Some clinicians have described the mode of interaction is based upon the acidification of the gastric contents and the release of CO 2  that causes disintegration. Three and a half liters given nasogastrically over 12 hours has been found to dissolve these bezoars. [ 12 ]   Coca-Cola has a pH of 2.6. This is due to  carbonic  and  phosphoric acid  which resemble gastric acid. Gastric acid is believed to facilitate the digestion of fibers. In Coca-Cola, NaHCO 3  has a mucolytic effect and CO 2  bubbles enhance dissolving the bezoar. Coca-Cola reduces the size and softens the make-up of the bezoar, and combined with other treatments, enhances the dissolution. [ 6 ]


A phytobezoar was first  successfully treated with Coca-Cola lavage in 2002. [ 1 ]


Cholera  ( / ˈ k ɒ l ər ə / ) is an  infection  of the  small intestine  by some  strains  of the  bacterium   Vibrio cholerae . [ 4 ] [ 3 ]  Symptoms may range from none, to mild, to severe. [ 3 ]  The classic symptom is large amounts of watery  diarrhea  lasting a few days. [ 2 ]   Vomiting  and  muscle cramps  may also occur. [ 3 ]  Diarrhea can be so severe that it leads within hours to severe  dehydration  and  electrolyte imbalance . [ 2 ]  This may result in  sunken eyes , cold skin, decreased skin elasticity, and wrinkling of the hands and feet. [ 5 ]  Dehydration can cause the skin to turn  bluish . [ 8 ]  Symptoms start two hours to five days after exposure. [ 3 ]


Cholera is caused by a number of  types  of  Vibrio cholerae , with some types producing more severe disease than others. [ 2 ]  It is spread mostly by  unsafe water  and  unsafe food  that has been contaminated with  human feces  containing the bacteria. [ 2 ]  Undercooked  shellfish  is a common source. [ 9 ]  Humans are the only known host for the  bacteria . [ 2 ]   Risk factors  for the disease include poor  sanitation , insufficient clean  drinking water , and  poverty . [ 2 ]  Cholera can be diagnosed by a  stool test , [ 2 ]  or a rapid  dipstick test , although the dipstick test is less accurate. [ 10 ]


Prevention methods against cholera include improved sanitation and access to  clean water . [ 5 ]   Cholera vaccines  that are given by mouth provide reasonable protection for about six months, and confer the added benefit of protecting against another type of diarrhea caused by  E. coli . [ 2 ]  In 2017, the  US Food and Drug Administration  (FDA) approved a single-dose, live, oral cholera vaccine called  Vaxchora  for adults aged 18–64 who are travelling to an area of active cholera transmission. [ 11 ]  It offers limited protection to young children. People who survive an episode of cholera have long-lasting immunity for at least three years (the period tested). [ 12 ]


The primary treatment for affected individuals is  oral rehydration salts  (ORS), the replacement of fluids and electrolytes by using slightly sweet and salty solutions. [ 2 ]  Rice-based solutions are preferred. [ 2 ]  In children,  zinc supplementation  has also been found to improve outcomes. [ 6 ]  In severe cases,  intravenous fluids , such as  Ringer's lactate , may be required, and  antibiotics  may be beneficial. [ 2 ]  The choice of antibiotic is aided by  antibiotic sensitivity testing . [ 3 ]


Cholera continues to affect an estimated 3–5 million people worldwide and causes 28,800–130,000 deaths a year. [ 2 ] [ 7 ]  To date,  seven cholera pandemics  have occurred, with the most recent beginning in 1961, and continuing today. [ 13 ]  The illness is rare in  high-income countries , and affects children most severely. [ 2 ] [ 14 ]  Cholera occurs as both  outbreaks  and  chronically in certain areas . [ 2 ]  Areas with an ongoing risk of disease include  Africa  and  Southeast Asia . [ 2 ]  The risk of death among those affected is usually less than 5%, given improved treatment, but may be as high as 50% without such access to treatment. [ 2 ]  Descriptions of cholera are found as early as the 5th century BCE in  Sanskrit literature . [ 5 ]  In Europe, cholera was a term initially used to describe any kind of gastroenteritis, and was not used for this disease until the early 19th century. [ 15 ]  The study of cholera in England by  John Snow  between 1849 and 1854 led to significant advances in the field of  epidemiology  because of his insights about transmission via  contaminated water , and a map of the same was the first recorded incidence of epidemiological tracking. [ 5 ] [ 16 ]


The primary symptoms of cholera are profuse  diarrhea  and  vomiting  of clear fluid. [ 17 ]  These symptoms usually start suddenly, half a day to five days after ingestion of the bacteria. [ 18 ]  The diarrhea is frequently described as "rice water" in nature and may have a fishy odor. [ 17 ]  An untreated person with cholera may produce 10 to 20 litres (3 to 5 US gal) of diarrhea a day. [ 17 ]  Severe cholera, without treatment, kills about half of affected individuals. [ 17 ]  If the severe diarrhea is not treated, it can result in life-threatening  dehydration  and  electrolyte  imbalances. [ 17 ]  Estimates of the ratio of  asymptomatic  to symptomatic infections have ranged from 3 to 100. [ 19 ]  Cholera has been nicknamed the "blue death" [ 20 ]  because a person's skin may turn  bluish-gray  from extreme loss of fluids. [ 21 ]


Fever is rare and should raise suspicion for secondary infection. Patients can be lethargic and might have sunken eyes, dry mouth, cold clammy skin, or wrinkled hands and feet.  Kussmaul breathing , a deep and labored breathing pattern, can occur because of  acidosis  from  stool   bicarbonate  losses and  lactic acidosis  associated with poor  perfusion .  Blood pressure  drops due to dehydration, peripheral pulse is rapid and thready, and urine output decreases with time. Muscle cramping and weakness, altered consciousness,  seizures , or even  coma  due to  electrolyte imbalances  are common, especially in children. [ 17 ]


Cholera bacteria have been found in  shellfish  and  plankton . [ 17 ]


Transmission  is usually through the  fecal-oral route  of contaminated food or water caused by poor  sanitation . [ 2 ]  Most cholera cases in  developed countries  are a result of transmission by food, while in  developing countries  it is more often water. [ 17 ]  Food transmission can occur when people harvest seafood such as  oysters  in waters infected with  sewage , as  Vibrio cholerae  accumulates in  planktonic   crustaceans  and the oysters eat the  zooplankton . [ 22 ]


People infected with cholera often have diarrhea, and disease transmission may occur if this highly liquid stool, colloquially referred to as "rice-water", contaminates water used by others. [ 23 ]  A single diarrheal event can cause a one-million fold increase in numbers of  V. cholerae  in the environment. [ 24 ]  The source of the contamination is typically other people with cholera when their untreated diarrheal discharge is allowed to get into waterways,  groundwater  or  drinking water  supplies. Drinking any contaminated water and eating any foods washed in the water, as well as  shellfish  living in the affected  waterway , can cause a person to contract an infection. Cholera is rarely  spread directly from person to person . [ 25 ] [ note 1 ]


V. cholerae  also exists outside the human body in natural water sources, either by itself or through interacting with  phytoplankton ,  zooplankton , or  biotic  and  abiotic  detritus. [ 26 ]  Drinking such water can also result in the disease, even without prior contamination through fecal matter. Selective pressures exist however in the aquatic environment that may reduce the virulence of  V. cholerae . [ 26 ]  Specifically, animal models indicate that the transcriptional profile of the pathogen changes as it prepares to enter an aquatic environment. [ 26 ]  This transcriptional change results in a loss of ability of  V. cholerae  to be cultured on standard media, a phenotype referred to as ' viable but non-culturable ' (VBNC) or more conservatively ' active but non-culturable ' (ABNC). [ 26 ]  One study indicates that the culturability of  V. cholerae  drops 90% within 24 hours of entering the water, and furthermore that this loss in culturability is associated with a loss in virulence. [ 26 ] [ 27 ]


Both toxic and non-toxic strains exist. Non-toxic strains can acquire  toxicity  through a  temperate   bacteriophage . [ 28 ]


About 100   million bacteria must typically be ingested to cause cholera in a normal healthy adult. [ 17 ]  This dose, however, is less in those with lowered  gastric acidity  (for instance those using  proton pump inhibitors ). [ 17 ]  Children are also more susceptible, with two- to four-year-olds having the highest rates of infection. [ 17 ]  Individuals' susceptibility to cholera is also affected by their  blood type , with those with  type O blood  being the most susceptible. [ 17 ]  Persons with  lowered immunity , such as persons with  AIDS  or  malnourished  children, are more likely to develop a severe case if they become infected. [ 29 ]  Any individual, even a healthy adult in middle age, can undergo a severe case, and each person's case should be measured by the loss of fluids, preferably in consultation with a professional  health care provider . [ medical citation needed ]


The  cystic fibrosis  genetic  mutation  known as  delta-F508  in humans has been said to maintain a selective  heterozygous advantage :  heterozygous  carriers of the mutation (who are not affected by cystic fibrosis) are more resistant to  V. cholerae  infections. [ 30 ]  In this model, the genetic deficiency in the  cystic fibrosis transmembrane conductance regulator  channel proteins interferes with bacteria binding to the  intestinal epithelium , thus reducing the effects of an infection.


