Graves' disease

Source: Wikipedia, the free encyclopedia.
(Redirected from
Basedow syndrome
)
Graves' disease
Other namesToxic diffuse goiter,
Flajani–Basedow–Graves disease
Radioiodine therapy, medications, thyroid surgery[1]
Frequency0.5% (males), 3% (females)[5]

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid.[1] It frequently results in and is the most common cause of hyperthyroidism.[5] It also often results in an enlarged thyroid.[1] Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss.[1] Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy.[1] About 25 to 30% of people with the condition develop eye problems.[1][4]

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.

T4, low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies.[4]

The three treatment options are

methimazole may 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 surgeon Robert Graves, who described it in 1835.[6] A number of prior descriptions also exist.[6]

Signs and symptoms

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 being

arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension.[8][9]

Cause

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 as post-traumatic stress disorder could 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

A

single-gene cause.[citation needed
]

Genes believed to be involved include those for

cytotoxic T-lymphocyte–associated antigen 4, among others.[12]

Infectious trigger

Since Graves' disease is an autoimmune disease that appears suddenly, often later in life, a

antigenic mimicry.[13]

The bacterium Yersinia enterocolitica bears 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. enterocolitica was suggested to be possibly

associated with Graves' disease.[15]
More recently, the role for Y. enterocolitica has been disputed.[16]

Epstein–Barr virus is another potential trigger.[17]

Mechanism

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

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

Graves' disease is an

thyroid hormones
T3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSHr and

chronically stimulate it. The TSHr is expressed on the thyroid follicular cells
of 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, but prevent TSI 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.

Thyrotoxicosis can 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

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

  • Rapid heartbeat (80%)
  • Diffuse palpable goiter with audible bruit (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 nonpitting edema (

computed tomography or ultrasound examination 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 to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Serologically detected thyroid-stimulating antibodies, radioactive iodine uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves' disease.

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

The goiter in Graves' disease is often not nodular, but

toxic multinodular goiter is important to determine proper treatment.[19] The differentiation 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

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 of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.[21]

Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular 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, and exposure keratopathy.[citation needed]

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

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

Treatment of Graves' disease includes

I-131) and thyroidectomy (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 as agranulocytosis and liver 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 as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and 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

The main antithyroid drugs are

methimazole (in the US), and propylthiouracil/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 include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugol's iodine may be used to block hormone synthesis before surgery.[citation needed
]

A

randomized control trial testing 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 positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), 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

radioiodine
therapy

Radioiodine (radioactive iodine-131) was developed in the early 1940s at the

Mallinckrodt 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 are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.[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 thyroiditis has been linked to this treatment.[33]

Surgery

Further information: Thyroidectomy

This modality is suitable for young and pregnant people. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery.

trachea), suspicious nodules or suspected cancer (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 subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.

Advantages are immediate cure and potential removal of

recurrent laryngeal nerve paralysis after 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 be levothyroxine
, 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

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

If left untreated, more serious

complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss[37] and, in extreme cases, death (e.g. indirectly through complications, or through a thyroid storm event). 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

Most common causes of hyperthyroidism by 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

Graves' disease owes its name to the Irish doctor

Medical eponyms
are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings of the same term.)

The German Karl Adolph von Basedow independently 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 called exophthalmic goiter.[45]

Less commonly, it has been known as Parry disease,

Henry 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 of Edward 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-century

Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.[44][54]

