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Graves' disease

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Graves' disease,also known astoxic diffuse goiterorBasedow’s disease,is anautoimmune diseasethat affects thethyroid.[1]It frequently results in and is the most common cause ofhyperthyroidism.[5]It also often results in anenlarged thyroid.[1]Signs and symptoms of hyperthyroidism may includeirritability,muscle weakness,sleeping problems,afast heartbeat,poor tolerance of heat,diarrheaandunintentional weight loss.[1]Other symptoms may include thickening of the skin on the shins, known aspretibial myxedema,andeye bulging,a condition caused byGraves' ophthalmopathy.[1]About 25 to 30% of people with the condition develop eye problems.[1][4]

Graves' disease
Other namesToxic diffuse goiter,
Flajani–Basedow–Graves disease
The classic finding ofexophthalmosand lid retraction in Graves' disease
SpecialtyEndocrinology
SymptomsEnlarged thyroid,irritability,muscle weakness,sleeping problems,fast heartbeat,weight loss,poor tolerance of heat,[1]anxiety,tremor of hands or fingers, warm and moist skin, increasedperspiration,goiter,changes in menstrual cycle, easy bruising,erectile dysfunction,reduced libido, frequent bowel movements, bulging eyes (Graves' ophthalmopathy), thick red skin on shins or the top of foot (pretibial myxedema)[2]
ComplicationsGraves' ophthalmopathy[1]
CausesUnknown[3]
Risk factorsFamily history, otherautoimmune diseases[1]
Diagnostic methodBlood tests,radioiodineuptake[1][4]
TreatmentRadioiodine therapy,antithyroidandbeta blockermedications,thyroid surgery[1]
Frequency0.5% (males), 3% (females)[5]

The exact cause of the disease is unclear, but symptoms are a result of antibodies binding to receptors on the thyroid causing over-expression of thyroid hormone.[3]Persons are more likely to be affected if they have a family member with the disease.[1]If onemonozygotic twinis affected, a 30% chance exists that the other twin will also have the disease.[6]The onset of disease may be triggered by physical or emotional stress, infection, orgiving birth.[4]Those with other autoimmune diseases, such astype 1 diabetesandrheumatoid arthritis,are more likely to be affected.[1]Smoking increases the risk of disease and may worsen eye problems.[1]The disorder results from anantibody,called thyroid-stimulating immunoglobulin (TSI), that has a similar effect tothyroid stimulating hormone(TSH).[1]These TSI antibodies cause thethyroid glandto produce excessthyroid hormones.[1]The diagnosis may be suspected based on symptoms and confirmed with blood tests andradioiodineuptake.[1][4]Typically, blood tests show a raisedT3andT4,low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies.[4]

The three treatment options areradioiodine therapy,medications, andthyroid surgery.[1]Radioiodine therapy involves takingiodine-131by mouth, which is then concentrated in the thyroid and destroys it over weeks to months.[1]The resultinghypothyroidismis treated withsynthetic thyroid hormones.[1]Medications such asbeta blockersmay control some of the symptoms, andantithyroid medicationssuch asmethimazolemay temporarily help people, while other treatments are having effect.[1]Surgery to remove the thyroid is another option.[1]Eye problems may require additional treatments.[1]

Graves disease develops in about 0.5% of males and 3.0% of females.[5]It occurs about 7.5 times more often in women than in men.[1]Often, it starts between the ages of 40 and 60, but can begin at any age.[6]It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).[1][4]The condition is named after Irish surgeonRobert Graves,who described it in 1835.[6]A number of prior descriptions also exist.[6]

Signs and symptoms

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Main article:Signs and symptoms of Graves' disease
Graves disease symptoms

The signs and symptoms of Graves disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions beingGraves ophthalmopathy,goiter,andpretibial myxedema(which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainlyinsomnia,handtremor,hyperactivity,hair loss, excessivesweating,oligomenorrhea,itching,heat intolerance,weight lossdespiteincreased appetite,diarrhea,frequentdefecation,palpitations,periodic partial muscle weakness or paralysisin those especially of Asian descent,[7]and skin warmth and moistness.[8]Further signs that may be seen onphysical examinationare most commonly a diffusely enlarged (usually symmetric), nontender thyroid,lid lag,excessivelacrimationdue to Graves' ophthalmopathy,arrhythmiasof the heart, such assinus tachycardia,atrial fibrillation,andpremature ventricular contractions,andhypertension.[8][9]

