half of 19th century but the
link with thyroid hyperfunction was recognized only after the description of Robert Graves and Karl A. von Basedow.
As in all autoimmune diseases, when self-tolerance is broken, T cells recognize self-antigens and B cells produce antibodies
targeting host cells. In this case, autoantibodies are directed against the TSH receptor. The binding of these antibodies causes an
overfunction of the follicular cell, and thus thyroid hormones, thyroxine (T4) and triiodothyronine (T3), thyroglobulin and small
amounts of an iodinated albumin-like protein and iodotyrosines are released into the blood stream at increased rates.
The overproduction of hormones by the thyroid itself is defined as hyperthyroidism and is the main cause of thyrotoxicosis, the
clinical pattern due to the exposure of peripheral tissues to excess thyroid hormones.

Clinical Manifestations

The presenting symptoms are mainly attributable to the effect of the excessive serum concentrations of thyroid hormones; ocular
changes and abnormalities of the skin and connective tissue are instead more related to the multi-organ autoimmune involvement.
The classical clinical picture includes weight loss, despite increased appetite, weakness, dyspnea, palpitations, increased bowel
movement, irritability, profuse sweating, sensitivity to heat or increased tolerance to cold and tremor. The most common clinical
manifestations are outlined in Table 1.
The involvement of the entire body in the hyperthyroid syndrome is due to the widespread distribution of T3 receptors in tissues,
although the cardiovascular system and the muscles are the main targets for thyroid hormones. Tachycardia is the most common

☆
Change History: February 2018. Danila Covelli and Mario Salvi updated all sections of the previous manuscript. Tables and Figures are unchanged.
This article is an update of Mark F. Prummel, Graves’ Disease, Hyperthyroidism in, In Encyclopedia of Endocrine Diseases, edited by Luciano Martini, Elsevier,
New York, 2004, Pages 354–356, ISBN 9780124755703, https://doi.org/10.1016/B0-12-475570-4/00563-1.

Encyclopedia of Endocrine Diseases, 2nd Edition https://doi.org/10.1016/B978-0-12-801238-3.98496-4 1

2 Hyperthyroidism in Graves’ Disease

Table 1 Common clinical manifestations of thyrotoxicosis

Symptoms Nervousness, hyperactivity

Fatigue, weakness, diminished sleep
Increased perspiration, heat intolerance
Palpitations
Tremor
Weight loss despite increased appetite
Menstrual disturbances
Signs Hyperactivity
Tachycardia, atrial fibrillation
Systolic hypertension
Warm moist skin
Fine skin and hair
Tremor
Hyperreflexia
Stare and eyelid retraction
Only in Graves’ disease Diffusely enlarged thyroid (goiter)
Orbitopathy
Pretibial myxedema and acropachy