Society and culture

Notable cases

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

Literature

Research

Agents that act as antagonists at thyroid stimulating hormone receptors are under investigation as a possible treatment for Graves' disease.[89]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z "Graves Disease". www.niddk.nih.gov. August 10, 2012. Archived from the original on April 2, 2015. Retrieved 2015-04-02.
  2. ^ "Graves' disease". Autoimmune Registry Inc. Retrieved 15 June 2022.
  3. ^
    PMID 24424182
    .
  4. ^
    PMID 18550875
    .
  5. ^
    PMID 26670972
    .
  6. ^
    ISBN 9781451114553. Archived
    from the original on 2017-09-08.
  7. ISBN 0721621902
    .
  8. ^
    ISBN 978-0-7817-7153-5
    .
  9. S2CID 20003511
    .
  10. PMID 23027804
    .
  11. ^
    PMID 8491150
    .
  12. PMID 27797318. Archived from the original
    (PDF) on 2020-08-01. Retrieved 2020-05-29.
  13. PMID 19138419
    .
  14. PMID 8199453
    .
  15. PMID 12699417
    .
  16. PMID 16968395
    .
  17. ISBN 9780786471898
    .
  18. ^ "Thyroid Disease, Osteoporosis and Calcium – Womens Health and Medical Information on". Medicinenet.com. 2006-12-07. Archived from the original on 2013-03-07. Retrieved 2013-02-27.
  19. ^
    PMID 9709909
    .
  20. PMID 15127319
    .
  21. S2CID 10998666
    .
  22. PMID 6548373
    .
  23. PMID 9669294
    .
  24. PMID 28492870
    .
  25. PMID 15310608
    .
  26. PMID 21402995
    .
  27. ^
    PMID 25726089
    .
  28. S2CID 24463399
    .
  29. PMID 11331213
    .
  30. ISBN 978-0387403601
    .
  31. PMID 21173898
    .
  32. ^ a b "Treatment of an Over-active or Enlarged Thyroid Gland with Radioactive Iodine – British Thyroid Foundation". Btf-thyroid.org. Archived from the original on 2016-09-02. Retrieved 2016-09-10.
  33. PMID 27843811
    .
  34. S2CID 24759725
    .
  35. S2CID 199388425
    .
  36. PMID 25932389
    .
  37. ^
    ISBN 9780781717502. Archived from the original on 2017-09-08. {{cite book}}: |last1= has generic name (help)CS1 maint: numeric names: authors list (link
    )
  38. PMID 21357288
    .
  39. PMID 28846288
    , retrieved 2020-12-04
  40. Who Named It?
  41. ^ Graves, RJ. Newly observed affection of the thyroid gland in females Archived 2016-03-31 at the Wayback Machine. (Clinical lectures.) London Medical and Surgical Journal (Renshaw), 1835; 7 (part 2): 516–517. Reprinted in Medical Classics, 1940;5:33–36.
  42. ^ Von Basedow, KA. Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhöhle. [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1840, 6: 197–204; 220–228. Partial English translation in: Ralph Hermon Major (1884–1970): Classic Descriptions of Disease. Springfield, C. C. Thomas, 1932. 2nd edition, 1939; 3rd edition, 1945.
  43. ^ Von Basedow, KA. "Die Glotzaugen". [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1848: 769–777.
  44. ^
    Who Named It?
    – the history and naming of the disease
  45. ^
    The Modern Home Physician, A New Encyclopedia of Medical Knowledge
    . WM. H. Wise & Company (New York)., pages 82, 294, and 295.
  46. ^ Goiter, Diffuse Toxic at eMedicine
  47. ^ Flajani, G. Sopra un tumor freddo nell'anterior parte del collo broncocele. (Osservazione LXVII). In Collezione d'osservazioni e reflessioni di chirurgia. Rome, Michele A Ripa Presso Lino Contedini, 1802;3:270–273.
  48. ^ Testa, AG. Delle malattie del cuore, loro cagioni, specie, segni e cura. Bologna, 1810. 2nd edition in 3 volumes, Florence, 1823; Milano 1831; German translation, Halle, 1813.
  49. Who Named It?
  50. ^ Parry CH (1825). "Enlargement of the thyroid gland in connection with enlargement or palpitations of the heart". Collections from the unpublished medical writings of C. H. Parry. London. pp. 111–129. According to Garrison, Parry first noted the condition in 1786. He briefly reported it in his Elements of Pathology and Therapeutics, 1815. Reprinted in Medical Classics, 1940, 5: 8–30
  51. PMID 9771526
    .
  52. Who Named It?
  53. ^ Sayyid Ismail Al-Jurjani. Thesaurus of the Shah of Khwarazm.
  54. PMID 6355710
    .
  55. ^ "水嶋ヒロ・絢香、2ショット会見で結婚報告 絢香はバセドウ病を告白、年内で休業へ" (in Japanese). Oricon. April 3, 2009. Archived from the original on December 8, 2015. Retrieved November 19, 2015.