When consumed, most bacteria do not survive the  acidic  conditions of the  human stomach . [ 31 ]  The few surviving bacteria conserve their energy and stored  nutrients  during the passage through the stomach by shutting down  protein  production. When the surviving bacteria exit the stomach and reach the  small intestine , they must propel themselves through the thick  mucus  that lines the small intestine to reach the intestinal walls where they can attach and thrive. [ 31 ]


Once the cholera bacteria reach the intestinal wall, they no longer need the  flagella  to move. The bacteria stop producing the protein  flagellin  to conserve energy and nutrients by changing the mix of proteins that they express in response to the changed chemical surroundings. On reaching the intestinal wall,  V. cholerae  start producing the  toxic proteins  that give the infected person a watery diarrhea. This carries the multiplying new generations of  V. cholerae  bacteria out into the drinking water of the next host if proper sanitation measures are not in place. [ 32 ]


The  cholera toxin  (CTX or CT) is an  oligomeric  complex made up of six  protein subunits : a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a  disulfide bond . The five B subunits form a five-membered ring that binds to  GM1   gangliosides  on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that  ADP-ribosylates   G proteins , while the A2 chain fits into the central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated  endocytosis . Once inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human partner protein called  ADP-ribosylation factor 6  (Arf6). [ 33 ]  Binding exposes its active site, allowing it to permanently ribosylate the  Gs alpha subunit  of the  heterotrimeric G protein . This results in constitutive  cAMP  production, which in turn leads to the secretion of water, sodium, potassium, and bicarbonate into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin was introduced into  V. cholerae  by  horizontal gene transfer . Virulent strains of  V. cholerae  carry a variant of a  temperate   bacteriophage  called  CTXφ .


Microbiologists have studied the  genetic mechanisms  by which the  V. cholerae  bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall. [ 34 ]  Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump  chloride  ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive amounts of diarrhea. The host can become rapidly dehydrated unless treated properly. [ 35 ]


By inserting separate, successive sections of  V. cholerae  DNA into the DNA of other bacteria, such as  E. coli  that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which  V. cholerae  responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered a complex cascade of regulatory proteins controls expression of  V. cholerae   virulence  determinants. [ 36 ]  In responding to the chemical environment at the intestinal wall, the  V. cholerae  bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of  virulence  genes that produce the toxins, causing diarrhea in the infected person and allowing the bacteria to colonize the intestine. [ 34 ]  Current [ when? ]  research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine." [ 34 ]


Amplified fragment length polymorphism   fingerprinting  of the pandemic  isolates  of  V. cholerae  has revealed variation in the genetic structure. Two  clusters  have been identified: Cluster I and Cluster II. For the most part, Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the strains from the African continent. [ 37 ]


In many areas of the world,  antibiotic resistance  is increasing within cholera bacteria. In  Bangladesh , for example, most cases are resistant to  tetracycline ,  trimethoprim-sulfamethoxazole , and  erythromycin . [ 38 ]  Rapid diagnostic  assay  methods are available for the identification of  multi-drug resistant  cases. [ 39 ]  New generation antimicrobials have been discovered which are effective against cholera bacteria in  in vitro  studies. [ 40 ]


A rapid  dipstick  test is available to determine the presence of  V. cholerae . [ 38 ]  In those samples that test positive, further testing should be done to determine antibiotic resistance. [ 38 ]  In  epidemic  situations, a clinical diagnosis may be made by taking a  patient history  and doing a brief examination. Treatment via hydration and over-the-counter hydration solutions can be started without or before confirmation by laboratory analysis, especially where cholera is a common problem. [ 41 ]


Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is  V. cholerae  O1. If  V. cholerae   serogroup  O1 is not isolated, the laboratory should test for  V. cholerae  O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory. [ citation needed ]


Infection with  V. cholerae  O139 should be reported and handled in the same manner as that caused by  V. cholerae  O1. The associated diarrheal illness should be referred to as cholera and must be reported in the United States. [ 42 ]


The  World Health Organization  (WHO) recommends focusing on prevention, preparedness, and response to combat the spread of cholera. [ 35 ]  They also stress the importance of an effective surveillance system. [ 35 ]  Governments can play a role in all of these areas.


Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper  sanitation  practices are followed. In  developed countries , due to their nearly universal advanced  water treatment  and sanitation practices, cholera is rare. For example, the last major outbreak of cholera in the United States occurred in 1910–1911. [ 43 ] [ 44 ]  Cholera is mainly a risk in  developing countries  in those areas where access to  WASH (water, sanitation and hygiene)  infrastructure is still inadequate.


Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. There are several points along the cholera transmission path at which its spread may be halted: [ 45 ]


Handwashing  with soap or ash after using a  toilet  and before handling food or eating is also recommended for cholera prevention by WHO Africa. [ 50 ]


Surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during  rainy seasons . Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provides guidance for improving cholera control activities for the most vulnerable. [ 51 ]  For prevention to be effective, it is important that cases be reported to national health authorities. [ 17 ]


Spanish physician  Jaume Ferran i Clua  developed the first successful cholera inoculation in 1885, the first to immunize humans against a bacterial disease. [ 52 ]  His vaccine and inoculation was rather controversial and was rejected by his peers and several investigation commissions but it ended up demonstrating its effectiveness and being recognized for it: out of the 30 thousand people he vaccinated only 54 died. [ 53 ] [ 54 ] [ 55 ] [ 56 ]  Russian-Jewish bacteriologist  Waldemar Haffkine  also developed a human cholera vaccine in July 1892. [ 53 ] [ 54 ] [ 55 ] [ 57 ]  He conducted a massive inoculation program in  British India . [ 55 ] [ 58 ]


Persons who survive an episode of cholera have long-lasting immunity for at least 3 years (the period tested.) [ 12 ]  A number of safe and effective oral vaccines for cholera are available. [ 59 ]  The World Health Organization (WHO) has three prequalified oral cholera vaccines (OCVs): Dukoral, Sanchol, and Euvichol.  Dukoral , an orally administered, inactivated  whole-cell vaccine , has an overall efficacy of about 52% during the first year after being given and 62% in the second year, with minimal side effects. [ 59 ]  It is available in over 60 countries. However, it is not currently [ when? ]  recommended by the  Centers for Disease Control and Prevention  (CDC) for most people traveling from the United States to endemic countries. [ 60 ]  The vaccine that the  US Food and Drug Administration  (FDA) recommends,  Vaxchora , is an  oral attenuated live vaccine , that is effective for adults aged 18–64 as a single dose. [ 61 ]


One injectable vaccine was found to be effective for two to three years. The protective efficacy was 28% lower in children less than five years old. [ 62 ]  However, as of 2010 [update] , it has limited availability. [ 2 ]  Work is under way to investigate the role of mass vaccination. [ 63 ]  The WHO recommends immunization of high-risk groups, such as children and people with  HIV , in countries where this disease is  endemic . [ 2 ]  If people are immunized broadly,  herd immunity  results, with a decrease in the amount of contamination in the environment. [ 38 ]


WHO recommends that oral cholera vaccination be considered in areas where the disease is endemic (with seasonal peaks), as part of the response to outbreaks, or in a humanitarian crisis during which the risk of cholera is high. [ 64 ]  Oral Cholera Vaccine (OCV) has been recognized as an adjunct tool for prevention and control of cholera. The World Health Organization (WHO) has prequalified three bivalent cholera vaccines—Dukoral (SBL Vaccines), containing a non-toxic B-subunit of cholera toxin and providing protection against V. cholerae O1; and two vaccines developed using the same transfer of technology—ShanChol (Shantha Biotec) and Euvichol (EuBiologics Co.), which have bivalent O1 and O139 oral killed cholera vaccines. [ 65 ]  Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists. [ 66 ]


Developed for use in  Bangladesh , the "sari filter" is a simple and cost-effective  appropriate technology  method for reducing the contamination of drinking water. Used  sari  cloth is preferable but other types of used cloth can be used with some effect, though the effectiveness will vary significantly. Used cloth is more effective than new cloth, as the repeated washing reduces the space between the fibers. Water collected in this way has a greatly reduced  pathogen  count—though it will not necessarily be perfectly safe, it is an improvement for poor people with limited options. [ 67 ]  In Bangladesh this practice was found to decrease rates of cholera by nearly half. [ 68 ]  It involves folding a  sari  four to eight times. [ 67 ]  Between uses the cloth should be rinsed in clean water and dried in the sun to kill any bacteria on it. [ 69 ]  A  nylon  cloth appears to work as well but is not as affordable. [ 68 ]


