Three main approaches have been proposed as new therapeutic modalities for coeliac disease: gluten detoxification, modulation of the  intestinal permeability , and modulation of the immune response. [ 175 ]


Using  genetically engineered  wheat species, or wheat species that have been  selectively bred  to be minimally immunogenic, may allow the consumption of wheat. This, however, could interfere with the effects that gliadin has on the quality of dough.


Alternatively, gluten exposure can be minimised by the ingestion of a combination of  enzymes  ( prolyl endopeptidase  and a barley glutamine-specific  cysteine endopeptidase  ( EP-B2 )) that degrade the putative 33-mer peptide in the  duodenum . [ 28 ]  Latiglutenase (IMGX003) is a  biotheraputic  digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials [ 176 ]  and is scheduled for phase 3 clinical trials. [ 177 ]


Alternative treatments under investigation include the inhibition of  zonulin , an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. One inhibitor of this pathway is  larazotide acetate , which is currently scheduled for phase 3 clinical trials. [ 178 ] [ needs update ]  Other modifiers of other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes. [ 28 ]


Attempts to modulate the immune response concerning coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial based on small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure. [ 175 ]


Although popularly used as an  alternative treatment  for people with autism, there is no good evidence that a  gluten-free diet  is of benefit in the treatment of autism. [ 179 ] [ 180 ] [ 181 ]  In the subset of autistic people who have  gluten sensitivity , there is limited evidence that suggests that a gluten free diet may improve hyperactivity and mental confusion in those with autism. [ 179 ] [ 182 ] [ 183 ]


Cronkhite–Canada syndrome  is a rare  syndrome  characterized by multiple  polyps  of the  digestive tract . It is sporadic (i.e. it does not seem to be a  hereditary disease ), [ 1 ]  and it is currently considered acquired [ 2 ]  and  idiopathic  (i.e. cause remains unknown).


About two-thirds of patients are of Japanese descent and the male to female ratio is 3:2. [ 3 ]   It was characterized in 1955 [ 4 ] [ 5 ]  by internal medicine physician Leonard Wolsey Cronkhite Jr. and radiologist Wilma Jeanne Canada. [ 6 ]


Polyps  are found throughout the GI tract (most frequently in the  stomach  and  large intestine , followed by the  small intestine ) though typically avoid the  esophagus . [ 6 ]  A  biopsy  will reveal them to be  hamartomas ; the possibility that they progress to cancer is generally considered to be low, [ 7 ]  although it has been reported multiple times in the past. Chronic  diarrhea  and  protein-losing enteropathy  are often observed. Possible collateral features include variable anomalies of  ectodermal  tissues, such as  alopecia ,  atrophy  of the  nails , or skin  pigmentation [ 3 ]


There is no specific test to diagnose Cronkhite–Canada syndrome. Diagnosis is based on symptoms and features of the disease. [ 8 ]


Nutritional support is fundamental, and may include dietary guidance, supplements, tube feeding, or intravenous solutions. [ 9 ]  Treatments proposed include  cromolyn sodium  and  prednisone , [ 10 ]  as well as histamine (H2) receptor antagonists or proton pump inhibitors. [ 9 ]


In  histology ,  cryptitis  refers to  inflammation  of an  intestinal crypt .


Cryptitis is a non-specific histopathologic finding that is seen in several conditions, e.g.  inflammatory bowel disease , [ 1 ]   diverticular disease , [ 2 ]  radiation colitis, [ 3 ]  infectious  colitis .


This  gastroenterology  article is a  stub . You can help Wikipedia by  expanding it .


Cuffitis  is inflammation at the anal transition zone or "cuff" created as a result of  ileal pouch-anal anastomosis  (IPAA). [ 1 ]  It is considered a variant form of  ulcerative colitis  that occurs in the rectal cuff. [ 2 ]  Cuffitis is a common complication of IPAA, particularly when a stapled  anastomosis  without  mucosectomy  procedure has been used. [ 2 ]


Symptoms of cuffitis mimic those of  pouchitis . [ 2 ]  In addition, patients with cuffitis often present with small volume bloody bowel movements. [ 2 ]  Often, cuffitis can produce the appearance of bright red blood on tissue. [ 1 ]


Surgery-associated  ischemia  may contribute inflammation at the anal transitional zone. [ 2 ]


Patients whose cuffitis is refractory to mesalamine and/or corticosteroids should be evaluated for other disease in the cuff area, such as  fistula  or anastomotic leaks. [ 2 ]  Cuffitis that is refractory to medication can also be a sign of  Crohn's disease  of the pouch. [ 2 ]


Chronic cuffitis can also contribute to the development of anastomotic  stricture . [ 2 ]


Cuffitis that is refractory, Crohn's-related, or is associated with surgical complications can contribute to pouch failure. [ 2 ]


Definitive diagnose of cuffitis is obtained by  endoscopy . [ 2 ]


Cuffitis is treated with  mesalamine  suppositories or topical application of  lidocaine  or  corticosteroid  medications. [ 2 ]   Systemic medications  are rarely used. [ 2 ]


Dientamoebiasis  is a medical condition caused by infection with  Dientamoeba fragilis , a single-cell parasite that infects the lower gastrointestinal tract of humans. It is an important cause of traveler's diarrhea, chronic abdominal pain, chronic fatigue, [ citation needed ]  and  failure to thrive  in children.


The most commonly reported symptoms in conjunction with infection with  D. fragilis  include abdominal pain (69%) and diarrhea (61%). [ 1 ]  Diarrhea may be intermittent and may not be present in all cases. It is often chronic, lasting over two weeks. The degree of symptoms may vary from asymptomatic to severe, [ 2 ]  and can include weight loss, vomiting, fever, and involvement of other digestive organs.


Symptoms may be more severe in children. Additional symptoms reported have included: [ 3 ]


As many individuals are asymptomatic carriers of  D. fragilis ,  pathogenic and nonpathogenic variants are proposed to exist. A study of  D. fragilis  isolates from 60 individuals with symptomatic infection in Sydney, Australia, found all were infected with the same genotype, [ 4 ]  which is the most common worldwide, but differed from the genotype first described from a North American isolate and later also detected in Europe. [ 5 ]


Organisms similar to  D. fragilis  are known to produce a cyst stage that is able to survive outside the host and facilitate infection of new hosts. However, the exact manner in which it is transmitted is not yet known, as the organism is unable to survive outside its human host for more than a few hours after excretion, and no cyst stage has been found. [ 6 ]


Early theories of transmission suggested   D. fragilis  was unable to produce a cyst stage in infected humans, but some animal existed that in which it did produce a cyst stage, and this animal was responsible for spreading it. However, no such animal has ever been discovered. [ 3 ]  A later theory suggested the organism was transmitted by pinworms, which provided protection for the parasite outside the host. DNA has been detected in surface-sterilized eggs of  Enterobius vermicularis  eggs, thus suggesting the latter may harbor the former. [ 7 ]  Experimental ingestion of  pinworm eggs established infection in two investigators. Numerous studies reported high rates of coinfection with helminthes. [ 8 ]  However, recent study has failed to show any association between  D. fragilis  infection and pinworm infection. Parasites similar to  D. fragilis  are transmitted by consuming water or food contaminated with feces. [ 6 ]  The high rate (40%) of concomitant infection with other protozoa reported by at St. Vincent's Hospital, Sydney, Australia, supports the oral-fecal route of transmission. [ citation needed ]


Diagnosis is usually performed by submitting multiple stool samples for examination by a parasitologist in a procedure known as an  ova and parasite  examination. About 30% of children with  D. fragilis  infection exhibit  peripheral blood   eosinophilia . [ citation needed ]


A minimum of three stool specimens having been immediately fixed in polyvinyl alcohol fixative, sodium acetate-acetic acid-formalin fixative, or Schaudinn's fixative should be submitted, as the protozoan does not remain morphologically identifiable for long. All specimens, regardless of consistency, are permanently stained prior to microscopic examination with an oil immersion lens. The disease may remain cryptic due to the lack of a cyst stage if these recommendations are not followed. [ 9 ]


The  trophozoite  forms have been recovered from formed stool, thus the need to perform the ova and parasite examination on specimens other than liquid or soft stools. DNA fragment analysis provides excellent sensitivity and specificity when compared to microscopy for the detection of  D. fragilis  and both methods should be employed in laboratories with  PCR  capability. The most sensitive detection method is parasite culture, and the culture medium requires the addition of  rice starch . [ citation needed ]


An  indirect fluorescent antibody  (IFA) for fixed stool specimens has been developed. [ citation needed ]


Concomitant  pinworm  infection should also be excluded, although the association has not been proven.  Successful treatment of the infection with  iodoquinol ,  doxycycline ,  metronidazole ,  paromomycin , and  secnidazole  has been reported. [ 3 ] [ 2 ]  Resistance requires the use of combination therapy to eradicate the organism. All persons living in the same residence should be screened for  D. fragilis , as asymptomatic carriers may provide a source of repeated infection.  Paromomycin  is an effective prophylactic for travellers who will encounter poor sanitation and unsafe drinking water. [ citation needed ]


Rates of infection increase in conditions of crowding and poor sanitation, and are higher in military personnel and mental institutions.
The true extent of disease has yet to emerge, as most laboratories do not use techniques to adequately identify this organism. An Australian study identified a large number of patients, considered to have  irritable bowel syndrome , who were actually infected with  Dientamoeba fragilis . [ 13 ]


Although  D. fragilis  has been described as an infection "emerging from obscurity", [ 3 ]  it has become one of the most prevalent gastrointestinal infections in industrialized countries, especially among children and young adults. A Canadian study reported a prevalence of around 10% in boys and girls aged 11–15 years, [ 6 ]  a prevalence of 11.5% in individuals aged 16–20, and a lower incidence of 0.3–1.9% in individuals over age 20.


