Graves' disease

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Graves%27_disease 

 

Graves' disease
Other names	Toxic diffuse goiter, Flajani–Basedow–Graves disease
The classic finding of exophthalmos and lid retraction in Graves' disease
Specialty	Endocrinology
Symptoms	Enlarged thyroid, irritability, muscle weakness, sleeping problems, fast heartbeat, weight loss, poor tolerance of heat
Complications	Graves' ophthalmopathy
Causes	Unknown
Risk factors	Family history, other autoimmune diseases
Diagnostic method	Blood tests, radioiodine uptake
Treatment	Radioiodine therapy, medications, thyroid surgery
Frequency	0.5% (males), 3% (females)

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 80% of people with the condition develop eye problems.

The exact cause of the disease is unclear; however, it is believed to involve a combination of genetic and environmental factors. A person is more likely to be affected if they have a family member with the disease. If one twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection or giving birth. Those with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T₃ and T₄, low TSH, increased radioiodine uptake in all areas of the thyroid and TSI antibodies.

The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.

Graves' disease will develop in about 0.5% of males and 3% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60 but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist.

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 Graves' ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension. People with hyperthyroidism may experience behavioral and personality changes, including psychosis, mania, anxiety, agitation, and depression.

Cause

The exact cause is unclear; however, it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as PTSD (Post traumatic stress disorder) could increase the risk of autoimmune disease and cause an aggravation of the autoimmune response that leads to Graves' disease, more robust clinical data are needed for a firm conclusion.

Genetics

A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.

Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte–associated antigen 4, among others.

Infectious trigger

Since Graves' disease is an autoimmune disease which appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.

The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. In the 1990s, it was suggested that Y. enterocolitica may be associated with Graves' disease. More recently, the role for Y. enterocolitica has been disputed.

Epstein–Barr virus (EBV) is another potential trigger.

Mechanism

Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (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.

Pathophysiology

Histopathological image of diffuse hyperplasia of the thyroid gland (clinically presenting as hyperthyroidism)

Graves' disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein: the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the 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 currently recognized 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.

Diagnosis

Graves' disease may present clinically with one or more of these characteristic signs:

• 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 (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 with computed tomography or ultrasound examination of the thyroid.

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.

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 (RAI) 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 thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. 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.

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.

Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycoaminoglycans 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. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.

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

• 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 (oedema of conjunctivae and lids, conjunctival injection, etc.)
• Class 3: Proptosis
• Class 4: Extraocular muscle involvement (usually with diplopia)
• Class 5: Corneal involvement (primarily due to lagophthalmos)
• 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.

Management

Treatment of Graves' disease includes antithyroid drugs which reduce the production of thyroid hormone; radioiodine (radioactive iodine I-131); and thyroidectomy (surgical excision of the gland). As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient "euthyroid" (i.e., normothyroid). Each of these treatments has advantages and disadvantages. No one treatment approach is considered the best for everyone.

Treatment with antithyroid medications must be given 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. 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 such time as 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 carbimazole (in the UK), 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.

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).

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%), 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.

Radioiodine

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

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.

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. In rare cases, radiation induced thyroiditis has been linked to this treatment.

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. The absolute indications are a large goiter (especially when compressing the 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 6 months after radioactive iodine treatment.

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 carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring. 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 permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. 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.

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.

Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves' disease on the eyelids. Eyelid muscles can become tight with Graves' disease, making it impossible to close the eyes all the way. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.

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.

Prognosis

If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss and, in extreme cases, death. 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.

Epidemiology

Most common causes of hyperthyroidism by age

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

History

Graves' disease owes its name to the Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. 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. As a result, on the European Continent, the terms Basedow syndrome, Basedow disease, or Morbus Basedow are more common than Graves' disease.

Graves' disease has also been called exophthalmic goiter.

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

However, fair credit for the first description of Graves' disease goes to the 12th century Persian physician Sayyid Ismail al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.