Continued eating speeds the recovery of normal intestinal function. The WHO recommends this generally for cases of diarrhea no matter what the underlying cause. [ 70 ]  A CDC training manual specifically for cholera states: "Continue to breastfeed your baby if the baby has watery diarrhea, even when traveling to get treatment. Adults and older children should continue to eat frequently." [ 71 ]


The most common error in caring for patients with cholera is to underestimate the speed
and volume of fluids required. [ 72 ]  In most cases, cholera can be successfully treated with  oral rehydration therapy  (ORT), which is highly effective, safe, and simple to administer. [ 38 ]  Rice-based solutions are preferred to glucose-based ones due to greater efficiency. [ 38 ]  In severe cases with significant dehydration,  intravenous  rehydration may be necessary.  Ringer's lactate  is the preferred solution, often with added potassium. [ 17 ] [ 70 ]  Large volumes and continued replacement until diarrhea has subsided may be needed. [ 17 ]  Ten percent of a person's body weight in fluid may need to be given in the first two to four hours. [ 17 ]  This method was first tried on a mass scale during the  Bangladesh Liberation War , and was found to have much success. [ 73 ]  Despite widespread beliefs, fruit juices and commercial fizzy drinks like cola are not ideal for rehydration of people with serious infections of the intestines, and their excessive sugar content may even harm water uptake. [ 74 ]


If commercially produced oral rehydration solutions are too expensive or difficult to obtain, solutions can be made. One such recipe calls for 1 liter of boiled water, 1/2 teaspoon of salt, 6 teaspoons of sugar, and added mashed banana for potassium and to improve taste. [ 75 ]


As there frequently is initially  acidosis , the  potassium  level may be normal, even though large losses have occurred. [ 17 ]  As the dehydration is corrected, potassium levels may decrease rapidly, and thus need to be replaced. [ 17 ]  This is best done by Oral Rehydration Solution (ORS). [ 76 ]


Antibiotic  treatments for one to three days shorten the course of the disease and reduce the severity of the symptoms. [ 17 ]  Use of antibiotics also reduces fluid requirements. [ 77 ]  People will recover without them, however, if sufficient hydration is maintained. [ 38 ]  The WHO only recommends antibiotics in those with severe dehydration. [ 76 ]


Doxycycline  is typically used first line, although some  strains  of  V. cholerae  have shown  resistance . [ 17 ]  Testing for resistance during an outbreak can help determine appropriate future choices. [ 17 ]  Other antibiotics proven to be effective include  cotrimoxazole ,  erythromycin ,  tetracycline ,  chloramphenicol , and  furazolidone . [ 78 ]   Fluoroquinolones , such as  ciprofloxacin , also may be used, but resistance has been reported. [ 79 ]


Antibiotics improve outcomes in those who are both severely and not severely dehydrated. [ 80 ]   Azithromycin  and  tetracycline  may work better than  doxycycline  or  ciprofloxacin . [ 80 ]


In Bangladesh  zinc  supplementation reduced the duration and severity of diarrhea in children with cholera when given with antibiotics and rehydration therapy as needed. It reduced the length of disease by eight hours and the amount of diarrhea stool by 10%. [ 81 ]  Supplementation appears to be also effective in both treating and preventing infectious diarrhea due to other causes among children in the developing world. [ 81 ] [ 82 ]


If people with cholera are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%. [ 17 ] [ 1 ]


For certain genetic strains of cholera, such as the one present during the  2010 epidemic in Haiti  and the 2004 outbreak in India, death can occur within two hours of becoming ill. [ 83 ]


Cholera affects an estimated 2.8 million people worldwide, and causes approximately 95,000 deaths a year (uncertainty range: 21,000–143,000) as of 2015 [update] . [ 84 ] [ 85 ]  This occurs mainly in the developing world. [ 86 ]


In the early 1980s, death rates are believed to have still been higher than three million a year. [ 17 ]  It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism of a country. [ 38 ]  As of 2004, cholera remained both  epidemic  and endemic in many areas of the world. [ 17 ]


Recent major outbreaks are the  2010s Haiti cholera outbreak  and the  2016–2022 Yemen cholera outbreak . In October 2016, an  outbreak of cholera  began in war-ravaged  Yemen . [ 87 ]   WHO  called it "the worst cholera outbreak in the world". [ 88 ]  In 2019, 93% of the reported 923,037 cholera cases were from  Yemen  (with 1911 deaths reported). [ 89 ]  Between September 2019 and September 2020, a global total of over 450,000 cases and over 900 deaths was reported; however, the accuracy of these numbers suffer from over-reporting from countries that report suspected cases (and not laboratory confirmed cases), as well as under-reporting from countries that do not report official cases (such as Bangladesh, India and Philippines). [ 89 ]


Although much is known about the mechanisms behind the spread of cholera, researchers still do not have a full understanding of what makes cholera outbreaks happen in some places and not others. Lack of treatment of human  feces  and lack of treatment of drinking water greatly facilitate its spread. Bodies of water have been found to serve as a  reservoir  of infection, and seafood shipped long distances can spread the disease.


Cholera had disappeared from the  Americas  for most of the 20th century, but it reappeared toward the end of that century, beginning with a severe outbreak in Peru. [ 90 ]  This was followed by the  2010s Haiti cholera outbreak [ 91 ]  and another outbreak of cholera in Haiti amid the  2018–2023 Haitian crisis . [ 92 ]  As of August 2021 [update]  the disease is endemic in Africa and some areas of eastern and western Asia (Bangladesh, India and Yemen). [ 91 ]  Cholera is not endemic in Europe; all reported cases had a travel history to endemic areas. [ 91 ]


The word cholera is from  Greek :  χολέρα   kholera  from χολή  kholē  "bile". Cholera likely has its origins in the  Indian subcontinent  as evidenced by its prevalence in the region for centuries. [ 17 ]


References to cholera appear in the European literature as early as 1642, from the Dutch physician  Jakob de Bondt's  description in his De Medicina Indorum. [ 93 ]  (The "Indorum" of the title refers to the East Indies. He also gave first European descriptions of other diseases.) But at the time, the word "cholera" was historically used by European physicians to refer to any gastrointestinal upset resulting in yellow diarrhea. De Bondt thus used a common word already in regular use to describe the new disease. This was a frequent practice of the time. It was not until the 1830s that the name for severe yellow diarrhea changed in English from "cholera" to "cholera morbus" to differentiate it from what was then known as "Asiatic cholera", or that associated with origins in India and the East.


Early outbreaks in the Indian subcontinent are believed to have been the result of crowded, poor living conditions, as well as the presence of pools of  still water , both of which provide ideal conditions for cholera to thrive. [ 94 ]  The disease first spread by travelers along  trade routes  (land and sea) to  Russia  in 1817, later to the rest of  Europe , and from Europe to  North America  and the rest of the world, [ 17 ]  (hence the name "Asiatic cholera" [ 1 ] ). Seven  cholera pandemics  have occurred since the early 19th century; the first one did not reach the Americas. The seventh  pandemic  originated in  Indonesia  in 1961. [ 95 ]


The  first cholera pandemic  occurred in the Bengal region of India, near Calcutta starting in 1817 through 1824. The disease dispersed from India to Southeast Asia, the Middle East, Europe, and Eastern Africa. [ 96 ]  The movement of British Army and Navy ships and personnel is believed to have contributed to the range of the pandemic, since the ships carried people with the disease to the shores of the Indian Ocean, from Africa to Indonesia, and north to China and Japan. [ 97 ]


The  second pandemic  lasted from 1826 to 1837 and particularly affected North America and Europe. Advancements in transport and global trade, and increased human migration, including soldiers, meant that more people were carrying the disease more widely. [ 98 ]


The  third pandemic  erupted in 1846, persisted until 1860, extended to North Africa, and reached North and South America. It was introduced to North America at  Quebec, Canada , via Irish immigrants from the Great Famine. In this pandemic, Brazil was affected for the first time.


The  fourth pandemic  lasted from 1863 to 1875, spreading from India to Naples and Spain, and reaching the United States at  New Orleans, Louisiana  in 1873. It spread throughout the Mississippi River system on the continent.


The  fifth  pandemic was from 1881 to 1896. It started in India and spread to Europe, Asia, and South America. The  sixth pandemic  ran from 1899 to 1923. These epidemics had a lower number of fatalities because physicians and researchers had a greater understanding of the cholera bacteria. Egypt, the Arabian peninsula, Persia, India, and the Philippines were hit hardest during these epidemics. Other areas, such as Germany in 1892 (primarily the city of Hamburg, where more than 8.600 people died) [ 99 ]  and Naples from 1910 to 1911, also had severe outbreaks.