  56. ^ "絢香、初のセルフ・プロデュース・アルバムが発売決定！" (in Japanese). CDJournal. December 1, 2011. Archived from the original on October 15, 2015. Retrieved November 19, 2015.
  57. ^ Shepley, Carol Ferring (2008). Movers and Shakers, Scalawags and Suffragettes: Tales from Bellefontaine Cemetery. St. Louis, Missouri: Missouri History Museum.
  58. ^ Okie, Susan (May 10, 1991). "Bush's Thyroid Condition Diagnosed As Graves' Disease". The Washington Post. Archived from the original on January 7, 2018. Retrieved June 17, 2023.
  59. ^ Altman LK (1991-05-28). "The Doctor's World — A White House Puzzle: Immunity Ailments-Science Section". The New York Times. Archived from the original on 2013-05-08. Retrieved 2013-02-27.
  60. ^ Islam S (2017-01-23). "Thyroid gland – Hyperplasia / goiter – Graves disease". Pathologyoutlines.com. Archived from the original on 2016-12-14. Retrieved 2017-01-25.
  61. ^ Oldenburg A (2011-06-24). "Update: Missy Elliott 'completely managing' Graves' disease". USA Today. Gannett.
  62. ^ "Famous People with Graves' Disease". HRFnd. December 15, 2013. Retrieved 2018-02-22.
  63. ^ Kuhlenbeck M (June 29, 2016). "Marty Feldman versus the Suits". Jewish Currents. Retrieved 2018-02-22. Viewers also could not help being amazed by his bulging eyes, which had resulted from a botched operation for Graves' disease.
  64. ^ Rota G. "Facts About Sia Furler | Popsugar Celebrity Australia". Popsugar.com.au. Archived from the original on 2015-02-09. Retrieved 2016-09-10.
  65. ^ Guart, Al (March 31, 2002). "Rare Disease Could Whack Sammy Bull". New York Post. Archived from the original on January 11, 2012. Retrieved January 28, 2020.
  66. ^ "Hamilton talks about his disease on his podcast". YouTube. Archived from the original on 2017-09-08.
  67. ^ "Crossover Crooner: The Strange Comeback of Germany's Wannabe Johnny Cash". Spiegel.de. 2013-02-07. Archived from the original on 2014-11-19. Retrieved 2014-07-27.
  68. ISBN 1-85411-233-3
    .
  69. ^ "Yayoi Kusama by Grady T. Turner". Bomb Magazine. January 1, 1999. Retrieved May 29, 2020.
  70. ^ "Revolutionary First Lady: the life and struggles of Lenin's wife". Russia Beyond. Archived from the original on 2018-04-18. Retrieved 2018-04-18.
  71. ^ "Barbara Leigh". Home.rmci.net. Archived from the original on 2012-07-10. Retrieved 2013-02-27.
  72. ^ "［歌手 増田恵子さん］バセドー病（１）マイク持つ手が震える". Yomiuri Shimbun. 2011-08-04. Retrieved 2020-02-01.
  73. ^ "［歌手 増田恵子さん］バセドー病（２）同じ病 姉の存在が支えに". Yomiuri Shimbun. 2011-08-11. Retrieved 2020-02-01.
  74. ^ "［歌手 増田恵子さん］バセドー病（３）ツアー中、甲状腺腫れ上がる". Yomiuri Shimbun. 2011-08-18. Retrieved 2020-02-01.
  75. ^ "［歌手 増田恵子さん］バセドー病（４）病気公表 無理せず我慢せず". Yomiuri Shimbun. 2011-08-25. Retrieved 2020-02-01.
  76. ^ "親子知新". www3.bigcosmic.com. Archived from the original on May 15, 2007. Retrieved December 18, 2017.
  77. ^ Rupert Murray "Meet the Climate Sceptics" Archived 2013-10-22 at the Wayback Machine, Storyville, 3 February 2011.
  78. ^ "Sophia Parnok, Russia's Sappho". 3 April 2017.
  79. S2CID 163967264
    .
  80. ^ https://www.king.org/event/the-esoterics-parnok-in-that-infinite-moment/[permanent dead link]
  81. ^ Simon, Bernard (31 May 2013). "This memorial is poetic justice for Sir Cecil Spring Rice". telegraph.co.uk. Archived from the original on 2014-03-12. Retrieved 2014-08-25.
  82. ^ "Christina Rossetti". Poetry Foundation. Archived from the original on 2016-04-17. Retrieved 2016-09-10.
  83. ^ Wolf M (March 18, 1990). "There is Nothing Like This Dame". New York Times. Archived from the original on August 10, 2016. Retrieved 2015-10-19.
  84. ^ "Biography". Archived from the original on 2015-07-16. Retrieved 2015-07-16.
  85. ^ Melas C (February 21, 2018). "Wendy Williams announces show hiatus due to Graves' disease". CNN. Retrieved February 21, 2018.
  86. ^ "Act Yasukawa Returns To Ring After Five Years Away". 15 November 2020.
  87. ISBN 0375727760
    .
  88. ^ Scarponi, Mattia (19 August 2017). "Il morbo di Basedow: lo sfinimento tra Zeno e la realtà". theWise Magazine (in Italian). Retrieved 25 March 2020.
  89. ^ "Thyroid". Mayo Clinic. Archived from the original on 4 November 2016. Retrieved 1 November 2016.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Graves%27_disease&oldid=1211171321"