Early microbiologists reported that the organism was not pathogenic,  though six of the seven individuals from whom they isolated it were experiencing symptoms of dysentery. Their report, published in 1918, concluded the organism was not pathogenic because it consumed bacteria in culture, but did not appear to engulf red blood cells, as was seen in the best-known disease-causing amoeba of the time,  Entamoeba histolytica .  This initial report may still be contributing to the reluctance of physicians to diagnose the infection. [ 3 ]


Distal intestinal obstruction syndrome  ( DIOS ) involves obstruction of the distal part of the small  intestines  by thickened  intestinal content   and occurs in about 20% of mainly adult individuals with  cystic fibrosis . [ 1 ]  DIOS was previously known as  meconium ileus  equivalent , a name which highlights its similarity to the intestinal obstruction seen in newborn infants with cystic fibrosis. [ 2 ]  DIOS tends to occur in older individuals with  pancreatic insufficiency . Individuals with DIOS may be predisposed to bowel obstruction, though it is a separate entity than true  constipation . [ 2 ]


Signs and symptoms of DIOS include a sudden onset of crampy  abdominal pain ,  vomiting , and a palpable mass (often in the right lower quadrant) in the abdomen. The characteristic abdominal pain is typically located in the center or right lower quadrant of the abdomen. [ 1 ]   X-rays  of the abdomen may reveal  stool  in the colon and air-fluid levels in the  small intestines . [ citation needed ]


A complete history and physical examination can be suggestive, especially if a palpable mass in the right lower quadrant of the abdomen is present (though this can be present in the absence of DIOS).  Ultrasound  and  computed tomography  (CT) imaging of the abdomen can confirm the diagnosis by demonstrating dilated loops of intestine with material in the intestinal lumen with bubbles. [ 1 ]  Air-fluid levels may be seen in those affected by DIOS. [ 1 ]


DIOS is sometimes classified by the degree of obstruction as incomplete or complete DIOS. [ 3 ]


Additional diagnoses which may present with similar symptoms to DIOS include severe  constipation ,  appendicitis , and  intussusception . [ 1 ]


Differentiation of DIOS from constipation is generally performed by a unit specializing in the treatment of cystic fibrosis. Adequate hydration and an aggressive regimen of laxatives are essential for treatment and prevention of DIOS.  Osmotic laxatives  such as  polyethylene glycol  are preferred. [ 1 ]  Individuals prone to DIOS tend to be at risk for repeated episodes and often require maintenance therapy with pancreatic enzyme replacement, hydration and laxatives (if the symptoms are also mild). [ 4 ] [ 5 ]  Oral contrast instillation into the colon/ileum under radiological control has been found to reduce the need for surgical intervention. [ citation needed ]


Diversion colitis  is an  inflammation  of the colon which can occur as a complication of  ileostomy  or  colostomy , where symptoms may occur between one month and three years following surgery. [ 1 ]  It also occurs frequently in a  neovagina  created by  colovaginoplasty , with varying delay after the original procedure. [ 2 ]  Despite the presence of a variable degree of inflammation the most suggestive histological feature remains the prominent lymphoid aggregates.


People may be asymptomatic but common symptoms are abdominal discomfort, anorectal pain,  mucous discharge  and rectal bleeding that develops from the inflamed  mucosa  of the distal, unused colon. [ 1 ]


Diagnosis is aided by knowing the full clinical history. [ 3 ]


In many milder cases after  ileostomy  or colostomy, diversion colitis is left untreated and disappears naturally. Possible pharmacologic treatments include  short-chain fatty acid  irrigation,  steroid   enemas  and  mesalazine . [ 4 ]  For surgical candidates,  reanastomosis  is a reversal procedure carried out to restore bowel continuity that effectively halts the symptoms of diversion colitis. [ 1 ]


Duodenal atresia  is the congenital absence or complete closure of a portion of the  lumen  of the  duodenum .  It causes increased levels of amniotic fluid during pregnancy ( polyhydramnios ) and intestinal obstruction in newborn babies.  Newborns present with bilious or non-bilous vomiting (depending on where in the duodenum the obstruction is) within the first 24 to 48 hours after birth, typically after their first oral feeding. Radiography shows a distended stomach and distended duodenum, which are separated by the pyloric valve, a finding described as the  double-bubble sign .


Treatment includes suctioning out any fluid that is trapped in the stomach, providing fluids intravenously, and surgical repair of the intestinal closure.


During pregnancy, duodenal atresia is associated with increased  amniotic fluid  in the uterus, which is called  polyhydramnios . [ 1 ]   This increase in amniotic fluid is caused by the inability of the fetus to swallow the amniotic fluid and absorb it in their digestive tract. [ citation needed ]


After birth, duodenal atresia may cause abdominal distension, especially of the upper abdomen.   Bilious  or non-bilious vomiting, depending on the position of the atresia in relation to the Ampulla of Vater, commonly occurs within the first day of life. [ citation needed ]


Approximately 20–40 percent of all infants with duodenal atresia have  Down syndrome  and 50% have a congenital cardiac anomaly. [ 2 ]  Approximately 8% of infants with Down syndrome have duodenal atresia. [ 1 ]


Antenatal ultrasonography  allows for earlier detection and diagnosis of duodenal atresia. The duodenum is not typically filled with fluid on imaging, however if fluid is visualized on ultrasound, this may suggest duodenal atresia as it causes obstruction and fluid may not pass distal to the atretic area. [ 3 ]  Early diagnosis of duodenal atresia provides time for clinicians to provide prenatal counseling and prepare for postnatal management. [ 4 ]


The diagnosis of duodenal atresia is usually confirmed by  radiography .  An  X-ray  of the abdomen is the first step in evaluation. The x-ray should be obtained after placement of a  nasogastric tube  (feeding tube), evacuating the stomach and filling 40-50 ml of air  [ 5 ]  to demonstrate two large air filled spaces, the so-called "double bubble" sign. [ 6 ] [ 7 ]  The air is trapped in the stomach and proximal duodenum, which are separated by the  pyloric sphincter , creating the appearance of two bubbles visible on x-ray. [ 8 ]   Since the closure of the duodenum is complete in duodenal atresia, no air is seen in the distal duodenum. Note that the double bubble sign is typically pathologic however it is not specific for duodenal atresia and may indicate other pathologies such as annular pancreas or midgut volvulus. [ 9 ]  A limited  upper gastrointestinal series  using barium contrast can be used to differentiate between duodenal atresia and midgut volvulus. [ 10 ]


The cause of duodenal atresia is not known. Dr.  Julius Tandler  hypothesized in 1900 that the etiology of duodenal atresia was due to occlusion of the duodenal lumen and failure to re-canalize during embryological development. Research surrounding duodenal atresia in recent years has switched focus to the fibroblast growth factor pathway in mouse models as Tandler's original hypothesis was unable to account for the different types of duodenal atresia. [ 11 ]


Duodenal atresia is classified into 3 types: [ 5 ]


Early treatment includes  removing fluids from the stomach  via a  nasogastric tube , and providing fluids  intravenously . [ 13 ]  The definitive treatment for duodenal atresia is surgery (duodenoduodenostomy or duodenojejunostomy), which may be performed  openly  or  laparoscopically . [ 14 ]  The surgery is required but not immediately urgent - a 24 to 48-hour delay is permissible to facilitate transport, further evaluation and fluid resuscitation. [ 13 ]  The initial repair has a 5 percent morbidity and mortality rate. [ 15 ]  Nasogastric suction is typically continued post-operatively and patients can be transitioned to small oral feeds once nasogastric tube output decreases significantly or stops completely. [ 5 ]


Prognosis is usually very good, although complications are more likely to occur when there are serious congenital anomalies. [ 13 ]  Complications from surgical repair include  Peptic ulcer disease ,  Gastroesophageal reflux disease ,  Cholecystitis ,  Esophagitis ,  Megaduodenum ,  Blind loop syndrome , and anastomotic leak. [ 10 ]   Late complications may occur in about 12 percent of patients with duodenal atresia, and the mortality rate for these complications is 6 percent. [ 15 ]


Duodenal atresia occurs in 1 in every 10,000 live births and is the most common intestinal atresia, constituting up to 60% of intestinal atresias. [ 16 ]


Duodenal lymphocytosis , sometimes called  lymphocytic duodenitis ,  lymphocytic duodenosis , or  duodenal intraepithelial lymphocytosis , is a condition where an increased number of intra-epithelial  lymphocytes  is seen in biopsies of the  duodenal   mucosa  when these are examined microscopically. This form of  lymphocytosis  is often a feature of  coeliac disease  but may be found in other disorders.


The condition is characterised by an increased proportion of lymphocytes in the  epithelium  of the duodenum, usually when this is greater than 20–25 per 100  enterocytes . [ 1 ]    Intra-epithelial lymphocyte (IEL) are normally present in intestine and numbers are normally greater in the  crypts  and in the  jejunum ; these are distinct from those found in the  lamina propria  of the intestinal mucosa.  IELs are mostly  T cells . [ 1 ]   Increased numbers of IELs are reported in around 3% of in duodenal biopsies, depending on case mix, but may be increasingly being found, in up to 7%. [ 2 ] [ 3 ]


The list of possible causes is wide, including coeliac disease,  environmental enteropathy  ( tropical sprue ),  autoimmune enteropathy ,  small intestinal bacterial overgrowth ,  NSAID  damage,  Helicobacter pylori , other infections and  Crohn's disease . [ 1 ]


Diagnosis is made by accurate counting of intraepithelial lymphocytes during histological examination of the duodenum. [ 1 ]   The definition of the condition includes the requirement that the duodenal histological appearances are otherwise unremarkable, specifically with normal  villous  architecture. [ 2 ]


In  coeliac disease  (also known as  gluten-sensitive enteropathy ), duodenal lymphocytosis is found in untreated or partially treated cases. This is the least severe type of change, known as the Marsh I stage, in the classification of histological changes in coeliac disease. Additional features including villous atrophy and  crypt   hyperplasia  are the other findings in other Marsh stages of coeliac disease. [ 4 ] [ 1 ]


Antibodies associated with coeliac disease were reported in around 11% of cases. [ 1 ]  These IgA  endomysial antibodies  and  anti-transglutaminase antibodies  are very sensitive and specific for coeliac disease implying that this proportion of duodenal lymphocytosis cases has definite coeliac disease.  Around 33% of cases have the  HLA-DQ 2 allele, which is found in over 90% of people with coeliac disease.  Absence of HLA-DQ2 (and the rarer HLA-DQ8) makes coeliac disease most unlikely. [ 5 ]   As antibody-negative coeliac disease is recognised, HLA status, persistence or progression of the duodenal IEL numbers following a gluten challenge, followed by symptomatic improvement on a gluten-free diet, has been used to be more certain about the diagnosis, which was made in 22% of one series of over 200 adult cases.  [ 5 ]


Helicobacter infection is a common finding at  endoscopy  and although duodenal IEL counts were found to be slightly higher with this infection, this was not considered to be a meaningful cause in children. [ 6 ]   Other infections, including  Cryptosporidiosis  and  Giardiasis  can also be associated with an increase in IELs. [ 2 ]


The management is that of any identified associated disorder such as a  gluten free diet  for cases with coeliac disease [ 5 ]  or treatment of associated infections. [ 2 ]


When duodenal lymphocytosis is associated with other features of coeliac disease, in particular positive antibodies, or HLA-DQ2/8 and a family history, treatment with a  gluten -free diet produces an improvement in IEL numbers. [ 5 ]   Diarrhoea, thyroiditis, weakness and folate deficiency were other predictors of the development of gluten sensitivity and coeliac disease, which developed in 23 of 85 patients over 2 years in one series. [ 7 ]


Dysphagia  is difficulty in swallowing. [ 1 ] [ 2 ]  Although classified under " symptoms and signs " in  ICD-10 , [ 3 ]  in some contexts it is classified as a  condition  in its own right. [ 4 ] [ 5 ] [ 6 ]