The  seventh pandemic  originated in 1961 in Indonesia and is marked by the emergence of a new strain, nicknamed  El Tor , which still persists (as of 2018 [update] [ 100 ] ) in developing countries. [ 101 ]  This pandemic had initially subsided about 1975 and was thought to have ended, but, as noted, it has persisted. There were a rise in cases in the 1990s and since.


Cholera became widespread in the 19th century. [ 102 ]  Since then it has killed tens of millions of people. [ 103 ]  In  Russia  alone, between 1847 and 1851, more than one million people died from the disease. [ 104 ]  It killed 150,000 Americans during the second pandemic. [ 105 ]  Between 1900 and 1920, perhaps eight million people died of cholera in India. [ 106 ]  Cholera officially became the first  reportable disease  in the United States due to the significant effects it had on health. [ 17 ]   John Snow , in  England , in 1854 was the first to identify the importance of contaminated water as its source of transmission. [ 17 ]  Cholera is now no longer considered a pressing health threat in Europe and North America due to  filtering  and  chlorination  of water supplies, but it still strongly affects populations in  developing countries .


In the past, vessels flew a yellow  quarantine  flag if any crew members or passengers had cholera. No one aboard a vessel flying a yellow flag would be allowed ashore for an extended period, typically 30 to 40 days. [ 107 ]


Historically many different claimed remedies have existed in folklore. Many of the older remedies were based on the  miasma theory , that the disease was transmitted by bad air. Some believed that abdominal chilling made one more susceptible, and flannel and  cholera belts  were included in army kits. [ 108 ]  In the 1854–1855 outbreak in Naples, homeopathic  camphor  was used according to  Hahnemann . [ 109 ]  Dr. Hahnemann laid down three main remedies that would be curative in that disease; in early and simple cases  camphor ; in later stages with excessive cramping,  cuprum  or with excessive evacuations and profuse cold sweat,  veratrum album . These are the Trio Cholera remedies used by homoeopaths around the world. [ 110 ]
T. J. Ritter's  Mother's Remedies  book lists tomato syrup as a home remedy from northern America.  Elecampane  was recommended in the United Kingdom, according to William Thomas Fernie. [ 111 ]  The first effective human vaccine was developed in 1885, and the first effective antibiotic was developed in 1948.


Cholera cases are much less frequent in developed countries where governments have helped to establish water sanitation practices and effective medical treatments. [ 112 ]  In the 19th century the United States, for example, had a severe cholera problem similar to those in some developing countries. It had three large cholera outbreaks in the 1800s, which can be attributed to  Vibrio cholerae 's  spread through interior waterways such as the  Erie Canal  and the extensive Mississippi River valley system, as well as the major ports along the  Eastern Seaboard  and their cities upriver. [ 113 ]  The island of Manhattan in New York City touches the Atlantic Ocean, where cholera collected from river waters and ship discharges just off the coast. At this time, New York City did not have as effective a sanitation system as it developed in the later 20th century, so cholera spread through the city's water supply. [ 114 ]


Cholera morbus is a historical term that was used to refer to  gastroenteritis  rather than specifically to what is now defined as the disease of cholera. [ 15 ]


One of the major contributions to fighting cholera was made by the physician and pioneer medical scientist  John Snow  (1813–1858), who in 1854 found a link between cholera and contaminated drinking water. [ 94 ]  Dr. Snow proposed a microbial origin for epidemic cholera in 1849. In his major "state of the art" review of 1855, he proposed a substantially complete and correct model for the cause of the disease. In two pioneering epidemiological field studies, he was able to demonstrate human  sewage  contamination was the most probable disease vector in two  major epidemics in London in 1854 . [ 115 ]  His model was not immediately accepted, but it was increasingly seen as plausible as medical microbiology developed over the next 30 years or so. For his work on cholera, John Snow is often regarded as the "Father of Epidemiology". [ 116 ] [ 117 ] [ 118 ]


The bacterium was isolated in 1854 by Italian anatomist  Filippo Pacini , [ 119 ]  but its exact nature and his results were not widely known. In the same year, the  Catalan   Joaquim Balcells i Pascual  discovered the bacterium. [ 120 ] [ 121 ]  In 1856  António Augusto da Costa Simões  and  José Ferreira de Macedo Pinto , two Portuguese researchers, are believed to have done the same. [ 120 ] [ 122 ]


Between the mid-1850s and the 1900s, cities in developed nations made massive investment in clean water supply and well-separated sewage treatment infrastructures. This eliminated the threat of cholera epidemics from the major developed cities in the world. In 1883,  Robert Koch  identified  V. cholerae  with a microscope as the bacillus causing the disease. [ 123 ]


Hemendra Nath Chatterjee , a Bengali scientist, was the first to formulate and demonstrate the effectiveness of  oral rehydration salt  (ORS) to treat  diarrhea . In his 1953 paper, published in  The Lancet , he states that  promethazine  can stop  vomiting  during cholera and then oral rehydration is possible. The formulation of the fluid replacement solution was 4 g of  sodium chloride , 25 g of  glucose  and 1000 ml of  water . [ 124 ] [ 125 ]


Indian  medical scientist  Sambhu Nath De  discovered the  cholera toxin , the  animal model  of cholera , and successfully demonstrated the method of transmission of cholera pathogen  Vibrio cholerae . [ 126 ]


Robert Allan Phillips , working at US  Naval Medical Research Unit Two  in Southeast Asia, evaluated the pathophysiology of the disease using modern laboratory chemistry techniques. He developed a protocol for rehydration. His research led the  Lasker Foundation  to award him its prize in 1967. [ 127 ]


More recently, in 2002, Alam,  et al. , studied stool samples from patients at the  International Centre for Diarrhoeal Disease  in  Dhaka, Bangladesh . From the various experiments they conducted, the researchers found a correlation between the passage of  V. cholerae  through the human digestive system and an increased infectivity state. Furthermore, the researchers found the bacterium creates a hyperinfected state where  genes  that control biosynthesis of  amino acids ,  iron  uptake systems, and formation of periplasmic nitrate reductase complexes were induced just before defecation. These induced characteristics allow the cholera vibrios to survive in the "rice water" stools, an environment of limited oxygen and iron, of patients with a cholera infection. [ 128 ]


In 2017, the WHO launched the "Ending Cholera: a global roadmap to 2030" strategy which aims to reduce cholera deaths by 90% by 2030. [ 129 ]  The strategy was developed by the Global Task Force on Cholera Control (GTFCC) which develops country-specific plans and monitors progress. [ 130 ]  The approach to achieve this goal combines surveillance, water sanitation, rehydration treatment and oral vaccines. [ 129 ]  Specifically, the control strategy focuses on three approaches: i) early detection and response to outbreaks to contain outbreaks, ii) stopping cholera transmission through improved sanitation and vaccines in hotspots, and iii) a global framework for cholera control through the GTFCC. [ 129 ]


The WHO and the GTFCC do not consider global cholera  eradication  a viable goal. [ 131 ]  Even though humans are the only host of cholera, the bacterium can persist in the environment without a human host. [ 132 ]  While global eradication is not possible, elimination of human to human transmission may be possible. [ 132 ]  Local elimination is possible, which has been underway most recently during the  2010s Haiti cholera outbreak . Haiti aims to achieve certification of elimination by 2022. [ 133 ]


The GTFCC targets 47 countries, 13 of which have established vaccination campaigns. [ 89 ]


In many developing countries, cholera still reaches its victims through contaminated water sources, and countries without proper sanitation techniques have greater incidence of the disease. [ 134 ]  Governments can play a role in this. In 2008, for example, the  Zimbabwean cholera outbreak  was due partly to the government's role, according to a report from the  James Baker Institute . [ 22 ]  The Haitian government's inability to provide safe drinking water after the 2010 earthquake led to an increase in cholera cases as well. [ 135 ]


Similarly, South Africa's cholera outbreak was exacerbated by the government's policy of privatizing water programs. The wealthy elite of the country were able to afford safe water while others had to use water from cholera-infected rivers. [ 136 ]


According to  Rita R. Colwell  of the  James Baker Institute , if cholera does begin to spread, government preparedness is crucial. A government's ability to contain the disease before it extends to other areas can prevent a high death toll and the development of an epidemic or even pandemic. Effective disease surveillance can ensure that cholera outbreaks are recognized as soon as possible and dealt with appropriately. Oftentimes, this will allow public health programs to determine and control the cause of the cases, whether it is unsanitary water or seafood that have accumulated a lot of  Vibrio cholerae  specimens. [ 22 ]  Having an effective surveillance program contributes to a government's ability to prevent cholera from spreading. In the year 2000 in the state of Kerala in India, the Kottayam district was determined to be "Cholera-affected"; this pronouncement led to task forces that concentrated on educating citizens with 13,670 information sessions about human health. [ 137 ]  These task forces promoted the boiling of water to obtain safe water, and provided chlorine and oral rehydration salts. [ 137 ]  Ultimately, this helped to control the spread of the disease to other areas and minimize deaths. On the other hand, researchers have shown that most of the citizens infected during the 1991 cholera outbreak in Bangladesh lived in rural areas, and were not recognized by the government's surveillance program. This inhibited physicians' abilities to detect cholera cases early. [ 138 ]