Society and culture

Notable cases

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

 

Umm Kulthum in Life Magazine, 1962

• Ayaka, Japanese singer, was diagnosed with Graves' disease in 2007. After going public with her diagnosis in 2009, she took a two-year hiatus from music to focus on treatment.
• Susan Elizabeth Blow, American educator and founder of the first publicly funded kindergarten in the United States, was forced to retire and seek treatment for Graves' disease in 1884.
• George H. W. Bush, former U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and treated with radioactive iodine. The president's wife, Barbara Bush, also developed the disease around the same time, which, in her case, produced severe infiltrative exophthalmos.
• Rodney Dangerfield, American comedian and actor
• Gail Devers, American sprinter: A doctor considered amputating her feet after she developed blistering and swelling following radiation treatment for Graves' disease, but she went on to recover and win Olympic medals.
• Missy Elliott, American hip-hop artist
• Marty Feldman, British comedy writer, comedian and actor
• Sia Furler, Australian singer and songwriter
• Sammy Gravano, Italian-American former underboss of the Gambino crime family.
• Jim Hamilton, Scottish rugby player, discovered he had Graves' disease shortly after retiring from the sport in 2017.
• Heino, German folk singer, whose dark sunglasses (worn to hide his symptoms) became part of his trademark look
• Herbert Howells, British composer; the first person to be treated with radium injections^[66]
• Yayoi Kusama, Japanese artist.
• Nadezhda Krupskaya, Russian Communist and wife of Vladimir Lenin
• Umm Kulthum was an Egyptian singer, songwriter, and film actress active from the 1920s to the 1970s. She was given the honorific title Kawkab al-Sharq. Umm Kulthum was known for her vocal ability and unique style.
• Barbara Leigh, an American former actress and fashion model, now spokeswoman for the National Graves' Disease Foundation
• Keiko Masuda, Japanese singer and one-half of the duo Pink Lady.
• Yūko Miyamura, Japanese voice actress
• Lord Monckton, former UKIP and Conservative politician and noted climate change skeptic.
• Sophia Parnok, Russian poet
• Sir Cecil Spring Rice, British ambassador to the United States during World War I, died suddenly of the disease in 1918.
• Christina Rossetti, English Victorian-era poet
• Dame Maggie Smith, British actress
• Mary Webb, British novelist and poet
• Wendy Williams, American TV show host
• Act Yasukawa, Japanese Professional wrestler.

Literature

In Italo Svevo's novel Zeno's Conscience, character Ada develops the disease.

Research

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

 

Autoimmune disease

From Wikipedia, the free encyclopedia

 

Autoimmune diseases
Young woman with the typical "butterfly rash" found in systemic lupus erythematosus

Specialty	Rheumatology, immunology, gastroenterology, neurology, dermatology
Symptoms	Depends on the condition. Commonly low grade fever, feeling tired
Usual onset	Adulthood
Types	List of autoimmune diseases (alopecia areata, celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, others)
Medication	Nonsteroidal anti-inflammatory drugs, immunosuppressants, intravenous immunoglobulin
Frequency	24 million / 7% (USA)

An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.

The cause is unknown. Some autoimmune diseases such as lupus run in families, and certain cases may be triggered by infections or other environmental factors. Some common diseases that are generally considered autoimmune include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. The diagnosis can be difficult to determine.

Treatment depends on the type and severity of the condition. Nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants are often used. Intravenous immunoglobulin may also occasionally be used. While treatment usually improves symptoms, they do not typically cure the disease.

About 24 million (~7.5%) people in the United States are affected by an autoimmune disease. Women are more commonly affected than men. Often they start during adulthood. The first autoimmune diseases were described in the early 1900s.

Signs and symptoms

Rheumatoid arthritis

Autoimmune diseases present similar symptoms across the more than eighty different types. The appearance and severity of these signs and symptoms depends on the location and type of autoimmune response that occurs. An individual may also have more than one autoimmune disease simultaneously, and display symptoms of multiple diseases. Signs and symptoms presented, and the disease itself, can be influenced by various other factors such as age, hormones, and environmental factors. In general, the common symptoms are:

• Fatigue
• Low grade fever
• General feeling of unwell (malaise)
• Muscle aches and joint pain
• Rash on different areas of the skin

The appearance of these signs and symptoms can fluctuate, and when they reappear, it is known as a flare-up. Such signs and symptoms may aid in diagnosis by supporting the results from biologic markers of autoimmune diseases.