It may be a sensation that suggests difficulty in the passage of solids or liquids from the mouth to the stomach, [ 7 ]  a lack of  pharyngeal  sensation or various other inadequacies of the swallowing mechanism. Dysphagia is distinguished from other symptoms including  odynophagia , which is defined as painful swallowing, [ 8 ]  and  globus , which is the sensation of a lump in the throat. A person can have dysphagia without odynophagia (dysfunction without pain), odynophagia without dysphagia (pain without dysfunction) or both together. A  psychogenic  dysphagia is known as  phagophobia . [ 9 ]


Dysphagia is classified into the following major types: [ 10 ]


Some patients have limited awareness of their dysphagia, so lack of the symptom does not exclude an underlying disease. [ 11 ]  When dysphagia goes undiagnosed or untreated, patients are at a high risk of  pulmonary aspiration  and subsequent  aspiration pneumonia  secondary to food or liquids going the wrong way into the lungs. Some people present with "silent aspiration" and do not cough or show outward signs of aspiration. Undiagnosed dysphagia can also result in dehydration, malnutrition, and kidney failure. [ 12 ]


Some signs and symptoms of oropharyngeal dysphagia include difficulty controlling food in the mouth, inability to control food or saliva in the mouth, difficulty initiating a swallow, coughing, choking, frequent  pneumonia , unexplained weight loss, gurgly or wet voice after swallowing, nasal regurgitation, and patient complaint of swallowing difficulty. [ 11 ]  When asked where the food is getting stuck, patients will often point to the cervical ( neck ) region as the site of the obstruction. The actual site of obstruction is always at or below the level at which the level of obstruction is perceived. [ citation needed ]


The most common symptom of esophageal dysphagia is the inability to swallow solid food, which the patient will describe as 'becoming stuck' or 'held up' before it either passes into the stomach or is regurgitated. Pain on swallowing or  odynophagia  is a distinctive symptom that can be highly indicative of  carcinoma , although it also has numerous other causes that are not related to cancer.  Achalasia  is a major exception to usual pattern of dysphagia in that swallowing of fluid tends to cause more difficulty than swallowing solids. In achalasia, there is idiopathic destruction of parasympathetic ganglia of the  Auerbach's (Myenteric) plexus  of the entire esophagus, which results in functional narrowing of the lower  esophagus , and peristaltic failure throughout its length. [ 13 ]


Complications of dysphagia may include  aspiration ,  pneumonia ,  dehydration , and weight loss. [ 14 ]


The following table enumerates possible causes of dysphagia:


Difficulty with or inability to swallow may be caused or exacerbated by usage of opiate and/or opioid drugs. [ 15 ]


All causes of dysphagia are considered as differential diagnoses. Some common ones are: [ 17 ]


Esophageal dysphagia is almost always caused by disease in or adjacent to the esophagus but occasionally the lesion is in the pharynx or stomach. In many of the pathological conditions causing dysphagia, the lumen becomes progressively narrowed and indistensible. Initially, only fibrous solids cause difficulty but later the problem can extend to all solids and later even to liquids. Patients with difficulty swallowing may benefit from  thickened fluids  if the person is more comfortable with those liquids, although, so far, there is no scientific study that proves that those thickened liquids are beneficial. [ 22 ]


Dysphagia may manifest as the result of  autonomic nervous system  pathologies including stroke [ 23 ]  and  ALS , [ 24 ]  or due to rapid iatrogenic correction of an electrolyte imbalance. [ 25 ]


In older adults,  presbyphagia  - the normal healthy changes in swallowing associated with age - should be considered as an alternative explanation for symptoms. [ 26 ]


There are many ways to treat dysphagia, such as swallowing therapy, dietary changes, feeding tubes, certain medications, and surgery. Treatment for dysphagia is managed by a group of specialists known as a multidisciplinary team. Members of the multidisciplinary team include: a speech language pathologist specializing in swallowing disorders (swallowing therapist), primary physician, gastroenterologist, nursing staff, respiratory therapist, dietitian, occupational therapist, physical therapist, pharmacist, and radiologist. [ 11 ]  The role of the members of the multidisciplinary team will differ depending on the type of swallowing disorder present. For example, the swallowing therapist will be directly involved in the treatment of a patient with  oropharyngeal dysphagia , while a gastroenterologist will be directly involved in the treatment of an esophageal disorder. [ citation needed ]


The implementation of a treatment strategy should be based on a thorough evaluation by the multidisciplinary team. Treatment strategies will differ on a patient to patient basis and should be structured to meet the specific needs of each individual patient. Treatment strategies are chosen based on a number of different factors including diagnosis, prognosis, reaction to compensatory strategies, severity of dysphagia, cognitive status, respiratory function, caregiver support, and patient motivation and interest. [ 11 ]


Adequate nutrition and hydration must be preserved at all times during dysphagia treatment. The overall goal of dysphagia therapy is to maintain or return the patient to, oral feeding. However, this must be done while ensuring adequate nutrition and hydration and a safe swallow (no aspiration of food into the lungs). [ 11 ]  If oral feeding results in increased mealtimes and increased effort during the swallow, resulting in not enough food being ingested to maintain weight, a supplementary nonoral feeding method of nutrition may be needed. In addition, if the patient aspirates food or liquid into the lungs despite the use of compensatory strategies, and is therefore unsafe for oral feeding, nonoral feeding may be needed. Nonoral feeding includes receiving nutrition through a method that bypasses the oropharyngeal swallowing mechanism including a nasogastric tube, gastrostomy, or jejunostomy. [ 11 ]  Some people with dysphagia, especially those nearing the  end of life , may choose to continue eating and drinking orally even when it has been deemed unsafe. This is known as "risk feeding". [ 27 ]


A 2018 Cochrane review found no certain evidence about the immediate and long-term effects of modifying the thickness of fluids for swallowing difficulties in people with dementia. [ 28 ]  While thickening fluids may have an immediate positive effect on swallowing and improving oral intake, the long-term impact on the health of the person with dementia should also be considered. [ 22 ]


Compensatory treatment procedures are designed to change the flow of the food/liquids and eliminate symptoms but do not directly change the physiology of the swallow. [ 11 ]


Therapeutic treatment procedures – designed to change and/or improve the physiology of the swallow. [ 11 ] [ 29 ]


Patients may need a combination of treatment procedures to maintain a safe and nutritionally adequate swallow. For example, postural strategies may be combined with swallowing maneuvers to allow the patient to swallow in a safe and efficient manner. [ citation needed ]


The most common interventions used for those with oropharyngeal dysphagia by speech language pathologists are rehabilitation of the swallow through oral motor exercises, texture modification of foods, thickening fluids and positioning changes during swallowing. [ 30 ]  The effectiveness of modifying food and fluid in preventing aspiration pneumonia has been questioned and these can be associated with poorer nutrition, hydration and quality of life. [ 31 ]  Also, there has been considerable variability in national approaches to describing different degrees of thickened fluids and food textures.  However, in 2015, the International Dysphagia Diet Standardisation Initiative (IDDSI) group produced an agreed IDDSI framework consisting of a continuum of 8 levels (0–7), where drinks are measured from Levels 0 – 4, while foods are measured from Levels 3 – 7. [ 32 ]   It is likely that this initiative, which has widespread support among dysphagia practitioners, will improve communication with carers and will lead to greater standardisation of modified diets [ citation needed ]


Swallowing disorders can occur in all age groups, resulting from congenital abnormalities, structural damage, and/or medical conditions. [ 11 ]  Swallowing problems are a common complaint among older individuals, and the  incidence  of dysphagia is higher in the elderly, [ 33 ] [ 34 ]  and in patients who have had strokes. [ 35 ]
Dysphagia affects about 3% of the population. [ 36 ]


The word "dysphagia" is derived from the  Greek   dys  meaning bad or disordered, and the root  phag-  meaning "eat". [ citation needed ]


Enteric neuropathy  is a  degenerative   neuromuscular  condition of the digestive system. [ 1 ]  In simple terms the  gut  stops functioning, due to degradation of the nerves and muscles. The condition affects all parts of the  digestive tract . There is no known cure or treatment for enteric neuropathy at this time; it is only possible to work on symptom management.


The name enteric neuropathy only seems to be used for diagnosis within the UK. The most common name worldwide for this condition is  Intestinal pseudoobstruction .


The main symptom of enteric neuropathy is severe and constant pain. Other symptoms include  nausea ,  vomiting ,  diarrhoea ,  constipation ,  bloating  and  abdominal  abnormalities. In addition  malabsorption  and  poor nutrition  are common, as the digestive system begins to fail. Symptom management is very important and the main priority is usually to get on top of the pain. However, as most people may have been waiting for years for a diagnosis they are often already addicted to  painkillers  (such as  tramadol  and  oramorph ) and these have adverse effects on the primary condition. [ citation needed ]


The diagnosis of enteric neuropathy is rather difficult, in that many symptoms present in ways that are common to many other  bowel-  and  gut -related diseases. It is common that many people undergo many  surgeries , sometimes over several years, to attempt to combat other possible diseases. The diagnosis itself is conducted by a physician  based on multiple tests and is subjective rather than definitive, which for those who have enteric neuropathy will show signs of severe abnormalities in the movement of the gut. An operation to take a section of muscle for  biopsy  which, if it shows signs of nerve degradation, assists in the diagnosis. [ citation needed ]


An  enterolith  is a mineral  concretion  or  calculus  formed anywhere in the  gastrointestinal system .  Enteroliths are uncommon and usually incidental findings but, once found, they require at a minimum  watchful waiting .  If there is evidence of complications, they must be removed. An enterolith may form around a  nidus , a small  foreign object  such as a seed, pebble, or piece of twine that serves as an irritant. In this respect, an enterolith forms by a process similar to the  creation of a pearl . An enterolith is not to be confused with a  gastrolith , which helps digestion.


Equine  enteroliths are found by walking pastures or turning over manure compost piles to find small enteroliths, during  necroscopy , and increasingly, during surgery for  colic .  Therefore, the incidence of asymptomatic enteroliths is unknown.


