Graves' disease

• 1. Introduction

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  Graves' disease is the autoimmune condition behind the dark sunglasses that became part of German folk singer Heino's trademark look. He wore them to hide his symptoms, and the disguise ended up defining him. Behind that image sits a disease in which antibodies imitate a hormone signal and push the thyroid into overdrive. It is the most common cause of hyperthyroidism, the medical term for an overactive thyroid. It also often enlarges the gland itself. The disease carries an unusually long list of names, and the doctor who first described it was not the one whose name it bears. How does a body turn a hormone's own signal against itself? What sets that process off? What happens to the eyes, the skin and the heart along the way? And how do doctors switch an overactive gland back down?

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• 2. Antibodies Against the Thyroid

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  The trouble starts with an antibody called thyroid-stimulating immunoglobulin, or TSI. It behaves much like thyroid-stimulating hormone, or TSH, the body's ordinary instruction to the thyroid. TSI recognizes the TSH receptor, binds to it, and keeps it switched on. That receptor sits on the thyroid follicular cells, which are the cells that make thyroid hormone. Under constant stimulation they release thyroxine, called T4, and triiodothyronine, called T3, in abnormally large amounts.

  These antibodies are mainly of the IgG type, and they act as long-acting thyroid stimulants. They work through a slower and more drawn-out process than TSH itself. The chronic stimulation also enlarges the gland, and that enlargement is visible as a goiter.

  The pituitary gland notices the flood. Its thyroxine receptors are activated by the excess hormone, and they suppress further release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormone alongside a low TSH level.

  Not every antibody aimed at the receptor stimulates it. Thyroid growth immunoglobulins bind directly to the receptor and have been implicated in the growth of thyroid follicles. Thyrotrophin binding-inhibiting immunoglobulins interfere with the normal union of TSH and its receptor. Some of them act as if TSH itself were binding, which induces thyroid function. Others do not stimulate the gland but block TSI and TSH from reaching the receptor. The body may also make antibodies to thyroglobulin and to the hormones T3 and T4 themselves.

  Thyrotoxicosis, the state of having too much thyroid hormone, can raise blood calcium by as much as 25 percent. That can bring stomach upset, excessive urination and impaired kidney function. The skeleton suffers as well. The body excretes more calcium and phosphorus in urine and feces, which causes bone loss from osteoporosis, and early treatment can minimize the damage.

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• 3. Reading the Signs

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  A rapid heartbeat is the most frequent sign, turning up in about 80 percent of patients. Next come a diffuse goiter with an audible bruit, a rushing sound heard over the gland, and fatigue, each in about 70 percent. Weight loss appears in 60 percent, and heat intolerance and tremulousness in 55 percent each. Palpitations occur in 50 percent, tremor in 40 percent, and bulging eyes with swelling around them in 25 percent.

  The wider list of symptoms reads like a body running too fast. Patients report insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, itching and diarrhea with frequent bowel movements. Periods may become infrequent. Skin feels warm and moist. Weight falls despite an increased appetite, though in the elderly appetite is often poor instead. Those of Asian descent may also have periodic partial muscle weakness or paralysis.

  A physical examination can add more. The thyroid is usually diffusely enlarged, symmetric and not tender. Doctors may see lid lag, excessive tearing, high blood pressure, and heart rhythm problems such as sinus tachycardia, atrial fibrillation and premature ventricular contractions.

  Only two signs are truly diagnostic, meaning they do not appear in other forms of hyperthyroidism. One is exophthalmos, the protrusion of one or both eyes. The other is pretibial myxedema, a non-pitting swelling and thickening of the skin on the shins. Its orange peel texture has been explained by antibodies infiltrating the skin, which causes an inflammatory reaction and then fibrous plaques.

  A large goiter can be seen with the naked eye, while a small one may be found only by examination. Occasionally it shows up only on computed tomography or ultrasound. Diffuse goiter occurs with other causes of hyperthyroidism too, but Graves' disease is the most common one.

  Blood tests do most of the confirming. Hyperthyroidism is established by measuring elevated free, or unbound, T4. TSH is usually undetectable, because the high T3 and T4 shut it down, and protein-bound iodine is elevated. Thyroid-stimulating antibodies, radioactive iodine uptake, or a thyroid ultrasound with Doppler can each independently confirm the diagnosis. A biopsy is not normally required.

  Telling Graves' disease apart from a single thyroid adenoma or a toxic multinodular goiter matters, because the proper treatment differs. In one study, measuring TSH-receptor antibodies with the h-TBII assay was the most efficient and practical approach.

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• 4. When the Eyes Bulge

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  About 25 to 30 percent of people with Graves' disease develop eye problems. The eye condition is called thyroid-associated ophthalmopathy, or thyroid eye disease, and it is the most common manifestation of Graves' disease outside the thyroid. It is a form of idiopathic lymphocytic orbital inflammation, meaning inflammation in the eye socket with no known outside cause.

  Its origin is not completely understood. One explanation holds that the thyroid and the muscles that move the eye share a common antigen, so antibodies binding to those muscles cause swelling behind the eyeball. Another points to orbital fibroblasts, connective tissue cells that carry the TSH receptor in this disease. Their autoimmune activation is thought to play a central role.