There are several areas that are commonly impacted by autoimmune diseases. These areas include: blood vessels, underlying connective tissues, joints and muscles, red blood cells, skin, and endocrine glands (such as thyroid or pancreas glands).

These diseases tend to have characteristic pathological effects that characterize them as an autoimmune disease. Such features include damage to or destruction of tissues where there is an abnormal immune response, altered organ growth, and altered organ function depending on the location of the disease. Some diseases are organ specific and are restricted to affecting certain tissues, while others are systemic diseases that impact many tissues throughout the body. Signs and symptoms may vary depending on which of these categories an individual's disease falls under.

Cancer

Research suggests an overall correlation between autoimmune diseases and cancer, in that having an autoimmune disease increases the risk or likelihood of developing certain cancers.  Autoimmune diseases cause inflammation through a variety of mechanisms, however, the way in which inflammation is created does not greatly influence cancer risk. Rather, the cancer risk is largely dependent on the fact that all autoimmune diseases increase chronic inflammation which has been linked to cancer. Below are some autoimmune diseases most commonly linked to cancer including celiac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

Examples

Following are the few examples of autoimmune diseases. See List of autoimmune diseases for a more exhaustive list.

Coeliac disease

Coeliac disease presents the strongest associations to gastrointestinal and lymphoproliferative cancers. In coeliac disease, the autoimmune reaction is caused by the body's loss of immune tolerance to ingested gluten, found primarily in wheat, barley, and rye. This explains the increased risk of gastrointestinal cancers, as the gastrointestinal tract includes the esophagus, stomach, small intestine, large intestine, rectum, and anus, all areas that the ingested gluten would traverse in digestion. The incidence of gastrointestinal cancer can be partially reduced or eliminated if a patient removes gluten from their diet. Additionally, celiac disease is correlated with lymphoproliferative cancers.

Inflammatory bowel disease

Inflammatory bowel disease is associated with cancers of the gastrointestinal tract and some lymphoproliferative cancers. Inflammatory bowel disease (IBD) can be further categorized as Crohn's disease or ulcerative colitis. In both cases, individuals with IBD lose immune tolerance for normal bacteria present in the gut microbiome. In this case, the immune system attacks the bacteria and induces chronic inflammation, which has been linked to increased cancer risk.

Multiple sclerosis

Multiple sclerosis is associated with decreased risk of cancer overall but an increased risk of central nervous system cancer, primarily in the brain. Multiple sclerosis is a neurodegenerative disease in which T-cells – a specific type of immune cells – attack the important myelin sheath in brain neurons. This reduces the nervous system function, creating inflammation and subsequent cancer of the brain.

Rheumatoid arthritis

Rheumatoid arthritis presents mild, yet significant associations with focal cancers all throughout the body as well as lymphoproliferative cancers. In rheumatoid arthritis, cells that make up the body's joints and cartilages become invasive and induce local inflammation. Additionally, the chronic inflammation and over-activation of the immune system creates an environment that favors further malignant transformation of other cells. This can explain the associations to cancer of the lungs and skin as well as the increased risk of other hematologic cancers none of which are directly affected by the inflammation of joints.

Systemic lupus erythematosus

Systemic lupus erythematosus is associated with focal cancers throughout the body and lymphoproliferative cancers. Systemic lupus erythematosus affects multiple organ systems and is characterized by a widespread loss of immune tolerance. The chronic inflammation throughout the entire body promotes the malignant transformation of other cells which contributes to the increased risk of systemic and lymphoproliferative cancers. Conversely, systemic lupus erythematosus is correlated with a decrease in some cancers. This is best explained by increased immunosurveillance in these areas, however, the mechanism for why these areas experience lower incidence is poorly understood.

Aplastic anemia

In aplastic anemia the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anaemia causes a deficiency of all blood cell types: red blood cells, white blood cells and platelets.