clinical sign of hyperthyroidism and it may eventually lead to atrial fibrillation, especially in elderly patients. A recent study has
shown that older age, elevated serum free T4 concentrations at diagnosis and male gender were independently associated with the
risk of atrial fibrillation (Boelaert et al., 2010).
In hyperthyroid patients a fine, rapid tremor of the outstretched fingers and generalized tremor, involving also the tongue, may
be evident. Muscular weakness occurs in nearly all patients and this may lead to myalgia and fatigue of the larger proximal limb
muscles. The weakness of respiratory muscles can induce dyspnea on exercise. 20%–40% of patients, mainly women, can experience
friable nails and diffuse loss of scalp hair.
The increased production of thyroid hormones initially may induce a condition of hyperactivity, which is perceived favorably by
some patients, who may then delay the time of reporting to a doctor and therefore the time of diagnosis. Later on, nervousness,
anxiety, irritability, attention deficits, and some memory loss may also be misinterpreted as a syndrome of anxiety or depression.
The change in the body weight is variable: some patients are wasting, but on the average the weight loss in 2–10 kg. The weight loss
is the most frequent complaint of hyperthyroid patients seeking medical advice.
Hyperdefecation is not uncommon and is associated with increased motility of the gastrointestinal tract. Interestingly, some
studies have evidenced an imbalance of gut microbiota in hyperthyroid patients (Zhou et al., 2014). Since the gut microbiota has an
essential role in the function of the immune system, it would not be surprising that its alteration may be involved in the
pathogenesis of Graves’ disease. What is not clear at the moment is if the microbiota imbalance is the cause or the consequence
of the bowel discomfort.
In women, oligomenorrhea is common, but fertility is not severely impaired. In men, there is no evidence of an effect of
hyperthyroidism on spermatogenesis, but the biological activity of estrogens is increased and mild gynecomastia may be found.
The action of high thyroid hormones on the palpebral Muller’s muscles generally induce lid retraction causing a sort of a
frightened expression in the patient. This sign will disappear when the euthyroid state is restored. On the other hand, proptosis of
the eyes, lid swelling, redness or edema of the conjunctiva and ocular pain or diplopia suggest associated orbitopathy (GO) and this
needs to be accurately diagnosed and classified. Approximately one third of patients with GD have some evident clinical signs and/
or symptoms of GO.
Most of the systemic effects of hyperthyroidism disappear when the euthyroid state is achieved. Interestingly, increasing age was
associated with reduced adjusted odds ratio for the presence of most classical symptoms, except for weight loss and shortness of
breath, and smokers had increased odds ratios for most symptoms (Boelaert et al., 2010).
Mortality is increased in both treated and untreated hyperthyroidism and mainly in males (Schwensen et al., 2017) and is related
to the cumulative periods in which serum TSH concentrations are low. This implies that it may not be caused by the fact that the
disease has not been treated, but rather to the inability to keep patients euthyroid during the course of therapy (Lillevang-Johansen
et al., 2017).
There is no clear evidence for direct toxic effects of elevated thyroid hormones on the liver, although a mild elevation of
transaminases is common during the initial phase of the disease. Thus, liver function should be assessed at least once before starting
thyrostatic drugs in order to be able to properly monitor the safety of the treatment. Serum alkaline phosphatase concentrations
may correlate with serum T3, with a pattern showing an equal distribution of the bone and the liver isoenzyme. After therapy, serum
alkaline phosphatase tends to increase, and the bone isoenzyme prevails, probably due to the skeletal repair (Cooper et al., 1979).
Patients with even mild increases in thyroid hormone lose bone mass, especially if postmenopausal and not receiving estrogen
therapy. Severe and premature osteoporosis might be seen in disease with a longer duration or not properly treated. Even if the
skeletal mass is recovered with therapy, bone density in not usually restored in the elderly (Cooper et al., 1979). Hypercalcemia and
hypercalciuria are common in hyperthyroid patients, but usually only moderate. While serum magnesium concentrations may
 Hyperthyroidism in Graves’ Disease 3

decrease, serum phosphate concentrations are generally higher. Red blood cells may be microcytic, but anemia is usually not seen.
Mild thrombocytopenia, due to shortened platelet survival may occur: if persistent after restoration of euthyroidism, autoimmune
thrombocytopenia should be excluded.