  The muscles thicken, fat grows, and deposits of hyaluronate and related compounds build up. All of this expands the muscle and fat compartments inside the rigid bony orbit. The crowding can press on the optic nerve, raise pressure in the eye, push the eye forward, and slowly remodel the walls of the socket.

  Doctors grade severity with the mnemonic NO SPECS. Class 0 means no signs or symptoms. Class 1 means only signs, limited to upper lid retraction and stare. Class 2 involves soft tissue, such as swollen lids. Class 3 is proptosis, the forward push of the eye. Class 4 involves the eye muscles, usually with double vision. Class 5 involves the cornea, and class 6 is sight loss from optic nerve involvement.

  The natural course follows Rundle's curve. Worsening is rapid at first, peaks at maximum severity, then improves to a plateau that never fully returns to normal.

  The risks are concrete. If the eyes protrude so far that the lids do not close at night, dryness sets in and a secondary corneal infection could lead to blindness. Pressure on the optic nerve behind the eyeball can cause visual field defects and vision loss.

  Mild cases are treated with lubricant or nonsteroidal anti-inflammatory eye drops. A lubricating gel at night, or tape over the lids, lets a patient close the eyes fully and sleep deeply. Prism glasses correct double vision, and surgery can follow once the process has been stable for a while. Stopping smoking is essential in every case.

  Severe cases that threaten vision call for steroids or orbital decompression. In that operation, bone is removed from the skull behind the eyes, which creates room for muscle and fatty tissue to fall back and lets the eyes retreat.

  For clinically active disease of at least mild to moderate severity, pulse intravenous methylprednisolone is the treatment of choice. Studies have consistently found it superior to oral glucocorticoids, both in effect and in fewer side effects.

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• 5. Genes, Germs and Stress

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  If one identical twin has Graves' disease, the other has a 30 percent chance of developing it too. That figure points to a genetic component, and people with a family member who has the disease are more likely to be affected. Yet no single faulty gene has been found. Inheritance seems to involve several genes, among them those for thyroglobulin, the thyrotropin receptor, PTPN22 and cytotoxic T-lymphocyte-associated antigen 4. A variant of human leukocyte antigen DR, especially DR3, also appears to play a role.

  The disease often appears suddenly and later in life, which has led researchers to suspect an infection. The idea is antigenic mimicry. A virus or bacterium may trigger antibodies that cross-react with the human TSH receptor.

  The bacterium Yersinia enterocolitica bears a structural similarity to the human thyrotropin receptor. In the 1990s it was suggested as a possible contributor in genetically susceptible people. More recently its role has been disputed. Epstein-Barr virus is another potential trigger.

  Other triggers include physical or emotional stress, infection and giving birth. A theoretical mechanism could link severe stressors, such as post-traumatic stress disorder, to worse autoimmune disease, but more robust clinical data are needed for a firm conclusion. People with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected. Smoking increases the risk and may worsen eye problems.

  The disease is far more common in women. Lifetime risk is around 3 percent for women and 0.5 percent for men, and women are affected about 7.5 times as often. It often starts between the ages of 40 and 60, but it can begin at any age. In the United States, it accounts for about 50 to 80 percent of all hyperthyroidism cases.

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• 6. Treating an Overactive Gland

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  Left untreated, Graves' disease can end in death, either indirectly through complications or through a thyroid storm. It can cause birth defects and raise the risk of miscarriage in pregnancy. The raised heart rate may bring on atrial fibrillation, a loss of the normal heart rhythm that can lead to stroke.

  Three treatments exist: antithyroid drugs, radioiodine and surgery. Each has advantages and disadvantages, and none is considered best for everyone. Preferences also differ by region. Radioiodine is the most common treatment in the United States, while antithyroid drugs or surgery are used more often in Europe, Japan and most of the world.

  The main antithyroid drugs are carbimazole in the UK, methimazole in the US, and propylthiouracil, known as PTU. They block iodine binding and the coupling of iodotyrosines. Treatment must run from six months to two years, and even then the hyperthyroid state may return. The risk of recurrence is about 40 to 50 percent.

  The most dangerous side effect is agranulocytosis, a potentially fatal drop in white blood cells. It affects about 1 in 250 patients, and more with PTU. Patients who develop a sore throat or fever should see a doctor. Rash and peripheral neuritis are the most common side effects. These drugs also cross the placenta and are secreted in breast milk.

  A randomized trial of single-dose treatment compared the two drugs. After 12 weeks, 77.1 percent of patients on 15 mg of methimazole had reached a normal thyroid state, against 19.4 percent on 150 mg of PTU. Two markers predict relapse. A positive TSH-receptor antibody at the end of treatment raises the risk of recurrence to 90 percent, while a negative result carries a 78 percent chance of remission. Smoking has an independent effect.

  Beta blockers such as propranolol can control a racing heart and nausea until the antithyroid drugs take effect. Pure beta blockers do not relieve lid retraction, which is mediated by alpha-adrenergic receptors.