Causes

The cause is unknown. Some autoimmune diseases such as lupus run in families, and certain cases may be triggered by infections or other environmental factors. There are more than 100 autoimmune diseases. Some common diseases that are generally considered autoimmune include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

Genetics

Autoimmune diseases are conditions in which the human immune system attacks healthy human tissues within the body. The exact genes responsible for causing each autoimmune disease have not been found. However, several experimental methods such as the genome-wide association scans have been used to identify certain genetic risk variants that may or may not be responsible. Research focusing on both genome scanning and family trait inheritance analysis has enabled scientists to further understand the etiology of autoimmune diseases such as Type 1 diabetes and Rheumatoid arthritis.

• Type 1 diabetes is a condition in which pancreatic β-cells are targeted and destroyed by the immune system. The condition is a result of neo-natal mutations to the insulin gene (INS) which is responsible for mediating the production of the insulin in the pancreas. The INS gene is located on the short arm of chromosome 11p15.5 in between the genes for tyrosine hydroxylase and insulin-like growth factor II. In addition to chromosome 11, a genetic determinant of type 1 diabetes is a locus called the major histocompatibility complex (MHC) located on chromosome 6p21.
• Rheumatoid arthritis: Although there is no complete genetic mapping for this condition, several genes are thought to play a role in causing RA. The genes that influence the human immune system contain a TNF receptor associated factor 1(TRAF1). This TRAF1 is located on chromosome 9q33-34. In addition, B1 genes in the human genome contain an increased concentration of HLA-DRB1 alleles that are most commonly seen in RA patients. RA can vary in severity as a consequence of polymorphisms within the genome.

Environmental factors

A range of environmental factors have been recognized as either having a direct role in development, or being a catalyst to many autoimmune diseases. Current studies "indicate" up to seventy percent of autoimmune disease are perhaps due to environmental factors, including: chemicals, infection, diet, and gut dysbiosis. A single set of steps has been identified to be the most likely theory for autoimmune disease onset still there is of yet no definitive proof.

1. Environmental triggers
2. Reduced oral tolerance
3. Gut dysbiosis
4. Enhanced gut permeability
5. Increased immune reactivity
6. Autoimmunity

Chemicals can be found within the direct environment or in the form of drugs, including: hydrazines, hair dyes, trichloroethylene, tartrazines, hazardous wastes, and industrial emissions.

UV radiation is found to be a possible cause of development of the autoimmune disease dermatomyositis, exposure to pesticides plays a role in rheumatoid arthritis development, and vitamin D has been found to be a key in preventing immune dysfunctions in older populations. Infectious agents are considered T cell activators, a step needed for activation of autoimmune diseases. These mechanisms are relatively unknown, but are one of the current alternative theories to explain autoimmune diseases triggered by infection such as Guillain-Barre syndrome and rheumatic fever.

Pathophysiology

The human immune system typically produces both T cells and B cells that are capable of being reactive with self-protein, but these self-reactive cells are usually either killed prior to becoming active within the immune system, placed into a state of anergy (silently removed from their role within the immune system due to over-activation), or removed from their role within the immune system by regulatory cells. When any one of these mechanisms fail, it is possible to have a reservoir of self-reactive cells that become functional within the immune system. The mechanisms of preventing self-reactive T cells from being created take place through negative selection process within the thymus as the T cell is developing into a mature immune cell.

Some infections, such as Campylobacter jejuni, have antigens that are similar (but not identical) to our own self-molecules. In this case, a normal immune response to C. jejuni can result in the production of antibodies that also react to a lesser degree with gangliosides of myelin sheath surrounding peripheral nerves' axons (i.e., Guillain–Barré). A major understanding of the underlying pathophysiology of autoimmune diseases has been the application of genome-wide association scans that have identified a degree of genetic sharing among the autoimmune diseases.

Autoimmunity, on the other hand, is the presence of self-reactive immune response (e.g., auto-antibodies, self-reactive T cells), with or without damage or pathology resulting from it. For this reason, autoantibodies are a hallmark of most autoimmune disorders. This may be restricted to certain organs (e.g. in autoimmune thyroiditis) or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney).