According to Colwell, the quality and inclusiveness of a country's health care system affects the control of cholera, as it did in the  Zimbabwean cholera outbreak . [ 22 ]  While sanitation practices are important, when governments respond quickly and have readily available vaccines, the country will have a lower cholera death toll. Affordability of vaccines can be a problem; if the governments do not provide vaccinations, only the wealthy may be able to afford them and there will be a greater toll on the country's poor. [ 139 ] [ 140 ]  The speed with which government leaders respond to cholera outbreaks is important. [ 141 ]


Besides contributing to an effective or declining public health care system and water sanitation treatments, government can have indirect effects on cholera control and the effectiveness of a response to cholera. [ 142 ]  A country's government can impact its ability to prevent disease and control its spread. A speedy government response backed by a fully functioning health care system and financial resources can prevent cholera's spread. This limits cholera's ability to cause death, or at the very least a decline in education, as children are kept out of school to minimize the risk of infection. [ 142 ]  Inversely, poor government response can lead to civil unrest and  cholera riots . [ 143 ]


Unlike  tuberculosis  ("consumption") which in literature and the arts was often romanticized as a disease of denizens of the  demimonde  or those with an artistic temperament, [ 154 ]  cholera is a disease which almost entirely affects the poor living in unsanitary conditions. This, and the unpleasant course of the disease – which includes voluminous "rice-water" diarrhea, the hemorrhaging of liquids from the mouth, and violent muscle contractions which continue even after death – has discouraged the disease from being romanticized, or even being factually presented in popular culture. [ 155 ]


In  Zambia , widespread cholera outbreaks have occurred since 1977, most commonly in the capital city of  Lusaka . [ 157 ]  In 2017, an outbreak of cholera was declared in Zambia after laboratory confirmation of  Vibrio cholerae  O1, biotype El Tor, serotype Ogawa, from stool samples from two patients with acute watery diarrhea. There was a rapid increase in the number of cases from several hundred cases in early December 2017 to approximately 2,000 by early January 2018. [ 158 ]  With intensification of the rains, new cases increased on a daily basis reaching a peak on the first week of January 2018 with over 700 cases reported. [ 159 ]


In collaboration with partners, the Zambia Ministry of Health (MoH) launched a multifaceted public health response that included increased chlorination of the Lusaka municipal water supply, provision of emergency water supplies, water quality monitoring and testing, enhanced surveillance, epidemiologic investigations, a cholera vaccination campaign, aggressive case management and health care worker training, and laboratory testing of clinical samples. [ 158 ]


The Zambian Ministry of Health implemented a reactive one-dose Oral Cholera Vaccine (OCV) campaign in April 2016 in three Lusaka compounds, followed by a pre-emptive second-round in December. [ 160 ]


Nigeria


In June 2024, the  Nigeria Centre for Disease Control and Prevention  (NCDC) announced a total of 1,141 suspected and 65 confirmed cases of cholera with 30 deaths from 96 Local Government Areas (LGAs) in 30 states of the country. [ 161 ]  NCDC, in its public health advisory, said Abia, Bayelsa, Bauchi, Cross River, Delta, Imo, Katsina, Lagos, Nasarawa and Zamfara states were the 10 states that contributed 90 percent of the burden of cholera in the country at the time. [ 162 ]


The city of  Kolkata ,  India  in the state of  West Bengal  in the  Ganges delta  has been described as the "homeland of cholera", with regular outbreaks and pronounced seasonality. In India, where the disease is  endemic , cholera outbreaks occur every year between  dry seasons  and  rainy seasons . India is also characterized by high population density, unsafe drinking water, open drains, and poor sanitation which provide an optimal niche for survival, sustenance and transmission of  Vibrio cholerae . [ 163 ]


In  Goma  in the  Democratic Republic of Congo , cholera has left an enduring mark on human and medical history. Cholera pandemics in the 19th and 20th centuries led to the growth of epidemiology as a science and in recent years it has continued to press advances in the concepts of  disease ecology , basic membrane biology, and transmembrane signaling and in the use of scientific information and treatment design. [ 164 ]


Chronic enteropathy associated with SLCO2A1  gene  is a rare  autosomal   recessive   enteropathy  that was first described in 1968. [ 1 ]  This condition was previously named chronic nonspecific multiple  ulcers  of the  small intestine . [ 2 ] [ 3 ]


This  disease  occurs most commonly in women.  Symptom  onset is usually in  adolescence . Symptoms include  fatigue ,  oedema  and  abdominal pain . The disease course is  chronic  and while  immunosuppressants  have been tried these have not been shown to be helpful. On small bowel endoscopy the ulcers may be visible. [ citation needed ]


Sequencing  the DNA of several  patients  suggested a  mutation  in the  SLCO2A1  gene. [ 4 ]  The presence of this mutation was confirmed by sequencing this gene in additional patients. [ citation needed ]


This gene encodes a  prostaglandin  transporter. As  non-steroidal anti-inflammatory drugs  inhibit prostaglandin synthesis this helps to explain the known similarity in the  histological  findings between these conditions. The identification of this mutation suggests that prostaglandin replacement may be helpful but this will need to be tested in a  clinical trial . [ citation needed ]


Within the small intestine there are multiple small shallow ulcers which may be linear or concentric. [ 5 ]   Stenosis  of the small bowel may be present due to healing of these ulcers. The ulcers resemble those associated with non steroidal use but occur in the absence of the use of these drugs. [ citation needed ]


Immunohistochemical staining  for SLCO2A1 in gastro-duodenal tissue biopsy, may be helpful in distinguishing chronic enteropathy from  Crohn's disease . [ 6 ]


Coeliac disease  ( British English ) or  celiac disease  ( American English ) is a long-term  autoimmune disorder , primarily affecting the  small intestine , where individuals develop  intolerance  to  gluten , present in foods such as  wheat ,  rye  and  barley . [ 10 ]  Classic symptoms include gastrointestinal problems such as chronic  diarrhoea ,  abdominal distention ,  malabsorption ,  loss of appetite , and among children  failure to grow normally . [ 1 ]


Non-classic symptoms are more common, especially in people older than two years. [ 8 ] [ 15 ] [ 16 ]  There may be mild or absent gastrointestinal symptoms, a wide number of  symptoms involving any part of the body , or no obvious symptoms. [ 1 ]  Coeliac disease was first described in childhood; [ 6 ] [ 8 ]  however, it may develop at any age. [ 1 ] [ 8 ]  It is associated with other  autoimmune diseases , such as  Type 1 diabetes mellitus  and  Hashimoto's thyroiditis , among others. [ 6 ]


Coeliac disease is caused by a reaction to gluten, a group of various proteins found in  wheat  and in other grains such as  barley  and  rye . [ 9 ] [ 17 ] [ 18 ]  Moderate quantities of  oats , free of contamination with other gluten-containing grains, are usually tolerated. [ 17 ] [ 19 ]  The occurrence of problems may depend on the  variety  of oat. [ 17 ] [ 20 ]  It occurs more often in people who are  genetically predisposed . [ 10 ]  Upon exposure to gluten, an abnormal  immune  response may lead to the production of several different  autoantibodies  that can affect a number of different  organs . [ 4 ] [ 21 ]  In the small bowel, this causes an  inflammatory reaction  and may produce shortening of the  villi  lining the small intestine ( villous atrophy ). [ 10 ] [ 11 ]  This affects the absorption of nutrients, frequently leading to  anaemia . [ 10 ] [ 18 ]


Diagnosis is typically made by a combination of blood antibody tests and intestinal  biopsies , helped by specific  genetic testing . [ 10 ]  Making the diagnosis is not always straightforward. [ 22 ]  About 10% of the time, the autoantibodies in the blood are negative, [ 23 ] [ 24 ]  and many people have only minor intestinal changes with normal villi. [ 25 ]  People may have severe symptoms and they may be investigated for years before a diagnosis is achieved. [ 26 ] [ 27 ]  As a result of  screening , the diagnosis is increasingly being made in people who have  no symptoms . [ 28 ]  Evidence regarding the effects of screening, however, is not sufficient to determine its usefulness. [ 29 ]  While the disease is caused by a  permanent intolerance  to gluten proteins, [ 10 ]  it is distinct from  wheat allergy , which is much more rare. [ 30 ] [ 31 ]