Equine enteroliths are typically smoothly spherical or tetrahedral, [ 1 ]  consist mostly of the mineral  struvite [ 1 ] [ 2 ]  ( ammonium   magnesium   phosphate ), and have concentric rings of mineral precipitated around a nidus. [ 1 ] [ 3 ]


Enteroliths in  horses  were reported widely in the 19th century, infrequently in the early 20th century, and now increasingly.  They have also been reported in  zebras : five in a  zoo  in  California [ 4 ]  and one in a zoo in  Wisconsin . [ 5 ]   Struvite enteroliths are associated with elevated  pH  and mineral concentrations in the  lumen . [ 6 ]   In  California , struvite enteroliths are associated also with a high proportion of  alfalfa  in the feed and less access to grass pasture.  This association has been attributed to the cultivation of alfalfa on  serpentine soils , resulting in high concentrations of  magnesium  in the alfalfa. [ citation needed ]


In  humans , enteroliths are rare and may be difficult to distinguish from  gall stones . Their chemical composition is diverse, and rarely can a nidus be found.  A  differential diagnosis  of an enterolith requires the enterolith, a normal gallbladder, and a  diverticulum . [ 7 ] [ 8 ]


An enterolith typically forms within a  diverticulum .  An enterolith formed in a  Meckel's diverticulum  sometimes is known as a Meckel's enterolith.  Improper use of  magnesium oxide  as a  long-term   laxative  has been reported to cause enteroliths and/or  medication bezoars . [ 9 ]


Most enteroliths are not apparent and cause no complications.  However, any complications that do occur are likely to be severe.  Of these,  bowel obstruction  is most common, [ 10 ]  followed by  ileus [ 11 ]  and  perforation .  Bowel obstruction and ileus typically occur when a large enterolith is expelled from a diverticulum into the  lumen .  Perforation typically occurs within the diverticulum. [ citation needed ]


On plain X-rays, the visibility of the enterolith depends on its calcium content. Calcium-rich stones usually demonstrate a radiodense rim and a relatively radioluscent core. Choleic acid stones are almost always radiolucent. They sometimes can be visualized on CT scans without contrast; presence of contrast in the lumen may reveal the enterolith as a void.  Most often, they are visualized using ultrasound. [ citation needed ]


Although recent surveys of enterolith composition are lacking, one early review notes struvite (as in equines),  calcium phosphate , and  calcium carbonate  and reports  choleic acid . [ 12 ]   Deoxycholic acid  and  cholic acid  have also been reported. [ 13 ]


In simple cases of obstruction, where there are no complications, a variety of non-surgical and surgical techniques are used to remove the enterolith. [ 11 ]   These include crushing the enterolith and milking it back to the stomach or forward to the colon, surgical removal via an uninvolved segment of the gastrointestinal tract, and  resection  of the involved segment. [ citation needed ]


Enteropathy  refers to any  pathology  of the  intestine . [ 1 ]  Although  enteritis  specifically refers to an  inflammation  of the intestine, and is thus a more specific term than "enteropathy", the two terms are sometimes used interchangeably.


Specific types of enteropathy include:


If the condition also involves the  stomach , it is known as "gastroenteropathy".


In pigs,  porcine proliferative enteropathy  is a diarrheal disease. [ 8 ]


Enteropathy-associated T-cell lymphoma  ( EATL ), previously termed  enteropathy-associated T-cell lymphoma, type I  and at one time termed enteropathy-type T-cell lymphoma (ETTL), is a complication of  coeliac disease  in which a malignant  T-cell lymphoma  develops in areas of the  small intestine  affected by the disease's intense  inflammation . [ 1 ]  While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma. [ 2 ]


EATL had been defined as a single type of small intestine lymphoma, but in 2008, the  World Health Organization  (WHO) divided the disease into two subtypes:  1)  EATL type I, which occurs in individuals with coeliac disease, a chronic immune disorder causing inflammatory responses to dietary  gluten  primarily in the upper reaches (i.e.  jejunum  and  duodenum ) of the small intestine; and  2)  EATL type II, a disorder similar to EATL type I that occurs without coeliac disease. While type I and II EATL share many similar features, post-2008 studies found some significant differences between the two types. In 2016, the WHO redefined the two diseases as separate entities, keeping the term enteropathy-associated T-cell lymphoma for the coeliac disease-associated lymphoma and terming type 2 disease as  monomorphic epitheliotropic intestinal T cell lymphoma  (MEITL). [ 3 ]  EATL is five to ten times more common than is MEITL. [ 4 ]  The WHO also defined a third type of intestinal T-cell lymphoma that cannot not be classified as EATL or MEITL as  peripheral T-cell lymphoma not otherwise specified  (ITCL-NOS). [ 5 ]


EATL arises from the malignant transformation of small-intestinal  intraepithelial lymphocytes  (IEL). IEL are a heterogeneous group of principally  T-cell  lymphocytes residing in  epithelial  tissues that interface the environment, such as the  mucosa  of the  bronchi ,  reproductive tract  and  gastrointestinal tract . [ 6 ]  At these sites, IEL are exposed and regulate immune responses to non-dietary and dietary  antigens ,  pathogenic  and non-pathogenic organisms and injured self tissues. [ 7 ]  Gastrointestinal tract IEL appear in the  epithelium  of the small intestine, colon, stomach and esophagus, residing between the epithelial cells that line these organs'  lumens . [ 7 ]  These IEL often exhibit  natural killer  and  cytotoxic T-cell  cell activation markers, [ 6 ]  contain various toxic agents (e.g.  perforin ,  granzyme ) and therefore are capable, if activated, of causing severe tissue injuries. [ 4 ]  With coeliac disease, the IEL react to the  glutelins  in dietary gluten by increasing their numbers, becoming pathologically active, producing chronic inflammation that injures intestinal cells, interfering with nutrient absorption and creating an environment conducive to their  malignant transformation  into EATL. [ 1 ]


Optimal treatment of EATL has used regimens consisting of intensive  chemotherapy ,  hematopoietic stem cell transplantation  and, in cases with bulky, obstructive and/or perforated bowel disease, surgical intervention. [ 3 ]  The disease has a five-year overall survival rate of only ~20%. [ 8 ]  However, recent studies focusing on the malignant IEL in EATL have increased understanding of the disease and suggested newer chemotherapy-based strategies and novel molecular targets that might be attacked therapeutically to improve the disease's prognosis. [ 7 ]


EATL typically occurs in patients with a history of coeliac disease and who may have been previously diagnosed with Type I or II refractory disease, [ 9 ]  but in any case, affected individuals present with worsening coeliac disease symptoms of abdominal pain,  malabsorption ,  diarrhea , weight loss, fever or  night sweats . [ 10 ] [ 3 ]  EATL diagnosis is more likely if symptoms develop suddenly, [ 4 ]  or if the serious symptoms of  bowel obstruction  and/or  bowel perforation  caused by bulky EATL masses develop. [ 10 ]  Patients with ulcerative  jejunitis  usually present with more severe symptoms, including more frequent  bowel perforations  and obstructions. [ 10 ]  Some patients with no history of coeliac disease present with symptoms or signs of a small-intestinal lymphoma but on diagnostic workup are found to have coeliac disease. [ citation needed ]


The cause of EATL, while not fully understood, is by definition related to celiac disease. Individuals are  genetically predisposed  to develop celiac disease because of the specific types of  HLA-DQ  proteins expressed by their  antigen-presenting cells  (APC). HLA-DQ proteins are on the surface of APC and function to present foreign or self  antigens  to the  T cell receptors  (TCR) expressed on the surface of T-cells and thereby to stimulate these cells either to initiate or suppress  immune responses  to the presented antigens. HLA-DQ proteins are composed of α and β  polypeptide chains  encoded by the  HLA-DQA1  and  HLA-DQB1  genes, respectively. Since there are several different  alleles  (i.e. gene variants) at these two  genetic loci , individuals are usually  heterozygous , i.e. have inherited different  alleles  from each parent at each locus; uncommonly, however, individuals are  homozygous  at one or both loci because their parents have the same alleles at one or both loci. The HLA-DQ proteins that predispose individuals to coeliac disease bind and respond specifically to gluten-related antigens presented to them by APC. [ 11 ]  The genetic predisposition to develop coeliac disease is clinically determined by identifying the  serotypes  of an individual's APC's HLA-DQ proteins using serotype-specific  antibody  preparations and/or by identifying the alleles at an individual's HLA-DQA1 and HLA-DQB1 genetic loci. Studies show that:


IEL are a diverse population of lymphocytes, which unlike most peripheral lymphocytes, do not recirculate through the  blood  and/or  lymphatic system  but rather reside permanently in the  epithelium  of various organs. [ 11 ]  In the GI tract, IEL localize between the epithelial cells lining the colon, small intestine, stomach, and esophagus where they serve to maintain the  mucosal  barrier, combat infection by  pathogens , and regulate immune responses to antigens originating from the diet,  pathogens , and damaged tissues. [ 6 ]  Human IEL are classified into those which express the TCR (i.e. TCL+IEL) and those which do not (i.e. TCR-IEL). TCL+IEL are further divided into 4 subtypes, TCRαβ+CD4+ IEL, TCRαβ+CD4+CD8αα+ IEL, TCRαβ+CD8αβ+ IEL, and TCRλδ+CD8αα+. These subtypes are based on the expression of alpha (α) and beta (β) chain-containing TCR (i.e. αβTCR); gamma (γ) and delta (δ) chain-containing TCR (i.e. γδTCR);  CD4 ;  CD8 αβ; and/or  CD8 αα by individual IEL.. A fifth TCL+IEL subtype, TCRαβ+CD8αα+, occurs in mice but its presence in the human intestine is disputed. [ 11 ]  Human TCR-IEL are also divided into 4 sub-types: their: ILC1-like IEL have  morphological  and functional similarities to normal intestinal epithelial cells and express  NKp46 ; ICL3-like IEL have morphological similarities to normal epithelial cells and, similar to  Th1 cells , make  Interleukin 17  (IL-17) and  Interleukin 22  (IL-22)  cytokines  and express the  RORγt  transcription factor and  NKp44 ; iCD3-IEL express  iCD3 ; and iCD8α-IEL express iCD3 and CD8α. [ 7 ]   CD3  designates a protein complex that is attached to the  cell surface membrane  whereas iCD3 refers to a CD3 protein complex in which one or more of its proteins resides abnormally in the cell's  cytosol [ 11 ]  Studies suggest that iCD3+IEL are the principal cell type that becomes malignant in EATL cases that are not classified as  de novo  (see next section). [ 7 ]  These cells also express  CD103  and, frequently,  CD30 . [ 4 ]


Coeliac disease patients may be  asymptomatic , minimally symptomatic, and/or well-controlled on a  gluten-free diet  (i.e. a diet free of cereal, rye, wheat, and barley [ 16 ] ) but nonetheless develop EATL. About 46% of all AETL cases occur in this setting and have had their malignancy described as  de novo  EATL. The remaining ~54% of EATL cases develop in coeliac disease patients whose disease becomes refractory to dietary control, exhibits increasing symptoms, and  progress over ~4–10 years through Type I refractor coeliac disease (Type 1 RCD) and Type II refractory coeliac disease (Type II RCD) to become EATL. [ 3 ]  The rates at which non-refractory celiac disease, Type I RCD, and Type II RCD progress to  de novo  or EATL are <1%, 3-14%, and 33-52%, respectively. [ 9 ]