There are many different theories as to how an autoimmune disease state arises. Some common ones are listed below.

Diagnosis

For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky's postulates (first formulated by Ernest Witebsky and colleagues in 1957 and modified in 1994):

• Direct evidence from transfer of disease-causing antibody or disease-causing T lymphocyte white blood cells
• Indirect evidence based on reproduction of the autoimmune disease in experimental animals
• Circumstantial evidence from clinical clues

Symptoms of early autoimmune disease are often the exact same as common illnesses, including: fatigue, fever, malaise, joint pain, and rash. Due to the fact symptoms vary for affected location, disease causing agents, and individuals, it is difficult for proper diagnosis. Typically, diagnosis begins with looking into a patient's family's history for genetic predisposition. This is combined with various tests, as no single test can identify an autoimmune disease.

Antinuclear antibody

A test used to identify abnormal proteins, known as antinuclear antibodies, produced when the body attacks its own tissues. It may test positive in several disorders. This test is most useful for diagnosing systemic lupus erythematosus, having a 95% positive test rate.

Complete blood count

A test taking measurements on maturity levels, count, and size of blood cells. Targeted cells include: red blood cells, white blood cells, hemoglobin, hematocrit, and platelets. Based on increased or decreased numbers in these counts, underlying medical conditions may be present; typically, autoimmune disease is represented by low white blood cell count (Leukopenia). For proper diagnosis, further testing is needed.

Complement

A test used to measure levels of a protein group of the immune system called complement within blood. If complement is found in low levels, this may be an indication of disease.

C reactive protein

C reactive protein, a protein made in the liver generally increases with inflammation, and may be high in autoimmune disease.

Erythrocyte sedimentation rate

This test measures the rate at which a patient's blood cells descend in a test tube. More rapid descents may indicate inflammation, a common symptom of autoimmune disease.

If these tests are indicative antibody abnormalities and inflammation, further tests will be conducted to identify the autoimmune disease present.

Treatment

Treatment depends on the type and severity of the condition. The majority of the autoimmune diseases are chronic and there is no definitive cure, but symptoms can be alleviated and controlled with treatment. Overall, the aim of the various treatment methods is to lessen the presented symptoms for relief and manipulate the body's autoimmune response, while still preserving the ability of the patient to combat diseases that they may encounter. Traditional treatment options may include immunosuppressant drugs to weaken the overall immune response, such as:

• Non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammation
• Glucocorticoids to reduce inflammation
• Disease-modifying anti-rheumatic drugs (DMARDs) to decrease the damaging tissue and organ effects of the inflammatory autoimmune response

Other standard treatment methods include:

• Vitamin or hormone supplements for what the body is lacking due to the disease (insulin, vitamin B12, thyroid hormone, etc.)
• Blood transfusions if the disease is blood related
• Physical therapy if the disease impacts bones, joints, or muscles

Because these drugs aim to reduce the immune response against the body's own tissues, there are side effects of these traditional treatment methods, such as being more vulnerable to infections that can potentially be life-threatening. There are new advancements in medicine for the treatment of autoimmune diseases that are currently being researched, developed, and used today, especially when traditional treatment options fail. These methods aim to either block the activation of pathogenic cells in the body, or alter the pathway that suppresses these cells naturally. The goal for these advancements is to have treatment options available that are less toxic to the patient, and have more specific targets. Such options include:

• Monoclonal antibodies that can be used to block pro-inflammatory cytokines
• Antigen-specific immunotherapy which allows immune cells to specifically target the abnormal cells that cause autoimmune disease
• Co-stimulatory blockade that works to block the pathway that leads to the autoimmune response
• Regulatory T cell therapy that utilizes this special type of T cell to suppress the autoimmune response