Diagnosis

When only some of the signs and symptoms described above are present it may take long to consider a thyroid disease as the cause
of the clinical manifestations. It is the combination of several signs and symptoms and their persistence that will lead the physician
to suspect hyperthyroidism. All patients with suspected hyperthyroidism should undergo a comprehensive history (including
iodine intake or exposure, drugs, family history for thyroid and autoimmune diseases) and physical examination, including
measurement of pulse rate, blood pressure, respiratory rate, and body weight. In addition, thyroid size, presence or absence of
thyroid tenderness, symmetry and nodularity; pulmonary, cardiac, and neuromuscular function and presence of eye signs or
pretibial myxedema should be assessed (Bahn et al., 2011).
When thyrotoxicosis is suspected, the biochemical diagnosis is straightforward and characterized by elevated serum concentra-
tions of T4 and T3 in the presence of low or undetectable serum TSH concentrations. Usually, both serum free T4 and T3
concentrations are elevated and in GD serum T3 is relatively higher than serum T4.
In milder hyperthyroidism, as in the earliest stages of GD, only serum T3 concentrations may be elevated (T3 toxicosis).
The presence of prominent eyes and lid retraction, the anxious behavior, the increased volume of the neck, due to the presence of
a goiter, signs of ocular involvement and a family history of autoimmune disease help distinguish GD from other forms of
hyperthyroidism (e.g., toxic multinodular goiter, toxic adenoma) or thyrotoxicosis (e.g., silent or subacute thyroiditis, exogenous
thyroid hormone use). The measurement of serum TSH-receptor autoantibodies (TRAb) will help confirm this diagnosis.
A recent study has shown that the measurement of TRAb for the diagnosis of GD, when compared to radioactive iodine uptake
(RAIU) determination, reduced costs by 47% and resulted in a 46% quicker diagnosis (McKee and Peyerl, 2012). TRAb bioassays
have a sensitivity of 96%–97% and a specificity of 99% for GD (Diana et al., 2017).There are two standardized methods for
measuring serum TRAb. Third generation TSH Binding Inhibiting Immunoglobulin (TBII) competition assays are very precise but
unable to distinguish the TSH-R antibody subtypes (stimulating or inhibitor). Newer bioassays for the Thyroid Stimulating
Immunoglobulin (TSI) specifically detect simulating antibodies by measuring the ability of TSI to increase the intracellular level
of cAMP.
RAIU should only be performed when the diagnosis is not clear, despite clinical examination, thyroid function assessment and
TRAb detection. The iodine uptake pattern in GD is diffuse, unless there are coexistent nodules or fibrosis. Technetium 99 may also
be used. The total body radiation exposure with technetium is lower than that with 123 iodine scintiscans.
When RAIU is contraindicated, such as during pregnancy or breastfeeding, thyroid ultrasound is performed. Increased color
Doppler flow may be helpful in confirming the diagnosis of thyroid hyperactivity. About 70% of patients with GD have been
reported to exhibit a low thyroid echogenicity pattern at ultrasonography (Vitti et al., 1992). A thyroid scan should be performed
also in the presence of thyroid nodularity at the neck examination or at a thyroid scintigram.

Management

The first goal of the treatment is to promptly alleviate the signs and symptoms of thyrotoxicosis. Physicians should recommend to
temporarily avoid pregnancy to all thyrotoxic fertile women and to quit smoking, especially in patients who have some degree of
ocular involvement.
Beta-adrenergic blocking drugs are recommended in all patients with symptomatic thyrotoxicosis, especially in elderly patients
and those with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease. In the latter, reduction of
intense activity is also suggested.
Anti-thyroid drugs such as methimazole (MMI), carbimazole (CBZ; rapidly converted in methimazole in the serum) and
propylthiouracil (PTU) reduce the synthesis and the secretion of thyroid hormones.
Initial daily therapy with 10–30 mg of MMI or CBZ or with 300–400 mg of PTU will render most patients euthyroid in
4–6 weeks. PTU has a shorter duration of action and is usually administered two or three times daily. When euthyroidism has
been achieved, the physicians can choose between progressively decreasing the dose (“titration method”) or maintaining the same
dose and adding L-thyroxine (“block and replace treatment”).
MMI or CBZ should not be used during the first trimester of pregnancy, when PTU is preferred, in the treatment of thyroid storm,
and in patients with minor reactions to MMI who refuse RAI therapy or surgery. The most common side effects during thyrostatic
treatment are a skin rash and mild abnormalities of liver function tests. Interestingly, thyrotoxicosis itself can induce cutaneous
irritation and mildly abnormal liver function tests in up to 30% of patients and this may be misdiagnosed as an adverse effect of
antithyroid drugs. Drug-induced cutaneous reactions are more common with PTU or higher dose MMI (30 mg/day) compared with
lower dose MMI (15 mg/day) and usually appear after a median of 18–22 days of treatment, significantly earlier than transaminase
elevations (median 28 days). They usually spontaneously regress in a few days, thus can be managed by using anti-histaminic drugs
and not discontinuing the thyrostatic treatment. PTU may cause transient elevations of serum aminotransferases in approximately
4 Hyperthyroidism in Graves’ Disease