De novo EATL  can occur in individuals whose coeliac disease was undiagnosed until EATL was found or who have mild/well-controlled coeliac disease. The findings in these patients usually differ little from those found in mild/well-controlled cases that do not progress to EATL; their small intestinal mucosa is populated by increased number of IEL and exhibits tissue destruction (e.g. small  intestinal villus   atrophy ), Nonetheless, their IEL are normal-appearing, small cells that on examination are polyclonal (i.e. genetically diverse), express CD3 and  CD8 , and do not have genetic abnormalities. The mechanism behind the development of EATL in these individuals is not understood. [ 3 ]


Type I RCD patients, who constitute 15–23% of all patients with RCD, [ 17 ]  are refractory to the gluten diet as evidenced by their worsening symptoms, increased tissue destruction, [ 10 ]  and rising numbers of TCRαβ+CD*αβ+IEL in tissue lesions. [ 3 ]  Some Type I RCD  patients may have failed to respond to the diet from the onset of their disease. If either cases, these patients show no change in the normal appearance and polyclonal nature of their small intestinal IEL and these IEL show no genetic abnormalities. [ 10 ]  The cause for these coeliac disease patients progressing to Type I RCD, after excluding the very common problem of failure to fully exclude gluten from their diets, is either due to their genetic makeup (see above section on genetics) or is unknown. [ 3 ]


Type I RCD patients may progress to Type II RCD as evidenced by their more severe symptoms, increased intestinal tissue destruction, and expanding numbers of intestinal IEL, particularly iCD3+IEL. [ 3 ]  Their IEL typically consist of genetically different subpopulations of cells that have a  monoclonal  rearrangement of their TCR and therefore are descendant from a single ancestral cell. [ 10 ]  Subpopulations of these IEL also have one or more of the following genetic abnormalities:  trisomy  of chromosome 1's long (or "q") arm at position 22–44 (abbreviated 1-q22-24); genomic alterations around the  TP53   tumor suppressor  gene at position 13.1 on the short or "p" arm of chromosome 17; genomic alterations around the  CDKN2A  tumor suppressor and  CDKN2B  cell proliferation regulator at position p21.3 on chromosome 9 that result in  loss of heterozygosity  for both genes; and/or  activating mutations  in  JAK1  (75% of cases) and  STAT3  (25% of cases). In Type II RCD, the same types of abnormal ILE found in the small intestine may be detected in the colon, stomach, [ 9 ]   mesenteric lymph nodes , blood, bone marrow, and epithelium of the airways and skin. [ 9 ]  Finally, the small intestinal lesions in Type II RCD contain  IL-2  and  IL-21 [ 18 ]  as well as increased levels of  IL-15 . [ 3 ]  Laboratory studies indicate that these 3  cytokines  acting individually or in  synergy  are potent stimulators of the  JAK1/STAT3  signaling pathway in iCD3+IEL and thereby promote these cells survival (by blocking  apoptosis ) and proliferation. [ 18 ] [ 19 ]  The small intestinal lesions also contain  a tumor necrosis factor  which stimulates iCD3+IEL survival and proliferation but does so by activating  NF-κB ,  MAPK , and/or  c-Jun N-terminal kinases  rather than JAK1/STAT3 signaling pathway. [ 18 ]  These data suggest that:  a)  Type II RCD is a low grade lymphoma; [ 9 ]   2)  the intense inflammation in Type II RCD, perhaps amplified by the cited cytokines, promotes the proliferation, survival,  genome instability , and consequential genetic abnormalities in IEL; and  3)  one or more of these factors cause the transformation of Type II RD to EATL. [ 3 ] [ 9 ] [ 19 ]  As currently understood, the release of IL-15 by mucosal epithelial cells, the binding of IL-15 to the  IL-15Rβ   cell surface receptor  on iCD3+IEL, and the stimulation thereby of these cells appears particularly important in driving Type II RCD to EATL in a significant number of cases. [ 3 ]


Ulcerative jejunitis [ 16 ]  (also termed chronic ulcerative jejunitis, multifocal ulcerated microlymphomas, [ 8 ]  ulcerative jejunoilitis, [ 10 ]  and chronic ulcerative jejunoilitis [ 3 ] ) is regarded as a rare complications or severe form of Type II RCD in which the  jejunum  or jejunum plus  ileum  portions of the small intestine contain multifocal ulcers. Patients with this disorder have a higher risk of developing EATL than other Type II RCD patients. [ 10 ] [ 16 ]


Besides the genetic gene abnormalities found in Type II RCD, the malignant IEL in EATL consist of one or more subpopulations that have mutations: in other JAK-STAT pathway genes viz.,  STAT5B ,  JAK3 , and  SOCS1  ( SOCS1  inhibits STAT signaling);  tumor suppressor  genes  BCL11B  and  SETD2  ( SETD2  is also involved in regulating lymphocyte development); another gene involved in lymphocyte development,  PRDM1 ; a gene promoting activation of the tumor suppressor  p53 ,  IRF1 ;  DNA repair  genes  BRIP1  and  TERT  ( TERT  is also involved in maintaining DNA  telomeres  and thereby  chromosome   stability ); the  NRAS  and  KRAS   oncogenes ; a gene involved in  progression of the cell cycle  and thereby cellular proliferation,  STK10 ; a gene involved in promoting cell death by  apoptosis ,  DAPK3 ; a gene involved in regulating  Interferon gamma  actions, inhibiting  toll-like receptor  signaling, and regulating activation of  innate  and  adaptive  immune systems,  IRF4 ; a gene involved in cell signaling through various cell receptors,  GNAS ; a gene involved in production of the immunoglobulin,  IgA ,  BBX ; and two  chromatin remodeling  genes,  TET2  and  YLPM1 .  These cells also overexpress or under express various genes that impact cell survival, growth, and malignancy. It is likely that one or more of these genetic and gene expression abnormalities contribute to the malignant behavior of EATL. [ 3 ] [ 20 ]


The diagnosis of EATL is based on  endoscopic  findings of:  1)  flattened duodenal folds and small intestinal fissures and ulcers;  2)  biopsy findings of small intestinal inflammation, increased IEL, villous atrophy, and  crypt hyperplasia ;  3)  HLA-DG serology typing and/or gene allele analyses showing results compatible with coeliac disease (see above section on genetics); and  4)  positive  serology  tests for  IgA antitissue translutamase antibodies ,  IgA antibodies to deamidated gliadin peptides ,  IgG antibodies to deamidated gliadin peptides , and/or  IgA antibodies to antitissue translutamase . [ 10 ]  About 35% of EATL cases will be found to have spread of the disease to extra-intestinal sites [ 3 ]  with lesions in the mesenteric lymph nodes (~35% of cases), bone marrow (<10% of cases), and, uncommonly, blood that contain IEL with the same genetic abnormalities and cell markers as those found in the IEL of their intestinal lesions. [ 4 ]  Intestinal biopsy specimens of EATL lesions also commonly show the presence of mucosal inflammatory cells (particularly  eosinophils  and  histiocytes ); a greatly  expanded population of medium- to large-sized or  anaplastic  IEL expressing iCD3 as well as cytotoxic and cell activation markers (e.g.  granzyme B  and usually  TIA1  and  perforin ); and, frequently  CD30 . [ 8 ]  In most cases these IEL also show genetic abnormalities, particularly activating mutations in JAK1 and/or STAT3 and to lesser extents those cited in the above section on EATL. The malignant IEL in EATL do not express  CD56 . [ 3 ] [ 20 ]   Rarely, patients present with EATL who have no gastrointestinal symptoms of celiac disease but rather with extra-intestinal manifestations that are associated with the disease such as  dermatitis herpetiformis , [ 3 ]   psoriasis , other chronic skin conditions,  dental enamel  defects,  gluten-induced cerebellar ataxia ,  arthritis , and   arthralgias . [ 10 ]


Other gastrointestinal T-cell lymphomas can resemble, and therefore need to be  differentiated  from, EATL. These include:


Strict adherence to a gluten-free diet has been shown in some but not all studies to prevent in a significant number of cases the progression of coeliac disease to Type I RCD, Type II RCD, and EATL. [ 9 ]  For example, an Italian study of 1757 patients found that the morbidity of EATL over 3 years fell from 6.42 to 0.22 in coeliac disease patients kept on a strict gluten-free diet. While two other studies found that the risk of malignancy in the diseases did not fall on this diet, current opinion strongly favors using it in all stages of coeliac disease. [ 4 ] [ 16 ]


Efforts have also been made to treat refractory coeliac disease in order to prevent EATL. Treatment with  corticosteroids , particularly  budesonide  gives temporary improvement in symptoms and histological responses in 30–40% of patients [ 9 ]  but few have attained a good overall response. [ 16 ]  The addition of  azathioprine ,  cyclosporin , or a  monoclonal antibody  directed against  tumor necrosis factor-α  to the corticosteroid regimen, the use, as single agents, of purine analogs (i.e.  pentostatin ,  cladribine ) or monoclonal antibody directed against CD52 as well as the use of intensive  chemotherapy  regimens have shown little therapeutic effects. Furthermore, azathioprine, anti-CD52 antibody, and cladribine have been reported to increase the disease's progression to EATL. [ 9 ]  In summary, the role these drugs, intensive chemotherapy regimens, and  hematopoietic stem cell transplantation  in the treatment of refractory coeliac disease is unclear and has not been shown to improve, and in some cases may worsen, the chances that Type I and Type II RCD, will progress to EATL. [ 3 ] [ 10 ] [ 16 ]


Patients with refractory coeliac disease, especially those with Type II RCD, should be examined at regular intervals for the development of EATL using  magnetic resonance imaging ,  capsule endoscopy ,  CT scan , and  Positron emission tomography ;. [ 9 ]  These examinations should also be used whenever patients with refractory disease experience worsening symptoms. [ 16 ]


In eligible patients, surgery where necessary (required in >80% of patients) to repair obstructed or perforated bowel or remove bulky disease followed by a conditioning regimen of high-dose chemotherapy (usually the  CHOP  regimen) and  autologous stem cell transplantion  has been the mainstay of treating EATL. [ 4 ] [ 32 ]  Previous chemotherapy treatment regimens that did not use autologous stem cell transplantation reported poor prognoses with  overall survival , progression free, and mortality rates over a 5-year period of 22%, 3%, and 81%. respectively whereas a regimen that included intensive chemotherapy, conditioning, and autologous stem cell transplantation had rates of 60%, 52%, and 39%, respectively. [ 4 ]