Epidemiology

The first estimate of US prevalence for autoimmune diseases as a group was published in 1997 by Jacobson, et al. They reported US prevalence to be around 9 million, applying prevalence estimates for 24 diseases to a US population of 279 million. Jacobson's work was updated by Hayter & Cook in 2012. This study used Witebsky's postulates, as revised by Rose & Bona, to extend the list to 81 diseases and estimated overall cumulative US prevalence for the 81 autoimmune diseases at 5.0%, with 3.0% for males and 7.1% for females. The estimated community prevalence, which takes into account the observation that many people have more than one autoimmune disease, was 4.5% overall, with 2.7% for males and 6.4% for females. National Health and Nutrition Examination Surveys conducted in the US from the 1980s to present day, have shown an increase of antinuclear antibodies, a common biomarker for autoimmune diseases. This shows that there has been an increase in the prevalence of autoimmune diseases in recent years pointing to a stronger influence of environment factors as a risk factor for autoimmune diseases.

Research

In both autoimmune and inflammatory diseases, the condition arises through aberrant reactions of the human adaptive or innate immune systems. In autoimmunity, the patient's immune system is activated against the body's own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by cytokines and chemokines, resulting in tissue damage.

Mitigation of inflammation by activation of anti-inflammatory genes and the suppression of inflammatory genes in immune cells is a promising therapeutic approach. There is a body of evidence that once the production of autoantibodies has been initialized, autoantibodies have the capacity to maintain their own production.

Stem-cell therapy

Main article: Stem-cell therapy

Stem cell transplantation is being studied and has shown promising results in certain cases.

Medical trials to replace the pancreatic β cells that are destroyed in type 1 diabetes are in progress.

Altered glycan theory

According to this theory, the effector function of the immune response is mediated by the glycans (polysaccharides) displayed by the cells and humoral components of the immune system. Individuals with autoimmunity have alterations in their glycosylation profile such that a proinflammatory immune response is favored. It is further hypothesized that individual autoimmune diseases will have unique glycan signatures.

Hygiene hypothesis

According to the hygiene hypothesis, high levels of cleanliness expose children to fewer antigens than in the past, causing their immune systems to become overactive and more likely to misidentify own tissues as foreign, resulting in autoimmune or allergic conditions such as asthma.

Vitamin D Influence on Immune Response

Vitamin D is known as an immune regulator that assists in the adaptive and innate immune response. A deficiency in Vitamin D, from hereditary or environmental influence, can lead to a more inefficient and weaker immune response and seen as a contributing factor to the development of autoimmune diseases. With Vitamin D present, vitamin D response elements (VDRE) are encoded and expressed via pattern recognition receptors (PRR) responses and the genes associated with those responses. The specific DNA target sequence expressed is known as 1,25-(OH)2D3. The expression of 1,25-(OH)2D3 can be induced by Macrophages, Dendritic cells, T-cells, and B-cells. In the presence of 1,25-(OH)2D3, the immune system's production of inflammatory cytokines are suppressed and more tolerogenic regulatory T-cells are expressed. This is due to Vitamin D's influence on cell maturation, specifically T-cells, and their phenotype expression. Lack of 1,25-(OH)2D3 expression can lead to less tolerant regulatory T-cells, larger presentation of antigens to less tolerant T-cells, and increased inflammatory response.

Majority rule

From Wikipedia, the free encyclopedia

Majority rule is a decision rule that selects alternatives which have a majority, that is, more than half the votes. It is the binary decision rule used most often in influential decision-making bodies, including all the legislatures of democratic nations.

Distinction with plurality

Decision-making in a legislature is different from election of representation, although the result of plurality (first-past-the post) elections is often mistaken for majority rule. Plurality elections elect the option that has more votes than any other, regardless of whether the fifty percent threshold is passed. A plurality election produces representation of a majority when there are only two candidates in an election or other situations where there are only two options. However, when there are more than two alternatives,such in many elections, a candidate that has less than fifty percent of the votes cast in its favor is often elected.

Use

Majority rule is used pervasively in many modern western democracies. It is frequently used in legislatures and other bodies in which alternatives can be considered and amended in a process of deliberation until the final version of a proposal is adopted or rejected by majority rule. It is one of the basic rules prescribed in books like Robert's Rules of Order. The rules in such books and those rules adopted by groups may additionally prescribe the use of a supermajoritarian rule under certain circumstances, such as a two-thirds rule to close debate.