one-third of patients. Significant elevations to threefold above the upper limit of normal are seen in up to 4% of patients taking
PTU, more than observed with MMI. Hepatotoxicity is usually seen in the first 120 days of treatment.
Agranulocytosis is a very rare, but life-threatening, event induced by thyrostatic drugs.
It occurs usually in the first 90 days of therapy and it manifests with acute pharyngitis and fever. Prompt discontinuation of the
medical treatment is mandatory: this will generally allow the leukocyte count to normalize within a week.
No consensus exists on the usefulness of periodic monitoring of WBC counts and liver function tests for predicting drug-induced
adverse reaction. Thus, patients have to be warned of discontinuing medications and measuring WBC in case of fever and sore-
throat during therapy and to assess liver function in case of pruritic rash, jaundice, light-colored stool or dark urine, joint pain,
abdominal pain or bloating, anorexia, nausea, or fatigue. A recent study provided evidence that switching from one thyrostatic drug
to another is safe as far as the occurrence of minor side effects, but not in the case of agranulocytosis or other serious side effects,
because of the risk of cross-reactivity between anti-thyroid medications.
Serum TSH, free T4 and T3 should be tested about 4–6 weeks after initiation of therapy, depending on the severity of the
thyrotoxicosis, and the dose of medication should be adjusted accordingly. TSH may remain suppressed for several weeks after
starting therapy, therefore serum T3 and T4 concentrations are better variables for monitoring therapy. Anti-thyroid treatment is
usually continued for 12–24 months, after which time up to 50% of patients may achieve remission of hyperthyroidism.
Measurement of serum TRAb levels before withdrawing thyrostatic drugs is suggested in order to assess the chances of remission.
GD is considered in a remission phase when serum TSH, free T4, and T3 concentrations remain normal for 1 year after the
discontinuation of anti-thyroid therapy. The remission rate varies considerably between geographical areas. A lower remission rate
has been described in men, smokers (especially men), and those with large goiters (>80 g). Higher initial doses of MMI (60–80 mg/
day) do not improve remission rates, while they increase the risk of side effects: thus they are not recommended.
During disease remission, thyroid function should be tested at 2- to 3-month intervals for the first 6 months, then at 4- to
6-month intervals for the following 6 months, and then every 6–12 months in order to eventually detect relapse as early as possible.
The patient should be counseled to contact the treating physician if symptoms of hyperthyroidism are recognized or in case of an
upcoming pregnancy. In general, factors that may predict remission are: a decrease in goiter size, normalization of serum TSH levels
during treatment, decline or negativity of serum TSH receptor antibodies titers, and the patient not smoking.
If hyperthyroidism persists after 18–24 months of medical treatment or relapses soon after a period of remission, a definitive
treatment by surgical thyroidectomy or radioactive iodine ablation (RAI) is suggested. In elderly patients, or in people with
contraindication to RAI and surgery, a long term medical treatment may be continued as the only treatment option. Definitive
treatment is also suggested in women planning a pregnancy: near-total or total thyroidectomy may be indicated if the woman
desires pregnancy within 6 months, RAI ablation can otherwise be programmed at least 12 months before in particular situations.
The long-term quality of life (QoL) following treatment for GD was found to be the same in patients randomly allocated to
either of the available treatment options. The goal of RAI therapy in GD is to control hyperthyroidism by rendering the patient
hypothyroid; this treatment is very effective, provided that a sufficient radiation dose is taken up by the thyroid. This can be
accomplished equally well by either administering a fixed 131-iodine activity or by calculating the dose based on the size of the
thyroid and its ability to trap RAI. Low activities are not recommended in order to avoid more than one cycle of treatment.
Thyrostatics must be withdrawn 2–3 days before RAI in order not to reduce the success rate of the treatment. A special diet is not
required before RAI therapy, but nutritional supplements that may contain excess iodine and seaweeds should be avoided for at
least 7 days.
RAI can induce a transient exacerbation of hyperthyroidism due both to follicular damage and increase of TRAb levels. Moreover
persistent hyperthyroidism has been found to be associated with a long-term increase in cardiovascular and cerebrovascular deaths
(Boelaert et al., 2013). Thus, using beta-blockers or resuming anti-thyroid drugs 3–7 days after RAI might be considered in the
presence of severe hyperthyroidism, in elderly patients and when severe comorbidity is an issue.
A recent meta-analysis found no increase in overall cancer risk after RAI treatment for hyperthyroidism, thus this treatment is a
safe option. However, a trend towards increased risk of thyroid, stomach, and kidney cancer was also recently reported (Hieu et al.,
2012). Conception after RAI ablation should be delayed for at least 6–12 months and, anyway, until stable euthyroidism is
achieved. In men, a delay of 3–4 months is suggested, to allow for turnover of sperm production.
Thyroid function must be assessed within the first 30–45 days after RAI and then monitored at 4- to 6-week intervals for
6 months, or until the patient becomes hypothyroid and is stable on thyroid hormone replacement. Hypothyroidism may occur
from 4 weeks on, with 40% of patients being hypothyroid by 8 weeks and >80% by 16 weeks (Stan et al., 2013). Since TSH may
take longer to normalize or increase, FT4 should be the variable to be assessed also during the patients’ follow-up and when serum
FT4 concentrations fall below normal range, L-thyroxine replacement treatment should be commenced. Overt hypothyroidism
should be avoided, especially in patients with GO, since it may trigger disease reactivation. If hyperthyroidism persists after
6–12 months following one cycle of RAI therapy, retreatment may be advised.
Surgical ablation is generally preferred for patients with larger goiters, in the presence of multinodular goiter or when the patients
require a quick restoration of euthyroidism.
Patients should be rendered euthyroid prior to the surgical procedure with thyrostatic treatment, with or without beta-adrenergic
block. Total thyroidectomy has a nearly 0% risk of recurrence, whereas near total thyroidectomy may result in 8% risk of persistence
or recurrence of hyperthyroidism at 5 years (Guo et al., 2013). The most common complications of total thyroidectomy are
hypocalcemia due to hypopara-thyroidism, recurrent or superior laryngeal nerve injury, postoperative bleeding, and complications
related to general anesthesia.
 Hyperthyroidism in Graves’ Disease 5