A phase 2 study sponsored by the Imagine Institute [ 33 ]  and being conducted in Paris, France is recruiting patients to examine the efficacy and side effects of a new treatment regimen on EATL. The regimen consists of treatment with  brentuximab vedotin  plus CHP (i.e.  cyclophosphamide ,  Adriamycin ,  prednisone ) followed by consolidation chemotherapy and autologous hematopoietic stem cell transplantation. Brentuximab vedotin is a  chimeric   monoclonal antibody  that is complexed to the  antimitotic agent ,  monomethyl auristatin E ; the drug binds to the cell-membrane protein  CD30  to deliver thereby the antimitotic aged into CD30-bearing target cells. This study is based on a phase 1 study finding that a regimen consisting of brentuximab vedotin plus CHP achieved objective responses in all 26 patients tested, with complete remissions obtained in the only patient with EATL, all 6 patients with ALCL, and 16 of 19 patients with other types of T-cell/NK-cell lymphomas. [ 34 ]


A phase 1 study sponsored by the  National Institutes of Health Clinical Center  is recruiting patients that have CD30-expressing lymphomas such as EATL to examine the effects of a conditioning drug regimen (i.e. cyclophosphamide and  fludarabine ) followed by infusions of the patients'  chimeric antigen receptor T cells  that have been modified to target and destroy cells bearing CD30. [ 35 ]


A phase 1 study sponsored by the  NIH  and  Mayo Clinic USA  is recruiting patients with peripheral T-cell lymphomas, including EATL, to study the efficacy and toxicity of  nivolumab . Nivolumab is  monoclonal antibody   checkpoint inhibitor  that binds to the  programmed cell death protein 1  (PD-1) thereby blocking this protein from being activated by  programmed death-ligand 1  (PD-L1). Many types of cancer cells increase their expression of PD-LI in order to inhibit immune cells that express PD-1 from killing them. Nivolumab blocks this inhibition and has been found effective in suppressing the growth of certain cancers. [ 36 ]


A recently completed  Phase 2 ,  randomized ,  double-blinded ,  placebo-controlled ,  parallel group  study evaluated the efficacy and safety of a monoclonal antibody (termed AMG 714) directed against IL-15 in adult patients with Type II RCD. [ 37 ]  The study found potential therapeutic effects of the treatment in that it halted the malignant progression of IEL in these patients. [ 17 ]   Expanded access  or compassionate use requests for AMG 714 may be considered for adult patients with biopsy-proven Type II RCD who have failed all available treatment options and do not have EATL. To request access, use Responsible Party contact information found by hitting the "More info..." linkage on the following clinical trials page. [ 38 ]


aggressive:   Sézary disease


Eosinophilic gastroenteritis  ( EG  or  EGE ), also known as  eosinophilic enteritis , [ 1 ]  is a rare and  heterogeneous condition  characterized by patchy or diffuse  eosinophilic  infiltration of  gastrointestinal  (GI) tissue, first described by Kaijser in 1937. [ 2 ] [ 3 ]  Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. [ 4 ] [ 5 ]  Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported. [ 6 ] [ 7 ]
The  stomach  is the  organ  most commonly affected, followed by the  small intestine  and the  colon . [ 8 ] [ 9 ]


EG typically presents with a combination of chronic nonspecific GI symptoms which include  abdominal pain ,  diarrhea , occasional  nausea  and  vomiting ,  weight loss  and  abdominal distension . Approximately 80% have symptoms for several years; [ 7 ]  a high degree of clinical suspicion is often required to establish the diagnosis, as the disease is extremely rare. It does not come all of a sudden but takes about 3–4 years to develop depending upon the age of the patient. Occasionally, the disease may manifest itself as an  acute abdomen  or  bowel obstruction . [ 10 ] [ 11 ]


Peripheral blood  eosinophilia  and elevated  serum   IgE  are usual but not universal. The damage to the  gastrointestinal tract  wall is caused by eosinophilic  infiltration  and  degranulation . [ 15 ]


As a part of  host defense  mechanism,  eosinophils  are normally present in gastrointestinal  mucosa , though the finding in deeper  tissue  is almost always pathologic. [ 16 ]  What triggers such dense infiltration in EG is not clear. It is possible that different  pathogenetic  mechanisms of disease is involved in several subgroups of patients. Food  allergy  and variable  IgE  response to food substances has been observed in some patients which implies role of  hypersensitive  response in pathogenesis. Many patients indeed have history of other  atopic  conditions like  eczema ,  asthma , etc. [ citation needed ]


Eosinophil recruitment into inflammatory tissue is a complex process, regulated by a number of  inflammatory   cytokines . In EG  cytokines   IL-3 ,  IL-5  and granulocyte macrophage colony stimulating factor ( GM-CSF ) may be behind the recruitment and activation. They have been observed  immunohistochemically  in diseased intestinal wall. [ 17 ]
In addition  eotaxin  has been shown to have an integral role in regulating the  homing  of eosinophils into the  lamina propria  of stomach and small intestine. [ 18 ]
In the allergic subtype of disease, it is thought that food  allergens  cross the intestinal mucosa and trigger an inflammatory response that includes  mast cell  degranulation and recruitment of eosinophils. [ 18 ] [ 19 ]


Talley et al. [ 20 ]  suggested three diagnostic criteria which are still widely used:


Hypereosinophilia , the hallmark of allergic response, may be absent in up to 20% of patients, but  hypoalbuminaemia  and other abnormalities suggestive of malabsorption may be present.  CT scans  may show nodular and irregular thickening of the folds in the distal stomach and proximal small bowel, but these findings can also be present in other conditions like  Crohn's disease  and  lymphoma . [ citation needed ]


The  endoscopic  appearance in eosinophilic gastroenteritis is nonspecific; it includes erythematous, friable, nodular, and occasional ulcerative changes. [ 21 ]
Sometimes diffuse inflammation results in complete loss of  villi , involvement of multiple layers,  submucosal   oedema  and  fibrosis . [ 22 ] [ 23 ]


Definitive diagnosis involves  histological  evidence of eosinophilic infiltration in biopsy slides.  Microscopy  reveals >20 eosinophils per  high power field . [ 12 ] [ 20 ]  Infiltration is often patchy, can be missed and  laparoscopic  full thickness biopsy may be required.


Radio isotope  scan using  technetium ( 99m Tc) exametazime -labeled  leukocyte   SPECT  may be useful in assessing the extent of disease and response to treatment but has little value in diagnosis, as the scan does not help differentiating EG from other causes of inflammation. [ 24 ] [ 25 ]


When eosinophilic gastroenteritis is observed in association with eosinophilic infiltration of other organ systems, the diagnosis of  idiopathic   hypereosinophilic syndrome  should be considered. [ 26 ]


Corticosteroids are the mainstay of therapy with a 90% response rate in some studies. Appropriate duration of steroid treatment is unknown and relapse often necessitates long term treatment. Various steroid sparing agents e.g.  sodium cromoglycate  (a stabilizer of mast cell  membranes ),  ketotifen  (an  antihistamine ), and  montelukast  (a selective, competitive  leukotriene receptor antagonist ) have been proposed, centering on an allergic hypothesis, with mixed results. [ 19 ] [ 27 ]   Oral  budesonide  (an oral steroid) can be useful in treatment, as well. [ 28 ]  An elimination diet may be successful if a limited number of food allergies are identified. [ 21 ] [ 29 ]  An elemental diet may also be successful in the treatment of children. [ 30 ]


In a  randomized clinical trial ,  lirentelimab  was found to improve  eosinophil  counts and symptoms in individuals with eosinophilic gastritis and duodenitis. [ 31 ] [ 32 ]


Epidemiology may differ between studies, as number of cases are small, with approximately 300 EG cases reported in published literature.


EG can present at any age and across all races, with a slightly higher incidence in males. [ 33 ]  Earlier studies showed higher incidence in the third to fifth decades of life. [ 2 ] [ 4 ]


Epiploic appendagitis  ( EA ) is an uncommon, benign, self-limiting  inflammatory process  of the  epiploic appendices . Other, older terms for the process include  appendicitis epiploica  and  appendagitis , but these terms are used less now in order to avoid confusion with  acute appendicitis .


Epiploic appendices are small, fat-filled sacs or finger-like projections along the surface of the upper and lower  colon  and  rectum . They may become acutely inflamed as a result of torsion (twisting) or  venous thrombosis . The inflammation causes pain, often described as sharp or stabbing, located on the left, right, or central regions of the  abdomen . There is sometimes  nausea  and  vomiting . The symptoms may mimic those of acute appendicitis,  diverticulitis , or  cholecystitis . The pain is characteristically intense during/after defecation or  micturition  (espec. in the sigmoid type) due to the effect of traction on the pedicle of the lesion caused by straining and emptying of the bowel and bladder.  Initial lab studies are usually normal. EA is usually diagnosed incidentally on  CT scan  which is performed to exclude more serious conditions.


Although it is self-limiting, epiploic appendagitis can cause severe pain and discomfort. It is usually thought to be best treated with an anti-inflammatory and a moderate to severe pain medication (depending on the case) as needed. Surgery is not recommended in nearly all cases.  Sand and colleagues, [ 1 ]  however, recommend laparoscopic surgery to excise the inflamed appendage in most cases in order to prevent recurrence.


The condition commonly occurs in patients in their 40s and 50s predominantly in men. Epiploic appendagitis is normally misdiagnosed in most patients. [ 2 ]  Epiploic appendagitis presents with an acute onset of pain, commonly in the left lower quadrant the symptoms often lead to a misdiagnosis for diverticulitis. Diverticulitis manifests with evenly distributed lower abdominal pain accompanied with nausea, fever, and  leukocytosis . Patients with acute epiploic appendagitis do not normally report a change in bowel habits, while a small number may have constipation or diarrhea. [ 2 ]


It is rare however possible for epiploic appendagitis to result in a peritoneal loose body. Peritoneal loose body is a free floating mass of dead fibrous tissue surrounded by several layers of calcification (deposit of calcium salts). The loose body is the result of torsed,  infarcted  or detached epiploic appendages that eventually become  fibrotic  (inflammation and scarring) masses. If the loose body becomes large enough it can cause urinary retention (inability to empty bladder) or bowel obstructions. [ 3 ]


Epiploic appendages are also called  appendices epiploicae . The appendages themselves are 50–100 appendages that are oriented in two rows anterior and posterior. The appendages are parallel to the superficial section of the  taenia coli . Furthermore, the appendages are between 0.5 and 5 cm long, each appendage is attached with one or two arterioles and a venule within vascular stalks attached to the colon. Torsion (twisting or wrenching motion) of the appendages can cause  ischemia  which can cause painful symptoms that mimic other conditions such as diverticulitis, and appendicitis; however, it is rare. The pain associated with the inflamed appendages is located in the left and sometimes in the right lower abdominal quadrant. Diagnosis of epiploic appendagitis can be challenging due to its infrequency. [ 4 ]


Epiploic appendagitis is more common in patients older than 40 years of age; however, it can occur at any age. "The reported ages range from 12 to 82 years. Men are slightly more affected than women." [ 2 ]   Patients with epiploic appendagitis describe having a localized, strong, non-migratory sharp pain after eating. Patients generally have tender abdomens as a symptom. Symptoms do not include fever, vomiting, or leukocytosis. The pain is typically located in the right or left lower abdominal quadrant. When there is pain in the right lower quadrant, it can mimic appendicitis; however, it more commonly mimics diverticulitis, with pain present on the left side. [ 2 ]


There are several conditions that mimic the symptoms of epiploic appendicitis.