Cause

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The exact cause is unclear, but it is believed to involve a combination of genetic and environmental factors.[3]While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such aspost-traumatic stress disordercould increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion.[10]

Genetics

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Ageneticpredisposition for Graves' disease is seen, with some people more prone to developTSH receptor-activating antibodies due to a genetic cause.Human leukocyte antigenDR (especially DR3) appears to play a role.[11]To date, no clear genetic defect has been found to point to asingle-genecause.[citation needed]

Genes believed to be involved include those forthyroglobulin,thyrotropin receptor,protein tyrosine phosphatasenonreceptor type 22 (PTPN22), andcytotoxic T-lymphocyte–associated antigen 4,among others.[12]

Infectious trigger

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Since Graves disease is an autoimmune disease that appears suddenly, often later in life, aviralorbacterialinfection may trigger antibodies, which cross-react with the human TSH receptor, a phenomenon known asantigenic mimicry.[13]

The bacteriumYersinia enterocoliticabears structural similarity with the human thyrotropin receptor[11]and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.[14] In the 1990s,Y. enterocoliticawas suggested to be possiblyassociatedwith Graves' disease.[15] More recently, the role forY. enterocoliticahas been disputed.[16]

Epstein–Barr virusis another potential trigger.[17]

Mechanism

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Thyroid-stimulating immunoglobulins recognize and bind to the TSH receptor, which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3). Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level.[citation needed]

Pathophysiology

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Histopathology of a case of Grave's disease. It shows marked hyperplasia ofthyroid follicular cells,generally more so thantoxic multinodular goitre,forming papillae into the thyroid follicles, and with scalloping of the peripheral colloid.

Graves' disease is anautoimmunedisorder, in which the body producesantibodiesthat are specific to aself-protein- the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to thethyroid hormonesT3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSHr andchronicallystimulate it. The TSHr is expressed on thethyroid follicular cellsof the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen, which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.

The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

The three types of autoantibodies to the TSH receptor are:

  1. Thyroid stimulating immunoglobulins:these antibodies (mainly IgG) act as long-acting thyroid stimulants, activating the cells through a slower and more drawn out process compared to TSH, leading to an elevated production of thyroid hormone.
  2. Thyroid growth immunoglobulins:these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
  3. Thyrotrophin binding-inhibiting immunoglobulins:these antibodies inhibit the normal union of TSH with its receptor.
    • Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
    • Other types may not stimulate the thyroid gland, butpreventTSI and TSH from binding to and stimulating the receptor.

Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early.Thyrotoxicosiscan also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.[18]

Diagnosis

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Graves disease may present clinically with one or more of these characteristic signs:[citation needed]

  • Rapid heartbeat (80%)
  • Diffuse palpable goiter with audiblebruit(70%)
  • Tremor (40%)
  • Exophthalmos(protuberance of one or both eyes), periorbital edema (25%)
  • Fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis
  • Heat intolerance (55%)
  • Tremulousness (55%)
  • Palpitations (50%)

Two signs are truly diagnostic of Graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and non-pitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only withcomputed tomographyorultrasoundexamination of the thyroid.[citation needed]Another sign of Graves' disease is hyperthyroidism, that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.[citation needed]

Other useful laboratory measurements in Graves disease include thyroid-stimulating hormone (TSH, usually undetectable in Graves disease due tonegative feedbackfrom the elevated T3 and T4), and protein-boundiodine(elevated).Serologicallydetected thyroid-stimulating antibodies, radioactive iodine uptake, or thyroidultrasound with Dopplerall can independently confirm a diagnosis of Graves disease.

Biopsyto obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed.