After thyroidectomy, L-thyroxine is started at a daily dose appropriate for the patient’s weight and age, and serum TSH
concentrations are first measured 6–8 weeks postoperatively. PTH and calcium levels need to be monitored in all patients
immediately after surgery. The detection of low intact PTH concentrations (<10–15 pg/mL) in the immediate postoperative setting
appears to predict symptomatic hypocalcemia and need for calcium and calcitriol (1,25 vitamin D) supplementation. Thus,
postoperative routine supplementation with oral calcium and calcitriol is continued until serum calcium concentrations remain
normal over a 24-h period, upon withdrawal.
In the pediatric population anti-thyroid drugs are the first-line treatment and MMI is preferred, since PTU is associated with an
increased risk of hepatotoxicity, particularly in children. In case of disease relapse or persistent hyperthyroidism, RAI or surgical
ablation are suggested following the same indications adopted for deciding therapy in the adult patients.

References

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Diana T, Wüster C, Olivo PD, et al. (2017) Performance and specificity of 6 immunoassays for TSH receptor antibodies: A multicenter study. European Thyroid Journal 6: 243–249.
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Further Reading

Bartalena L, Baldeschi L, Boboridis K, et al. (2016) The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’
Orbitopathy. European Thyroid Journal 5: 9–26. https://doi.org/10.1159/000443828.
Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, and Boyle P (1999) Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: A population-based cohort
study. Lancet 353: 2111–2115.
Lazarus JH (1997) Hyperthyroidism. Lancet 349: 339–342.
McDougall IR (1991) Graves’ disease: Current concepts. The Medical Clinics of North America 75: 79–95.
Pedersen IB, Knudsen N, Perrild H, Ovesen L, and Laurberg P (2001) TSH receptor antibody measurement for differentiation of hyperthyroidism into Graves’ disease and multinodular
toxic goiter: A comparison of two competitive binding assays. Clinical Endocrinology 55: 381–390.
Perros P, Zarkovic M, Azzolini C, et al. (2015) PREGO (presentation of graves’ orbitopathy) study: Changes in referral patterns to European group on graves’ orbitopathy (EUGOGO)
centres over the period from 2000 to 2012. The British Journal of Ophthalmology 99: 1531–1535.
Solomon B, Glinoer D, Lagasse R, and Wartofsky L (1990) Current trends in the management of graves’ disease. The Journal of Clinical Endocrinology and Metabolism
70: 1518–1524.
Vestergaard P and Mosekilde L (2003) Hyperthyroidism, bone mineral, and fracture risk—A meta-analysis. Thyroid 13: 585.