Omental infarction :  Omental infarction  is uncommon reason for acute abdomen. It is similar to acute appendicitis. The pain is of a few days duration centering in the right lower or upper quadrant. Imaging is required to obtain an accurate diagnosis due to the common misdiagnosis of omental infarction as  appendicitis  or  cholecystitis . Omental infarction occurs commonly in pediatric patients approximately 15 percent of cases. The most frequent cause of non- torsion related omental infarction is due to trauma as well as  thrombosis  or the omental veins. The predisposition for omental infarction includes obesity, strenuous activity,  congestive heart failure , digitalis administration, recent abdominal surgery and trauma. [ 2 ]  "The typical CT findings are a solitary large non-enhancing omental mass with heterogeneous attenuation, which is most often located in the right lower quadrant, deep to the rectus abdominis muscle and either anterior to the transverse colon or anteromedial to the ascending colon". [ 2 ]  Omental Infarction can be difficult to differentiate from diverticulitis however omental infarction is not normally attributed with bowel wall thickening. It is rare that the colonic wall will be thickened due to spread of the inflammation from the  omentum  (a fold of peritoneum connecting or supporting abdominal structures) to the  tenia omentalis  of the colon. [ 2 ]


Diverticulitis :  Diverticulitis  normally happens in older patients than in epiploic appendagitis. The two inflammatory conditions are quite indistinguishable based on physical manifestations. Patients with diverticulitis will present with nausea, vomiting, fever, elevated leukocyte count, rebound tenderness, and will have more extensive lower abdominal pain than patients with epiploic appendagitis. Additionally inflammation from diverticulitis may spread to the epiploic appendages making it difficult to diagnose, for inflammation of the appendices epiploicae may be resultant to other inflammatory conditions in the colonic wall and surrounding  mesocolon . [ 2 ]


Ultrasound  and  CT scans  are the normal means of positive diagnosis of epiploic appendagitis. Ultrasound scans show "an oval, non-compressible hyperechoic mass with a subtle  hypoechoic  rim directly under the site of maximum tenderness". [ 4 ]  Normally, epiploic appendages cannot be seen on  CT  scan. [ 4 ]  After cross-sectional imaging and the increased use of abdominal CT for evaluating lower abdominal pain, EA is increasingly diagnosed.  Pathognomonic  CT scan data represent EA as 2–4 cm, oval shaped, fat density lesions, surrounded by inflammation. Contrasting with diverticulitis findings, the colonic wall is mostly unchanged. [ citation needed ]


Epiploic appendagitis is self-limiting and can be managed conservatively with NSAIDs. [ citation needed ]


Acute epiploic appendagitis is usually associated with obesity, hernia and unaccustomed exercise. The inflammation of the epiploic appendages normally resolves on its own for most patients. It is possible however uncommon for acute epiploic appendagitis to result in adhesion, bowel obstruction,  intussusception , intraperitoneal loose body,  peritonitis , and/or abscess formation. [ 2 ]  Treatment consists of reassurance of the patient and analgesics. Under non invasive treatment, symptoms resolve in two weeks. Hospitalization is not necessary. [ 5 ]


Fecal incontinence  ( FI ), or in some forms,  encopresis , is a lack of control over  defecation , leading to involuntary loss of bowel contents — including  flatus  (gas), liquid stool elements and  mucus , or solid  feces . FI is a  sign  or a  symptom , not a  diagnosis . Incontinence can result from different causes and might occur with either  constipation  or  diarrhea . Continence is maintained by several interrelated factors, including the  anal sampling mechanism , and incontinence usually results from a deficiency of multiple mechanisms. The most common causes are thought to be immediate or delayed  damage from childbirth , complications from prior  anorectal surgery  (especially involving the anal  sphincters  or hemorrhoidal vascular cushions), altered bowel habits (e.g., caused by  irritable bowel syndrome ,  Crohn's disease ,  ulcerative colitis , food intolerance, or constipation with overflow incontinence). [ 1 ]  An estimated 2.2% of community-dwelling adults are affected. [ 2 ]  However, reported prevalence figures vary. A prevalence of 8.39% among non-institutionalized U.S adults between 2005 and 2010 has been reported, and among institutionalized elders figures come close to 50%. [ 3 ] [ 4 ]


Fecal incontinence has three main consequences: local reactions of the perianal skin and urinary tract, including  maceration  (softening and whitening of the skin due to continuous moisture),  urinary tract infections , or  decubitus ulcers  (pressure sores); [ 1 ]  a financial expense for individuals (due to the cost of medication and incontinence products, and loss of productivity), employers (days off), and  medical insurers  and society generally ( health care costs ,  unemployment ); [ 1 ]  and an associated decrease in  quality of life . [ 5 ]  There is often reduced self-esteem, shame, humiliation,  depression , a need to organize life around easy access to a  toilet , and avoidance of enjoyable activities. [ 1 ]  FI is an example of a  stigmatized  medical condition, which creates barriers to successful management and makes the problem worse. [ 6 ]  People may be too embarrassed to seek medical help and attempt to self-manage the symptom in secrecy from others.


FI is one of the most psychologically and socially debilitating conditions in an otherwise healthy individual and is generally treatable. [ 2 ]  More than 50% of hospitalized seriously ill patients rated bladder or fecal incontinence as "worse than death". [ 7 ]  Management may be achieved through an individualized mix of dietary, pharmacologic, and surgical measures. Health care professionals are often poorly informed about treatment options, [ 2 ]  and may fail to recognize the effect of FI. [ 5 ]


FI affects virtually all aspects of peoples' lives, greatly diminishing physical and mental health, and affecting personal, social, and professional life. Emotional effects may include stress, fearfulness, anxiety, exhaustion, fear of public humiliation, feeling dirty, poor body image, reduced desire for sex, anger, humiliation, depression, isolation, secrecy, frustration, and embarrassment. Some patients cope by controlling their emotions or behavior. Physical symptoms such as skin soreness, pain and odor may also affect quality of life. Physical activity such as shopping or exercise is often affected. Travel may be affected, requiring careful planning. Working is also affected for most. Relationships, social activities and self-image likewise often suffer. [ 8 ]  Symptoms may worsen over time. [ 1 ]


FI is a sign or a symptom, not a diagnosis, [ 8 ]  and represents an extensive list of causes. Usually, it is the result of a complex interplay of several coexisting factors, many of which may be simple to correct. [ 8 ]  Up to 80% of people may have more than one abnormality that is contributing. [ 9 ]  Deficits of individual functional components of the continence mechanism can be partially compensated for a certain period, until the compensating components themselves fail. For example,  obstetric  injury may precede onset by decades, but  postmenopausal  changes in the tissue strength reduce in turn the competence of the compensatory mechanisms. [ 1 ] [ 10 ]  The most common factors in the development are thought to be obstetric injury and after-effects of anorectal surgery, especially those involving the anal sphincters and hemorrhoidal vascular cushions. [ 1 ]  The majority of incontinent persons over the age of 18 fall into one of several groups: those with structural anorectal abnormalities (sphincter  trauma , sphincter degeneration,  perianal fistula , rectal prolapse),  neurological disorders  ( multiple sclerosis ,  spinal cord  injury,  spina bifida ,  stroke , etc.), constipation/ fecal loading  (presence of a large amount of feces in the rectum with stool of any consistency), cognitive and/or behavioral dysfunction ( dementia ,  learning disabilities ), diarrhea,  inflammatory bowel diseases  (e.g. ulcerative colitis, Crohn's disease), irritable bowel syndrome,  disability  related (people who are frail, acutely unwell, or have  chronic / acute  disabilities), and those cases which are  idiopathic  (of unknown cause). [ 8 ] [ 11 ]   Diabetes mellitus  is also known to be a cause, but the mechanism of this relationship is not well understood. [ 12 ]


Anorectal anomalies  and spinal cord defects may be a cause in children. These are usually picked up and operated upon during early life, but continence is often imperfect thereafter. [ 2 ]


The functioning of the  anal canal  can be damaged, traumatically or atraumatically. The resting tone of the anal canal is not the only important factor; both the length of the high-pressure zone and its radial translation of force are required for continence. This means that even with normal anal canal pressure, focal defects such as the  keyhole deformity  can be the cause of substantial symptoms.  External anal sphincter  (EAS) dysfunction is associated with impaired voluntary control, whereas  internal anal sphincter  (IAS) dysfunction is associated with impaired fine-tuning of fecal control. [ 1 ]   Lesions  which mechanically interfere with, or prevent the complete closure of the anal canal can cause a liquid stool or mucous  rectal discharge . Such lesions include  piles  (inflamed hemorrhoids),  anal fissures ,  anal cancer , or fistulae. Obstetric injury may tear the anal sphincters, and some of these injuries may be occult (undetected). The risk of injury is greatest when labor has been especially difficult or prolonged, when  forceps  are used, with higher  birth weights , or when a midline  episiotomy  is performed. Only when there is post-operative investigation of FI such as  endoanal ultrasound  is the injury discovered. [ 2 ]  FI is a much under-reported complication of surgery. The IAS is easily damaged with an anal  retractor  (especially the  Park's anal retractor ), leading to reduced resting pressure postoperatively. Since the hemorrhoidal vascular cushions contribute 15% of the resting anal tone, surgeries involving these structures may affect continence status. [ 2 ]  Partial internal  sphincterotomy ,  fistulotomy , anal stretch ( Lord's operation ),  hemorrhoidectomy  or transanal advancement flaps may all lead to FI postoperatively, with soiling being far more common than solid FI. The "keyhole deformity" refers to scarring within the anal canal and is another cause of mucus leakage and minor incontinence. This defect is also described as a groove in the anal canal wall and may occur after posterior midline  fissurectomy  or fistulotomy, or with lateral IAS defects. Rare causes of traumatic injury to the anal sphincters include military or traffic accidents complicated by  pelvic fractures , spine injuries or  perineal   lacerations , insertion of  foreign bodies  in the rectum, and  sexual abuse . [ 2 ]  Nontraumatic conditions causing anal sphincter weakness include  scleroderma , damage to the  pudendal nerves , and IAS degeneration of unknown cause. [ 5 ]  Radiation-induced FI may involve the anal canal as well as the rectum, when  proctitis , anal fistula formation, and diminished function of internal and external sphincter occur. [ 2 ]  Irradiation may occur during  radiotherapy , e.g. for  prostate cancer .