  Radioiodine, or iodine-131, was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. Taken by mouth, it accumulates in the thyroid and irradiates the gland with beta and gamma radiation. About 90 percent of the radiation comes from the beta particles, which are electrons. It suits most patients and is indicated when drugs or surgery have failed or cannot be used.

  The cost is hypothyroidism, an underactive thyroid, in up to 80 percent of patients. That requires a daily thyroid hormone pill for life. The gland is destroyed slowly, over months to years, and patients need regular blood tests so hormone replacement starts before symptoms appear. Pregnancy is an absolute contraindication, and eye disease is a relative one because the treatment can aggravate it. Pregnancy should be delayed for six months afterward. Not every patient is cured, and the relapse rate depends on the dose.

  Surgery is suited to young people and pregnant women. Before an operation, antithyroid drugs are given to make the patient euthyroid, because operating on a hyperthyroid patient is dangerous. Lugol's iodine may also be used to block hormone synthesis beforehand. Absolute indications include a large goiter pressing on the trachea, suspicious nodules or suspected cancer, eye disease, or a patient who prefers surgery or refuses radioiodine.

  Two operations are possible: a bilateral subtotal thyroidectomy, or the Hartley-Dunhill procedure, which removes one side's lobe entirely and part of the other. The advantages are an immediate cure and the chance to find cancer, since the removed gland can be examined fully. The risks include injury to the recurrent laryngeal nerve, hypoparathyroidism from removing the parathyroid glands, scarring, and a hematoma that can be life-threatening if it compresses the trachea. Permanent paralysis of that nerve is reported in about 1 percent of complete thyroidectomies. Afterward, a patient takes levothyroxine for life.

  A 2013 review concluded that surgery appears to be the most successful way to manage Graves' disease, with total thyroidectomy as the preferred operation. Meanwhile, agents that block the TSH receptor are under investigation as a possible new treatment.

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• 7. A Disease of Many Names

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  In 1835, the Anglo-Irish doctor Robert James Graves described a case of goiter with exophthalmos, and his name stuck in the English-speaking world. In 1840 the German Karl Adolph von Basedow independently reported the same cluster of symptoms. For that reason, on the European continent the terms Basedow syndrome, Basedow disease and Morbus Basedow are more common than Graves' disease. The condition has also been called exophthalmic goiter, and doctors also call it toxic diffuse goiter.

  Less commonly, it has been called Parry disease, Begbie disease, Flajan disease, Flajani-Basedow syndrome and Marsh disease. Those names honor Caleb Hillier Parry, James Begbie, Giuseppe Flajani and Henry Marsh. Medical eponyms are often styled without the possessive, so Graves' disease and Graves disease are the same term.

  The Italians Giuseppe Flajani and Antonio Giuseppe Testa published early reports of goiter with exophthalmos in 1802 and 1810, though these were not widely circulated. Earlier still, Caleb Hillier Parry, a notable provincial physician in late 18th-century England and a friend of Edward Miller-Gallus, described a case in 1786. It was not published until 1825, ten years ahead of Graves.

  Even Parry was not first. Fair credit for the first description goes to the 12th-century Persian physician Sayyid Ismail al-Jurjani. He noted the link between goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.

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• 8. Famous Patients

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  The Japanese singer Ayaka was diagnosed in 2007 and went public in 2009. She then took a two-year break from music to focus on treatment. Susan Elizabeth Blow, the American educator who founded the first publicly funded kindergarten in the United States, was forced to retire and seek treatment in 1884.

  In 1991, former U.S. president George H. W. Bush developed new atrial fibrillation and was diagnosed with hyperthyroidism due to the disease. He was treated with radioactive iodine. His wife, Barbara Bush, developed the disease around the same time, and in her case it produced severe infiltrative exophthalmos.

  The sprinter Gail Devers developed blistering and swelling after radiation treatment, and a doctor considered amputating her feet. She recovered and went on to win Olympic medals. The British composer Herbert Howells was the first person treated with radium injections. The Scottish rugby player Jim Hamilton discovered he had the disease shortly after retiring from the sport in 2017. The Jamaican dancehall musician Vybz Kartel contracted it while incarcerated.

  The list spans many fields. It includes the hip-hop artist Missy Elliott, the singer Sia, the comedian Rodney Dangerfield, the writer and comedian Marty Feldman, the artist Yayoi Kusama, and the actresses Dame Maggie Smith and Daisy Ridley. The Egyptian singer Umm Kulthum, the Russian Communist Nadezhda Krupskaya, who was the wife of Vladimir Lenin, and the poet Christina Rossetti are on it too. The British ambassador to the United States during World War I, Sir Cecil Spring Rice, died suddenly of the disease in 1918. The actress Barbara Leigh now serves as spokeswoman for the National Graves' Disease Foundation.

  Fiction has borrowed the illness as well. In Italo Svevo's novel Zeno's Conscience, the character Ada develops it. The Australian poet Ern Malley, whose work was not published until after his death from Graves' disease in 1943, was acclaimed. His existence and entire biography were later revealed to be a literary hoax.

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