The only known effective treatment is a strict lifelong  gluten-free diet , which leads to recovery of the intestinal lining ( mucous membrane ), improves symptoms, and reduces the risk of developing complications in most people. [ 13 ]  If untreated, it may result in  cancers  such as intestinal  lymphoma , and a slightly increased risk of early death. [ 3 ]  Rates vary between different regions of the world, from as few as 1 in 300 to as many as 1 in 40, with an average of between 1 in 100 and 1 in 170 people. [ 14 ]  It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria. [ 5 ] [ 26 ] [ 32 ]  Coeliac disease is slightly more common in women than in men. [ 33 ]


The classic symptoms of untreated coeliac disease include  diarrhea ,  steatorrhoea ,  iron-deficiency anemia , and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself. [ 34 ]  It is also possible to have coeliac disease without any of the classic symptoms at all. [ 18 ]  This has been shown to comprise at least 43% of presentations in children. [ 35 ]  Further, many adults with subtle disease may only present with fatigue,  anaemia  or  low bone mass . [ 28 ]  Many undiagnosed individuals who consider themselves asymptomatic are in fact not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored. [ 5 ] [ 27 ] [ 32 ]


Diarrhoea  that is characteristic of coeliac disease is chronic, sometimes pale, of large volume, and abnormally foul in odor.  Abdominal pain , cramping, bloating with  abdominal distension  (thought to be the result of fermentative production of bowel gas), and  mouth ulcers [ 36 ]  may be present. As the bowel becomes more damaged, a degree of  lactose intolerance  may develop. [ 18 ]  Frequently, the symptoms are ascribed to  irritable bowel syndrome  (IBS), only later to be recognised as coeliac disease. In populations of people with symptoms of IBS, a diagnosis of coeliac disease can be made in about 3.3% of cases, or four times more likely than in general. [ 37 ]  Screening them for coeliac disease is recommended by the  National Institute for Health and Clinical Excellence  (NICE), the  British Society of Gastroenterology  and the  American College of Gastroenterology , but is of unclear benefit in North America. [ 37 ] [ 38 ]


Coeliac disease leads to an increased risk of both  adenocarcinoma  and  lymphoma  of the small bowel ( enteropathy-associated T-cell lymphoma  (EATL) or other  non-Hodgkin lymphomas ). [ 39 ]  This risk is also higher in first-degree relatives such as siblings, parents and children. Whether a gluten-free diet brings this risk back to baseline is not clear. [ 40 ]  Long-standing and untreated disease may lead to other complications, such as  ulcerative jejunitis  (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel). [ 41 ]


The changes in the bowel reduce its ability to  absorb  nutrients, minerals, and the  fat-soluble vitamins  A, D, E, and K. [ 18 ] [ 42 ]


Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.


Coeliac disease is associated with several other medical conditions, many of which are autoimmune disorders:  diabetes mellitus type 1 ,  hypothyroidism ,  primary biliary cholangitis ,  microscopic colitis ,  gluten ataxia ,  psoriasis ,  vitiligo ,  autoimmune hepatitis ,  primary sclerosing cholangitis , and more. [ 4 ]


Coeliac disease is caused by an inflammatory reaction to  gliadins  and  glutenins  ( gluten  proteins) [ 50 ]  found in wheat and to similar proteins found in the crops of the  tribe   Triticeae  (which includes other common grains such as  barley  and  rye ) [ 18 ]  and to the tribe  Aveneae  ( oats ). [ 51 ]  Wheat subspecies (such as  spelt ,  durum , and  Kamut ) and wheat hybrids (such as  triticale ) also cause symptoms of coeliac disease. [ 51 ] [ 52 ]


A small number of people with coeliac disease react to oats. [ 18 ]  Oat toxicity in coeliac people depends on the oat  cultivar  consumed because the prolamin genes, protein amino acid sequences, and the  immunoreactivities  of toxic prolamins are different in different oat varieties. [ 20 ] [ 53 ]  Also, oats are frequently cross-contaminated with other grains containing gluten. [ 20 ] [ 53 ] [ 54 ]  The term "pure oats" refers to oats uncontaminated with other gluten-containing cereals. [ 20 ]  The long-term effects of pure oat consumption are still unclear, [ 55 ]  and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in a  gluten-free diet . [ 54 ]  Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic  intestinal biopsies . [ 55 ]


Other cereals such as  corn ,  millet ,  sorghum ,  teff ,  rice , and  wild rice  are safe for people with coeliac disease to consume, as well as non-cereals such as  amaranth ,  quinoa , and  buckwheat . [ 52 ] [ 56 ]  Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms. [ 52 ]


There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress. [ 57 ]


The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after six months may increase it. [ 58 ] [ 59 ]  There is uncertainty whether being breastfed reduces risk. Prolonging  breastfeeding  until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear. [ 60 ]  These factors may just influence the timing of onset. [ 61 ]


Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person. [ 62 ]


Almost all people (95%) with coeliac disease have either the variant  HLA-DQ2   allele  or (less commonly) the  HLA-DQ8   allele . [ 28 ] [ 63 ]  However, about 20–30% of people without coeliac disease have also inherited either of these alleles. [ 64 ]  This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below). [ 28 ]


The vast majority of people with coeliac have one of two types (out of seven) of the  HLA-DQ  protein. [ 64 ]   HLA-DQ is part of the  MHC class II antigen-presenting receptor  (also called the  human leukocyte antigen ) system and distinguishes cells between self and non-self for the purposes of the  immune system . The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of  chromosome 6 . [ citation needed ]


There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate  T lymphocytes  and initiate the autoimmune process. [ 28 ]


Most people with coeliac bear a two-gene HLA-DQ2  haplotype  referred to as  DQ2.5 haplotype . This haplotype is composed of two adjacent gene  alleles , DQA1*0501 and  DQB1*0201 , which encode the two subunits, DQ α 5  and DQ β 2 . In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from  both  parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications. [ 66 ]


Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the  DQ2.2  isoform, and the remaining 2% lack DQ2 or DQ8. [ 67 ]


The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe ( Basque Country  and Ireland [ 68 ]  with highest frequencies) and portions of Africa and is associated with disease in India, [ 69 ]  but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac  phenotype . [ 70 ]


Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. [ 71 ]  Many of the loci detected have been found in association with other autoimmune diseases. One locus, the  LPP  or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant ( SNP =rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease ( p  < 10 −39 ) in samples taken from a broad area of Europe and the US. [ 71 ]


The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition,  lactose intolerance , which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981). [ 72 ]  By now, however, it is apparent that this is not the case; on the contrary, there is evidence of  positive  selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections. [ 73 ] [ 74 ]


The majority of the proteins in food responsible for the immune reaction in coeliac disease are the  prolamins . These are storage proteins rich in  proline  ( prol- ) and  glutamine  ( -amin ) that dissolve in alcohols and are resistant to  proteases  and  peptidases  of the gut. [ 28 ] [ 75 ]  Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley ( hordein ), rye ( secalin ) and  oats  ( avenin ). [ 51 ]  One region of  α-gliadin  stimulates membrane cells,  enterocytes , of the intestine to allow larger molecules around the sealant between cells. Disruption of  tight junctions  allow peptides larger than three  amino acids  to enter the intestinal lining. [ 76 ]


Membrane leaking permits peptides of gliadin that stimulate two levels of the immune response: the innate response, and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of  interleukin-15 . This  innate response to gliadin  results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals. [ 28 ]  The strongest and most common adaptive response to gliadin is directed toward an  α2-gliadin fragment  of 33 amino acids in length. [ 28 ]


The response to the 33mer occurs in most coeliacs who have  a DQ2   isoform . This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells. [ 77 ]  Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease. [ 28 ] [ 51 ] [ 78 ]  Avenin's toxicity in people with coeliac disease depends on the oat  cultivar  consumed, as prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins vary among oat varieties. [ 20 ]


Anti-transglutaminase antibodies  to the enzyme  tissue transglutaminase  (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions. [ 23 ]  Tissue transglutaminase modifies gluten  peptides  into a form that may stimulate the immune system more effectively. [ 28 ]  These peptides are modified by tTG in two ways,  deamidation  or  transamidation . [ 79 ]


Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg. [ 80 ]  This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop. [ 81 ] [ 82 ] [ 83 ]


Stored biopsies from people with suspected coeliac disease have revealed that  autoantibody  deposits in the  subclinical  coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population. [ 84 ]  Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease. [ 85 ]  In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with work showing that gliadin has an innate response component, [ 86 ]  suggest that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of people with coeliac, the anti-tTG antibodies also recognise a  rotavirus  protein called VP7. These antibodies stimulate  monocyte  proliferation, and rotavirus infection might explain some early steps in the cascade of  immune cell  proliferation. [ 87 ]


Indeed, earlier studies of rotavirus damage in the gut showed this causes villous atrophy. [ 88 ]   This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies. [ citation needed ]