The goiter in Graves disease is often not nodular, butthyroid nodulesare also common.[19]Differentiating common forms of hyperthyroidism such as Graves' disease, singlethyroid adenoma,andtoxic multinodular goiteris important to determine proper treatment.[19]Thedifferentiation among these entities has advanced,as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.[20]

Eye disease

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Further information:Graves ophthalmopathy

Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves' disease. It is a form ofidiopathic lymphocytic orbital inflammation,and although its pathogenesis is not completely understood, autoimmune activation of orbitalfibroblasts,which in TAO express theTSH receptor,is thought to play a central role.[21]

Hypertrophyof the extraocular muscles,adipogenesis,and deposition of nonsulfatedglycosaminoglycansand hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead todysthyroid optic neuropathy,increasedintraocular pressures,proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls.[22][23][24]Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, andexposure keratopathy.[citation needed]

Severity of eye disease may be classified by the mnemonic: "NO SPECS":[25]

  • Class 0: No signs or symptoms
  • Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
  • Class 2: Soft tissue involvement (oedemaofconjunctivaeand lids, conjunctival injection, etc.)
  • Class 3:Proptosis
  • Class 4:Extraocular muscleinvolvement (usually withdiplopia)
  • Class 5: Corneal involvement (primarily due tolagophthalmos)
  • Class 6: Sight loss (due to optic nerve involvement)

Typically, the natural history of TAO follows Rundle's curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition.[26]

Management

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Treatment of Graves disease includesantithyroid drugsthat reduce the production of thyroid hormone,radioiodine(radioactive iodineI-131) andthyroidectomy(surgical excision of the gland). As operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. Each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone.[citation needed]

Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such asagranulocytosisandliver disease.[27]Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.

β-Blockers(such aspropranolol) may be used to inhibit thesympathetic nervous systemsymptoms oftachycardiaand nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by Alpha adrenergic receptors.

Antithyroid drugs

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The main antithyroid drugs arecarbimazole(in the UK),methimazole(in the US), andpropylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others includegranulocytopenia(dose-dependent, which improves on cessation of the drug) andaplastic anemia.Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash andperipheral neuritis.These drugs also cross theplacentaand are secreted in breast milk.Lugol's iodinemay be used to block hormone synthesis before surgery.[citation needed]

Arandomized control trialtesting single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).[28]

No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positiveTSHrantibody(TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity39%,specificity98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.[29]

Radioiodine

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Scan of affected thyroid before (top) and after (bottom)radioiodinetherapy

Radioiodine (radioactive iodine-131) was developed in the early 1940s at theMallinckrodt General Clinical Research Center.This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours.[30]Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid.[31]

Contraindications to RAI arepregnancy(absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitarynodules.[32]

Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered.[32]In rare cases,radiation induced thyroiditishas been linked to this treatment.[33]

Surgery

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Further information:Thyroidectomy

This modality is suitable for young people and pregnant females. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery.[27]The absolute indications are a large goiter (especially when compressing thetrachea), suspicious nodules or suspectedcancer(to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the person's preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for six months after radioactive iodine treatment.[27]

Both bilateral subtotalthyroidectomyand the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.

Advantages are immediate cure and potential removal ofcarcinoma.Its risks are injury of therecurrent laryngeal nerve,hypoparathyroidism(due to removal of theparathyroid glands),hematoma(which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), andscarring.[27]The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanentrecurrent laryngeal nerve paralysisafter complete thyroidectomy.[27]Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will belevothyroxine,or thyroid replacement pills to be taken for the rest of the patient's life.

A 2013 review article concludes that surgery appears to be the most successful in the management of Graves' disease, with total thyroidectomy being the preferred surgical option.[34]

Eyes

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Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).

Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.

Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull.[35]

For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves' orbitopathy.[36]

Prognosis

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If left untreated, more seriouscomplicationscould result, includingbirth defectsin pregnancy, increased risk of amiscarriage,bone mineral loss[37]and, in extreme cases, death (e.g. indirectly through complications, or through athyroid stormevent). Graves' disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated.[37]

Epidemiology

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Most common causes ofhyperthyroidismby age[38]

Graves' disease occurs in about 0.5% of people.[4]Graves' disease data has shown that the lifetime risk for women is around 3% and 0.5% for men.[39]It occurs about 7.5 times more often in women than in men[1]and often starts between the ages of 40 and 60.[6]It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).[1][4]

History

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Graves disease owes its name to theAnglo-IrishdoctorRobert James Graves,[40]who described a case of goiter with exophthalmos in 1835.[41](Medical eponymsare often styled nonpossessively; thusGraves' diseaseandGraves diseaseare variant stylings of the same term.)

The GermanKarl Adolph von Basedowindependently reported the same constellation of symptoms in 1840.[42][43]As a result, on the European continent, the terms "Basedow syndrome",[44]"Basedow disease", or "Morbus Basedow"[45]are more common than "Graves' disease".[44][46]

Graves disease[44][45]has also been calledexophthalmic goiter.[45]

Less commonly, it has been known as Parry disease,[44][45]Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease.[44]These names for the disease were derived fromCaleb Hillier Parry,James Begbie,Giuseppe Flajani,andHenry Marsh.[44]Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani[47]and Antonio Giuseppe Testa,[48]in 1802 and 1810, respectively.[49]Prior to these, Caleb Hillier Parry,[50]a notable provincial physician in England of the late 18th century (and a friend ofEdward Miller-Gallus),[51]described a case in 1786. This case was not published until 1825 - ten years ahead of Graves.[52]

However, fair credit for the first description of Graves disease goes to the 12th-centuryPersian physicianSayyid Ismail al-Jurjani,[53]who noted the association of goiter and exophthalmos in hisThesaurus of the Shah of Khwarazm,the major medical dictionary of its time.[44][54]

Society and culture

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Notable cases

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Marty Feldmanused his bulging eyes, caused by Graves' disease, for comedic effect.

Literature

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  • InItalo Svevo's novelZeno's Conscience,character Ada develops the disease.[90][91]
  • Ern Malleywas an acclaimed Australian poet whose work was not published until after his death from Graves' disease in 1943. However, Malley's existence and entire biography was actually later revealed to be aliterary hoax.

Research

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Agents that act as antagonists at thyroid stimulating hormone receptors are under investigation as a possible treatment for Graves' disease.[92]

References

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  2. ^"Graves' disease".Autoimmune Registry Inc.Archived fromthe originalon 15 June 2022.Retrieved15 June2022.
  3. ^abcMenconi F, Marcocci C, Marinò M (2014). "Diagnosis and classification of Graves disease".Autoimmunity Reviews.13(4–5): 398–402.doi:10.1016/j.autrev.2014.01.013.PMID24424182.
  4. ^abcdefghBrent GA (June 2008). "Clinical practice. Grave disease".The New England Journal of Medicine.358(24): 2594–605.doi:10.1056/NEJMcp0801880.PMID18550875.
  5. ^abcBurch HB, Cooper DS (December 2015). "Management of Graves Disease: A Review".JAMA.314(23): 2544–54.doi:10.1001/jama.2015.16535.PMID26670972.
  6. ^abcdeNikiforov YE, Biddinger PW, Nikiforova LD, Biddinger PW (2012).Diagnostic pathology and molecular genetics of the thyroid(2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 69.ISBN9781451114553.Archivedfrom the original on 2017-09-08.
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  8. ^abpage 157 in:Agabegi ED, Agabegi SS (2008).Step-Up to Medicine (Step-Up Series).Hagerstwon, MD: Lippincott Williams & Wilkins.ISBN978-0-7817-7153-5.
  9. ^Bunevicius R, Prange AJ (2006). "Psychiatric manifestations of Graves hyperthyroidism: pathophysiology and treatment options".CNS Drugs.20(11): 897–909.doi:10.2165/00023210-200620110-00003.PMID17044727.S2CID20003511.
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  19. ^abCarnell NE, Valente WA (July 1998). "Thyroid nodules in Graves' disease: classification, characterization, and response to treatment".Thyroid.8(7): 571–6.doi:10.1089/thy.1998.8.571.PMID9709909.
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