Many referendums are decided by majority rule.

Properties

May's Theorem

Main article: May's Theorem

According to Kenneth May, majority rule is the only reasonable decision rule that is "fair", that is, that does not privilege voters by letting some votes count for more or privilege an alternative by requiring fewer votes for its passing. Stated more formally, majority rule is the only binary decision rule that has the following properties:

• Fairness: This can be further separated into two properties:
  • Anonymity: The decision rule treats each voter identically. When using majority rule, it makes no difference who casts a vote; indeed the voter's identity need not even be known.
  • Neutrality: The decision rule treats each alternative equally. This is unlike supermajoritarian rules, which can allow an alternative that has received fewer votes to win.
• Decisiveness: The decision rule selects a unique winner.
• Monotonicity: The decision rule would always, if a voter were to change a preference, select the alternative that the voter preferred, if that alternative would have won before the change in preference. Similarly, the decision rule would never, if a voter were to change a preference, select a candidate the voter did not prefer, if that alternative would not have won before the change in preference.

Strictly speaking, it has been shown that majority rule meets these criteria only if the number of voters is odd or infinite. If the number of voters is even, there is the chance that there will be a tie, and so the criterion of neutrality is not met. Many deliberative bodies reduce one participant's voting capacity—namely, they allow the chair to vote only to break ties. This substitutes a loss of total anonymity for the loss of neutrality.

Other properties

In group decision-making it is possible for a voting paradox to form. That is, it is possible that there are alternatives a, b, and c such that a majority prefers a to b, another majority prefers b to c, and yet another majority prefers c to a. Because majority rule requires an alternative to have only majority support to pass, a majority under majority rule is especially vulnerable to having its decision overturned. (The minimum number of alternatives that can form such a cycle (voting paradox) is 3 if the number of voters is different from 4, because the Nakamura number of the majority rule is 3. For supermajority rules the minimum number is often greater, because the Nakamura number is often greater.)

As Rae argued and Taylor proved in 1969, majority rule is the rule that maximizes the likelihood that the issues a voter votes for will pass and that the issues a voter votes against will fail.

Schmitz and Tröger (2012) consider a collective choice problem with two alternatives and they show that the majority rule maximizes utilitarian welfare among all incentive compatible, anonymous, and neutral voting rules, provided that the voters’ types are independent. Yet, when the votersʼ utilities are stochastically correlated, other dominant-strategy choice rules may perform better than the majority rule. Azrieli and Kim (2014) extend the analysis for the case of independent types to asymmetric environments and by considering both anonymous and non-anonymous rules.

Limitations

Arguments for limitations

Minority rights

Because a majority can win a vote under majority rule, it has been commonly argued that majority rule can lead to a tyranny of the majority. Supermajoritarian rules, such as the three-fifths supermajority rule required to end a filibuster in the United States Senate, have been proposed as preventative measures of this problem. Other experts argue that this solution is questionable. Supermajority rules do not guarantee that it is a minority that will be protected by the supermajority rule; they only establish that one of two alternatives is the status quo, and privilege it against being overturned by a mere majority. To use the example of the US Senate, if a majority votes against cloture, then the filibuster will continue, even though a minority supports it. Anthony McGann argues that when there are multiple minorities and one is protected (or privileged) by the supermajority rule, there is no guarantee that the protected minority won't be one that is already privileged, and if nothing else it will be the one that has the privilege of being aligned with the status quo.

Another way to safeguard against tyranny of the majority, it is argued, is to guarantee certain rights. Inalienable rights, including who can vote, which cannot be transgressed by a majority, can be decided beforehand as a separate act, by charter or constitution. Thereafter, any decision that unfairly targets a minority's right could be said to be majoritarian, but would not be a legitimate example of a majority decision because it would violate the requirement for equal rights. In response, advocates of unfettered majority rule argue that because the procedure that privileges constitutional rights is generally some sort of supermajoritarian rule, this solution inherits whatever problems this rule would have. They also add the following: First, constitutional rights, being words on paper, cannot by themselves offer protection. Second, under some circumstances, the rights of one person cannot be guaranteed without making an imposition on someone else; as Anthony McGann wrote, "one man's right to property in the antebellum South was another man's slavery". Finally, as Amartya Sen stated when presenting the liberal paradox, a proliferation of rights may make everyone worse off.