Other intestinal disorders may have  biopsy  that look like coeliac disease including lesions caused by Candida. [ 89 ]


The inflammatory process, mediated by  T cells , leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption as it impairs the body's ability to absorb  nutrients , minerals, and fat-soluble  vitamins  A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of  lactase  but typically resolves once the condition is treated. [ citation needed ]


Alternative causes of this tissue damage have been proposed and involve the release of  interleukin 15  and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of  enterocytes  by lymphocytes in the  epithelium . [ 28 ]  The villous atrophy seen on biopsy may also be due to unrelated causes, such as  tropical sprue ,  giardiasis  and  radiation enteritis . While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to the diet may require these alternative diagnoses to be considered. [ 41 ]


Diagnosis  is often difficult and as of 2019, there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay. [ 26 ] [ 22 ]  It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it. [ 26 ]


Several tests can be used. The level of  symptoms  may determine the order of the tests, but  all  tests lose their usefulness if the person is already eating a  gluten-free diet .  Intestinal  damage begins to heal within weeks of gluten being removed from the diet, and  antibody  levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a  rechallenge  with some gluten-containing food in one meal a day over six weeks before repeating the investigations. [ 21 ]


Serological  blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present with minor damage to the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti- endomysial  (EMA) antibodies of the  immunoglobulin A  (IgA) type can detect coeliac disease with a  sensitivity and specificity  of 90% and 99%, respectively. [ 90 ]   Serology  for  anti-transglutaminase antibodies  (anti-tTG) was initially reported to have a higher  sensitivity  (99%) and  specificity  (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibodies. [ 90 ]  Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions ( duodenal lymphocytosis ) with normal villi. [ 23 ] [ 24 ]


Tissue transglutaminase  (abbreviated as tTG or TG2) modifies gluten  peptides  into a form that may stimulate the immune system more effectively. [ 28 ]  These peptides are modified by tTG in two ways, deamidation or transamidation. [ 79 ]  Modern anti-tTG assays rely on a human  recombinant protein  as an  antigen . [ 91 ]  tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies. [ 21 ]


Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic. [ 21 ] [ 92 ]


If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests. [ 8 ]


Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive  blood test  is still followed by an  endoscopy / gastroscopy  and  biopsy . A negative serology test may still be followed by a recommendation for endoscopy and  duodenal  biopsy if clinical suspicion remains high. [ 21 ] [ 41 ] [ 93 ]


Historically three other antibodies were measured: anti- reticulin  (ARA), anti- gliadin  ( AGA ) and anti-endomysial (EMA) antibodies. [ 94 ]  ARA testing, however, is not accurate enough for routine diagnostic use. [ 95 ]  Serology may be unreliable in young children, with anti- gliadin  performing somewhat better than other tests in children under five. [ 94 ]  Serology tests are based on  indirect immunofluorescence  (reticulin, gliadin and endomysium) or  ELISA  (gliadin or tissue  transglutaminase , tTG). [ 96 ]


Other antibodies such as  anti– Saccharomyces cerevisiae  antibodies  occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood. [ 97 ]


Antibody testing may be combined with  HLA  testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximises sensitivity and negative predictive values. [ 64 ]  In the United Kingdom, the  National Institute for Health and Clinical Excellence  (NICE) does not (as of 2015) recommend the use of HLA typing to rule out coeliac disease outside of a specialist setting, for example, in children who are not having a biopsy, or in patients who already have limited gluten ingestion and opt not to have a gluten challenge. [ 21 ]


An  upper endoscopy  with  biopsy  of the  duodenum  (beyond the  duodenal bulb ) or  jejunum  is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative. [ 41 ]  Even in the same bioptic fragment, different degrees of
damage may be present. [ 16 ]


Most people with coeliac disease have a  small intestine  that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with high specificity for coeliac disease: scalloping of the small bowel folds ( pictured ), paucity in the folds, a  mosaic  pattern to the  mucosa  (described as a "cracked-mud" appearance), prominence of the  submucosa   blood vessels , and a nodular pattern to the mucosa. [ 98 ]


European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if  anti-tTG antibodies  titres are very high (10 times the upper limit of normal). [ 8 ]


Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After  x-ray  verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. Often-utilised capsule systems were the  Watson capsule  and the  Crosby–Kugler capsule . This method has now been largely replaced by  fibre-optic  endoscopy, which carries a higher sensitivity and a lower frequency of errors. [ 99 ]


Capsule endoscopy  (CE) allows identification of typical mucosal changes observed in coeliac disease but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis, and adenocarcinoma in refractory or complicated coeliac disease. [ 100 ]


The classic pathology changes of coeliac disease in the small bowel are categorised by the " Marsh  classification": [ 101 ]


Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages. [ 103 ]  Further studies demonstrated that this system was not always reliable and that the changes observed in coeliac disease could be described in one of three stages: [ 18 ] [ 104 ]


The changes classically improve or reverse after  gluten  is removed from the diet. However, most guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on diet. [ 41 ] [ 93 ]  In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect. [ 41 ]


In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions ( duodenal lymphocytosis ) with normal  intestinal villi . [ 11 ] [ 25 ]


At the time of diagnosis, further investigations may be performed to identify complications, such as  iron deficiency  (by  full blood count  and iron studies),  folic acid  and  vitamin B 12  deficiency  and  hypocalcaemia  (low calcium levels, often due to decreased  vitamin D  levels).  Thyroid function tests  may be requested during blood tests to identify  hypothyroidism , which is more common in people with coeliac disease. [ 42 ]


Osteopenia  and  osteoporosis , mildly and severely reduced bone mineral density, are often present in people with coeliac disease, and investigations to measure bone density may be performed at diagnosis, such as  dual-energy X-ray absorptiometry  (DXA) scanning, to identify the risk of fracture and need for bone protection medication. [ 41 ] [ 42 ]


Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis, [ 24 ] [ 90 ]  occasionally the response to gluten withdrawal on a  gluten-free diet  is needed to support the diagnosis. Currently,  gluten challenge  is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet. [ 24 ]  Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet. [ 24 ]  Gluten challenge is discouraged before the age of 5 years and during  pubertal  growth. [ 105 ]  The alternative diagnosis of  non-coeliac gluten sensitivity  may be made where there is only symptomatic evidence of gluten sensitivity. [ 106 ]  Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease, [ 16 ]  and improve when gluten is removed from the diet, [ 107 ] [ 108 ]  after coeliac disease and  wheat allergy  are reasonably excluded. [ 109 ]


Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet. [ 13 ]  A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent, [ 11 ]  or be due to other commonly associated conditions such as  small intestinal bacterial overgrowth  (SIBO),  lactose intolerance ,  fructose , [ 110 ]   sucrose , [ 111 ]  and  sorbitol [ 112 ]  malabsorption,  exocrine pancreatic insufficiency , [ 113 ] [ 114 ]  and  microscopic colitis , [ 114 ]  among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage. [ 111 ] [ 112 ] [ 115 ] [ 116 ] [ 117 ]  They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with  pancreatic enzymes , [ 116 ] [ 117 ]  dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods, [ 111 ] [ 115 ]  or treatment with oral antibiotics in the case of associated bacterial overgrowth. [ 117 ]  In addition to gluten withdrawal, some people need to follow a low- FODMAPs  diet or avoid consumption of commercial gluten-free products, which are usually rich in  preservatives  and  additives  (such as  sulfites ,  glutamates ,  nitrates  and  benzoates ) and might have a role in triggering functional gastrointestinal symptoms. [ 118 ]


There is debate as to the benefits of screening. As of 2017, the  United States Preventive Services Task Force  found insufficient evidence to make a recommendation among those without symptoms. [ 29 ]  In the United Kingdom, the  National Institute for Health and Clinical Excellence  (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B 12  or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes,  autoimmune thyroid disease , [ 21 ]  and with newly diagnosed  chronic fatigue syndrome [ 119 ]  and  irritable bowel syndrome . [ 38 ]   Dermatitis herpetiformis  is included in other recommendations. [ 120 ]  The NICE also recommend offering serological testing for coeliac disease in people with  metabolic bone disease  (reduced bone mineral density or  osteomalacia ), unexplained neurological disorders (such as  peripheral neuropathy  and  ataxia ), fertility problems or recurrent  miscarriage , persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of  Down syndrome  or  Turner syndrome . [ 21 ]


Some evidence has found that early detection may decrease the risk of developing health complications, such as osteoporosis, anaemia, and certain types of cancer, neurological disorders,  cardiovascular diseases , and reproductive problems. [ 7 ] [ 28 ] [ 47 ] [ 121 ] [ 122 ]  They thus recommend screening in people with certain health problems. [ 122 ]


Serology  has been proposed as a  screening  measure, because the presence of antibodies would detect some previously undiagnosed cases of coeliac disease and prevent its complications in those people. However, serologic tests have high sensitivity only in people with total villous atrophy and have a very low ability to detect cases with partial villous atrophy or minor intestinal lesions. [ 24 ]  Testing for coeliac disease may be offered to those with commonly associated conditions. [ 18 ] [ 21 ]


At present, the only effective treatment is a lifelong  gluten-free diet . [ 52 ]  No medication exists that prevents damage or prevents the body from attacking the gut when gluten is present. Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility. [ 123 ]  Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet. [ 124 ]


Dietitian  input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on  prescription  and may be reimbursed by  health insurance  plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods. [ 125 ]  Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch. [ 126 ]


The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence. [ 127 ]  The exact level at which gluten is harmless is uncertain and controversial. A recent  systematic review  tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done. [ 127 ]  Regulation of the label "gluten-free" varies. In the European Union, the  European Commission  issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20 mg/kg of gluten, and "very low gluten" labels for those with less than 100 mg/kg. [ 128 ]  In the United States, the  FDA  issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20  ppm  of gluten. [ 129 ] [ 130 ] [ 131 ]  The current international  Codex Alimentarius  standard allows for 20 ppm of gluten in so-called "gluten-free" foods. [ 132 ]


Gluten-free diet improves  healthcare-related quality of life , and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet does not completely normalise the quality of life. [ 133 ]


Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines against  vaccine preventable diseases  (VPDs) as the general population. Moreover, some pathogens could be harmful to coeliac patients. According to the European Society for the Study of Celiac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. For this reason, patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine. [ 134 ]  However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against  Haemophilus ,  meningococcus , and  influenza  should be considered if not previously given. [ 134 ]  However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in celiac patients. [ 135 ]


Between 0.3% and 10% of affected people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months. [ 114 ]  Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made. [ 114 ]  People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors. [ 13 ] [ 114 ] [ 136 ]  Also, a lack of symptoms is not a reliable indicator of intestinal recuperation. [ 114 ]


If alternative causes of villous atrophy have been eliminated,  steroids  or  immunosuppressants  (such as  azathioprine ) may be considered in this scenario. [ 41 ]


Refractory coeliac disease should not be confused with the persistence of symptoms despite gluten withdrawal [ 114 ]  caused by transient conditions derived from the intestinal damage, [ 111 ] [ 112 ] [ 115 ]  which generally revert or improve several months after starting a gluten-free diet, [ 116 ] [ 117 ]  such as  small intestinal bacterial overgrowth ,  lactose intolerance ,  fructose , [ 110 ]   sucrose , [ 111 ]  and  sorbitol [ 112 ]  malabsorption,  exocrine pancreatic insufficiency , [ 113 ] [ 114 ]  and microscopic colitis [ 114 ]  among others.


Refractory celiac disease can be divided in type I and II. A recent studied compared patients with type I and II. Refractory celiac disease type I more frequently exhibits diarrhea, anemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory celiac disease type II is more common to develope lymphoma. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality.
 [ 137 ]


Globally coeliac disease affects between 1 in 100 and 1 in 170 people. [ 14 ] [ 138 ]  Rates, however, vary between different regions of the world from as few as 1 in 300 to as many as 1 in 40. [ 14 ]  In the United States it is thought to affect between 1 in 1750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by presence of IgA TG in blood donors). [ 139 ]  Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed. [ 140 ]  The percentage of people with clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the percentage of people with the disease may be between 0.33 and 1.06% in children (but 5.66% in one study of children of the predisposed  Sahrawi people [ 141 ] ) and 0.18–1.2% in adults. [ 28 ]  Among those in primary care populations who report gastrointestinal symptoms, the rate of coeliac disease is about 3%. [ 90 ]  In Australia, approximately 1 in 70 people have the disease. [ 142 ]  The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively. [ 40 ]


People of African, Japanese and Chinese descent are rarely diagnosed; [ 143 ]  this reflects a much lower prevalence of the genetic  risk factors , such as  HLA-B8 . [ 144 ]  People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry. [ 40 ]  Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition and also due to the fact it can be asymptomatic. [ 145 ]  Coeliac disease is slightly more common in women than in men. [ 33 ]  A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic people, 2.6% in second-degree relatives (like grandparents, aunt or uncle, grandchildren, etc.) of a person with coeliac disease and 4.5% in first-degree relatives (siblings, parents or children). [ 40 ]  This profile is similar to the prevalence in Europe. [ 40 ]  Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with  Down  and  Turner syndromes ,  type 1 diabetes , and autoimmune thyroid disease, including both  hyperthyroidism  (overactive  thyroid ) and  hypothyroidism  (underactive thyroid). [ 146 ]


Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%. [ 146 ]  The reason for the recent increases in the number of reported cases is unclear. [ 138 ]  It may be at least in part due to changes in diagnostic practice. [ 147 ]  There also appears to be an approximately 4.5 fold true increase that may be due to less exposure to bacteria and other pathogens in Western environments. [ 138 ]  In the United States, the median age at diagnosis is 38 years. [ 148 ]  Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age. [ 148 ]


The term  coeliac  comes from Greek κοιλιακός ( koiliakós ) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as an  Ancient Greek  description of the disease by  Aretaeus of Cappadocia . [ 149 ] [ 150 ]


Humans first started to cultivate grains in the  Neolithic  period (beginning about 9500 BCE) in the  Fertile Crescent  in Western Asia, and, likely, coeliac disease did not occur before this time.  Aretaeus of Cappadocia , living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body. [ 149 ]  His "Cœliac Affection" gained the attention of Western medicine when  Francis Adams  presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water." [ 149 ] [ 150 ]


The  paediatrician   Samuel Gee  gave the first modern-day description of the condition in children in a lecture at  Hospital for Sick Children, Great Ormond Street , London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch  mussels  daily." However, the child could not bear this diet for more than one season. [ 150 ] [ 151 ]


Christian Archibald Herter , an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal  infantilism ". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The  eponym   Gee-Herter disease  was sometimes used to acknowledge both contributions. [ 152 ] [ 153 ]   Sidney V. Haas , an American paediatrician, reported positive effects of  a diet of bananas  in 1924. [ 154 ]  This diet remained in vogue until the actual cause of coeliac disease was determined. [ 150 ]


While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr  Willem Karel Dicke . [ 155 ]  It is likely that clinical improvement of his patients during the  Dutch famine of 1944  (during which flour was scarce) may have contributed to his discovery. [ 156 ]  Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by coeliac disease from greater than 35% to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. [ 157 ]  The link with the gluten component of wheat was made in 1952 by a team from  Birmingham , England. [ 158 ]  Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery. [ 159 ]  This paved the way for biopsy samples taken by endoscopy. [ 150 ]


Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965. [ 160 ]  In 1966, dermatitis herpetiformis was linked to  gluten sensitivity . [ 150 ] [ 45 ]


May has been designated as "Coeliac Awareness Month" by several coeliac organisations. [ 161 ] [ 162 ]


Speaking generally, the various denominations of Christians celebrate a  Eucharist  in which a wafer or small piece of  sacramental bread  from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram. [ 163 ]   Wheat flour  contains around 10–13% gluten, so a single communion wafer may have more than 50 mg of gluten, an amount that harms many people with coeliac, especially if consumed every day (see  Diet  above). [ citation needed ]


Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include the  United Methodist ,  Christian Reformed ,  Episcopal , the Anglican Church (Church of England, UK) and  Lutheran .  Catholics  may receive from the Chalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered to still be wheat bread and hence invalid matter. [ 164 ]


Roman Catholic  doctrine  states that for a valid  Eucharist , the bread to be used at  Mass  must be made from wheat. Low-gluten  hosts  meet all of the Catholic Church's requirements, but they are not entirely gluten free. Requests to use rice wafers have been denied. [ 165 ]


The issue is more complex for priests. As a celebrant, a priest is, for the fullness of the sacrifice of the Mass, absolutely required to receive under both species. On 24 July 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm." [ 166 ]


By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia. [ 167 ]  As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion. [ 168 ]


[ citation needed ]  The Jewish festival of  Pesach  (Passover) may present problems with its obligation to eat  Matzah , which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye.


In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover by  Ashkenazi Jews . Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free.  Potato starch  is the primary starch used to replace the grains.


Coeliac disease is the preferred spelling in  Commonwealth English , while celiac disease is typically used in  North American English . [ 169 ] [ 170 ]


The search for environmental factors that could be responsible for genetically susceptible people becoming intolerant to gluten has resulted in increasing research activity looking at gastrointestinal infections. [ 171 ]  Research published in April 2017 suggests that an often-symptomless infection by a common strain of  reovirus  can increase sensitivity to foods such as gluten. [ 172 ]


Various treatment approaches are being studied, including some that would reduce the need for dieting. All are still under development, and are not expected to be available to the general public for a while. [ 28 ] [ 173 ] [ 174 ]