Erroneous priorities

The erroneous priorities effect (EPE) states that groups acting upon what they initially consider important are almost always misplacing their effort. When groups do this they have not yet determined which factors are most influential in their potential to achieve desired change. Only after identifying those factors are they ready to take effective action. EPE was discovered by Kevin Dye after extensive research at the Food and Drug Administration. The discovery of EPE led to the recognition that even with good intentions for participatory democracy, people cannot collectively take effective actions unless they change the paradigm for languaging and voting. EPE is a negative consequence of phenomena such as spreadthink and groupthink. Effective priorities for actions that are dependent on recognizing the influence patterns of global interdependencies, are defeated by the EPE, when priorities are chosen on the basis of aggregating individual stakeholder subjective voting that is largely blind to those interdependencies. Dye's work resulted in the discovery of the 6th law of the science of structured dialogic design, namely: "Learning occurs in a dialogue as the observers search for influence relationships among the members of a set of observations."

Other arguments for limitations

Some argue that majority rule can lead to poor deliberation practice or even to "an aggressive culture and conflict". Along these lines, some have asserted that majority rule fails to measure the intensity of preferences. For example, the authors of An Anarchist Critique of Democracy argue that "two voters who are casually interested in doing something" can defeat one voter who has "dire opposition" to the proposal of the two.

Voting theorists have often claimed that cycling leads to debilitating instability. Buchanan and Tullock argue that unanimity is the only decision rule that guarantees economic efficiency.

Supermajority rules are often used in binary decisions where a positive decision is weightier than a negative one. Under the standard definition of special majority voting, a positive decision is made if and only if a substantial portion of the votes support that decision—for example, two thirds or three fourths. For example, US jury decisions require the support of at least 10 of 12 jurors, or even unanimous support. This supermajoritarian concept follows directly from the presumption of innocence on which the US legal system is based. Rousseau advocated the use of supermajority voting on important decisions when he said, "The more the deliberations are important and serious, the more the opinion that carries should approach unanimity."

Arguments against limitations

Minority rights

McGann argues that majority rule helps to protect minority rights, at least in settings in which deliberation occurs. The argument is that cycling ensures that parties that lose to a majority have an interest to remain part of the group's process, because the decision can easily be overturned by another majority. Furthermore, if a minority wishes to overturn a decision, it needs to form a coalition with only enough of the group members to ensure that more than half approves of the new proposal. (Under supermajority rules, a minority might need a coalition consisting of something greater than a majority to overturn a decision.)

To support the view that majority rule protects minority rights better than supermajority rules McGann points to the cloture rule in the US Senate, which was used to prevent the extension of civil liberties to racial minorities. Ben Saunders, while agreeing that majority rule may offer better protection than supermajority rules, argues that majority rule may nonetheless be of little help to the most despised minorities in a group.

Other arguments against limitations

Some argue that deliberative democracy flourishes under majority rule. They argue that under majority rule, participants always have to convince more than half the group at the very least, while under supermajoritarian rules participants might only need to persuade a minority. Furthermore, proponents argue that cycling gives participants an interest to compromise, rather than strive to pass resolutions that only have the bare minimum required to "win".

Another argument for majority rule is that within this atmosphere of compromise, there will be times when a minority faction will want to support the proposal of another faction in exchange for support of a proposal it believes to be vital. Because it would be in the best interest of such a faction to report the true intensity of its preference, so the argument goes, majority rule differentiates weak and strong preferences. McGann argues that situations such as these give minorities incentive to participate, because there are few permanent losers under majority rule, and so majority rule leads to systemic stability. He points to governments that use majority rule which largely goes unchecked—the governments of the Netherlands, Austria, and Sweden, for example—as empirical evidence of majority rule's stability.