Many people with FI have a generalized weakness of the  pelvic floor , especially  puborectalis . [ 5 ]  A weakened puborectalis leads to widening of the anorectal angle and impaired barrier to the stool in the rectum entering the anal canal, and this is associated with incontinence to solids. Abnormal descent of the pelvic floor can also be a sign of pelvic floor weakness. Abnormal descent manifests as  descending perineum syndrome  (>4 cm perineal descent). [ 5 ]  This syndrome initially gives constipation, and later FI. The pelvic floor is innervated by the  pudendal nerve  and the  S3  and  S4  branches of the  pelvic plexus . With recurrent straining, e.g. during difficult labour or long-term constipation, then stretch injury can damage the nerves supplying  levator ani . The pudendal nerve is especially vulnerable to irreversible damage, (stretch-induced pudendal  neuropathy ) which can occur with a 12% stretch. [ 2 ]  If the pelvic floor muscles lose their innervation, they cease to contract and their muscle fibres are in time replaced by fibrous tissue, which is associated with pelvic floor weakness and incontinence. Increased pudendal nerve terminal motor latency may indicate pelvic floor weakness. Any damage to the pudendal nerve occurring during childbirth may not become fully apparent until years later, for example at the onset of  menopause . [ 13 ]  The various types of prolapse of the posterior compartment (e.g.  external rectal prolapse ,  mucosal prolapse  and  internal rectal intussusception  &  solitary rectal ulcer syndrome ) may also cause coexisting  obstructed defecation . [ citation needed ]


The  rectum  needs to be of a sufficient volume to store stool until defecation. The rectal walls need to be "compliant" i.e. able to distend to an extent to accommodate stool. Rectal sensation is required to detect the presence, nature, and amount of rectal contents. The rectum must also be able to evacuate its contents fully. There must also be efficient coordination of rectal sensation and relaxation of the anal canal. [ 14 ]   Rectal storage capacity (i.e. rectal volume + rectal compliance) may be affected in the following ways. Surgery involving the rectum (e.g.  lower anterior resection , often performed for colorectal cancer), radiotherapy directed at the rectum, and inflammatory bowel disease can cause scarring, which may result in the walls of the rectum becoming stiff and inelastic, reducing compliance. Reduced rectal storage capacity may lead to urge incontinence, where there is an urgent need to defecate as soon as stool enters the rectum, where normally stool would be stored until there was enough to distend the rectal walls and initiate the defecation cycle. Tumors and  rectal strictures  also may impair reservoir function. Conversely, increased rectal volume ( megarectum ), may cause fecal loading and overflow FI (see  overflow incontinence ). Reduced rectal sensation may be a contributory factor. [ citation needed ]  If the sensory nerves are damaged, the detection of stool in the rectum is dulled or absent, and the person will not feel the need to defecate until too late. Rectal hyposensitivity may manifest as constipation, FI, or both. Rectal hyposensitivity was reported to be present in 10% of people with FI. [ 15 ]  Pudendal neuropathy is one cause of rectal hyposensitivity and may lead to fecal loading/impaction, megarectum and overflow FI. [ 16 ]  Normal evacuation of rectal contents is 90–100%. [ 2 ]  If there is incomplete evacuation during defecation, residual stool will be left in the rectum and threaten continence once defecation is finished. This is a feature of people with soiling secondary to obstructed defecation. [ 17 ]  Obstructed defecation is often due to  anismus  (paradoxical contraction or relaxation failure of the puborectalis). [ 2 ] : 38   Whilst anismus is largely a  functional disorder ,  organic  pathologic lesions may mechanically interfere with rectal evacuation. Other causes of incomplete evacuation include non-emptying defects like a  rectocele . Straining to defecate pushes stool into the rectocele, which acts like a  diverticulum  and causes stool sequestration. Once the voluntary attempt to defecate, albeit dysfunctional, is finished, the voluntary muscles relax, and residual rectal contents are then able to descend into the anal canal and cause leaking. [ 2 ] : 37


Nitrates ,  calcium channel antagonists ,  beta-adrenoceptor antagonists  ( beta-blockers ),  sildenafil ,  selective serotonin reuptake inhibitors


Cephalosporins ,  penicillins ,  macrolides


Glyceryl trinitrate  ointment,  diltiazem  gel,  bethanechol  cream,  botulinum toxin  A injection


Laxatives ,  metformin ,  orlistat , selective serotonin reuptake inhibitors, magnesium-containing  antacids ,  digoxin


Loperamide ,  opioids ,  tricyclic antidepressants , aluminium-containing antacids,  codeine


Benzodiazepines , tricyclic antidepressants, selective serotonin reuptake inhibitors,  anti-psychotics


Continence requires conscious and subconscious networking of information from and to the anorectum. Defects/brain damage may affect the  central nervous system  focally (e.g. stroke, tumor, spinal cord lesions, trauma, multiple sclerosis) or diffusely (e.g. dementia, multiple sclerosis, infection,  Parkinson's disease  or drug-induced). [ 1 ] [ 19 ]  FI (and  urinary incontinence ) may also occur during  epileptic seizures . [ 20 ]   Dural ectasia  is an example of a spinal cord lesion that may affect continence. [ 21 ]


Liquid stool is more difficult to control than formed, solid stool. Hence, FI can be exacerbated by diarrhea. [ 8 ]  Some consider diarrhea to be the most common aggravating factor. [ 2 ]   [ citation needed ]  Where diarrhea is caused by temporary problems such as mild infections or food reactions, incontinence tends to be short-lived. Chronic conditions, such as irritable bowel syndrome or  Crohn's disease , can cause severe diarrhea lasting for weeks or months. Diseases, drugs, and indigestible dietary fats that interfere with the  intestineal  absorption may cause  steatorrhea  (oily rectal discharge & fatty diarrhea) and degrees of FI. Respective examples include  cystic fibrosis ,  orlistat , and  olestra .  Postcholecystectomy diarrhea  is diarrhea that occurs following gall bladder removal, due to excess  bile acid . [ 22 ]  Orlistat is an  anti-obesity  (weight loss) drug that blocks the absorption of fats. This may give side effects of FI, diarrhea, and steatorrhea. [ 23 ]


This may occur when there is a large mass of feces in the rectum (fecal loading), which may become hardened ( fecal impaction ). Liquid stool elements can pass around the obstruction, leading to incontinence. Megarectum (enlarged rectal volume) and rectal hyposensitivity are associated with overflow incontinence. Hospitalized patients and care home residents may develop FI via this mechanism, [ 8 ]  possibly a result of lack of mobility, reduced alertness, the constipating effect of medication, and/or dehydration. In overflow incontinence, the rectum is constantly distended because of the presence of retained feces in the rectum. [ 24 ]  Therefore, the recto-anal inhibitory reflex (RAIR) is persistently activated, meaning the internal anal sphincter relaxes, which is not under voluntary control. [ 24 ]


The mechanisms and factors contributing to normal continence are multiple and interrelated. The puborectalis sling, forming the anorectal angle (see diagram), is responsible for the gross continence of solid stool. [ 5 ]  The IAS is an involuntary muscle, contributing about 55% of the resting anal pressure. Together with the hemorrhoidal vascular cushions, the IAS maintains continence of flatus and liquid during rest. The EAS is a voluntary muscle, that doubles the pressure in the anal canal during contraction, which is possible for a short time. The  rectoanal inhibitory reflex (RAIR)  is an involuntary IAS relaxation in response to rectal distension, allowing some rectal contents to descend into the anal canal where it is brought into contact with specialized sensory mucosa to detect consistency. The rectoanal excitatory reflex (RAER) is an initial, semi-voluntary contraction of the EAS and puborectalis which in turn prevents incontinence following the RAIR. Other factors include the specialized anti-peristaltic function of the last part of the sigmoid colon, which keeps the rectum empty most of the time, sensation in the lining of the rectum and the anal canal to detect when there is stool present, its consistency and quantity, and the presence of normal rectoanal reflexes and defecation cycle which completely evacuates stool from the rectum and anal canal. Problems affecting any of these mechanisms and factors may be involved in the cause. [ 2 ]


Identification of the exact causes usually begins with a thorough  medical history , including detailed questioning about symptoms, bowel habits, diet, medication, and other medical problems.  Digital rectal examination  is performed to assess resting pressure and voluntary contraction (maximum squeeze) of the sphincter complex and puborectalis. Anal sphincter defects, rectal prolapse, and abnormal perineal descent may be detected. [ 5 ]  Anorectal physiology tests assess the functioning of the anorectal anatomy.  Anorectal manometry  records the pressure exerted by the anal sphincters and puborectalis during rest and contraction. The procedure is also able to assess the sensitivity of the anal canal and rectum.  Anal electromyography  tests for nerve damage, which is often associated with obstetric injury. Pudendal nerve terminal motor latency tests for damage to the pudendal motor nerves. Proctography, also known as  defecography , shows how much stool the rectum can hold, how well the rectum holds it, and how well the rectum can evacuate the stool. It will also highlight defects in the structure of the rectum such as  internal rectal intussusception . Dynamic pelvic  MRI , also called MRI defecography is an alternative that is better for some problems but not as good for other problems. [ 25 ]   Proctosigmoidoscopy  involves the insertion of an  endoscope  (a long, thin, flexible tube with a camera) into the anal canal, rectum and sigmoid colon. The procedure allows for visualization of the interior of the gut and may detect signs of disease or other problems that could be a cause, such as inflammation, tumors, or scar tissue. Endoanal ultrasound, which some consider the gold standard for detection of anal canal lesions, [ 26 ]  evaluates the structure of the anal sphincters and may detect occult sphincter tears that otherwise would go unseen.


Functional  FI is common. [ 27 ]  The  Rome process  published  diagnostic criteria  for functional FI, which they defined as "recurrent uncontrolled passage of fecal material in an individual with a developmental age of at least four years". The diagnostic criteria are, one or more of the following factors present for the last 3 months: abnormal functioning of normally innervated and structurally intact muscles, minor abnormalities of sphincter structure/innervation (nerve supply), normal or disordered bowel habits, (i.e., fecal retention or diarrhea), and psychological causes. Furthermore, exclusion criteria are given. These are factors that all must be excluded for a diagnosis of functional FI, and are abnormal innervation caused by lesion(s) within the brain (e.g., dementia), spinal cord (at or below  T12 ), or  sacral nerve  roots, or mixed lesions (e.g., multiple sclerosis), or as part of a generalized peripheral or autonomic neuropathy (e.g., due to diabetes), anal sphincter abnormalities associated with a multisystem disease (e.g., scleroderma), and structural or neurogenic abnormalities that are the major cause. [ 28 ]


There is no globally accepted definition, [ 1 ]  but fecal incontinence is generally defined as the recurrent inability to voluntarily control the passage of bowel contents through the anal canal and expel it at a socially acceptable location and time, occurring in individuals over the age of four. [ 1 ] [ 2 ] [ 5 ] [ 8 ] [ 10 ]  "Social continence" has been given various precise definitions for the purposes of research; however, generally it refers to symptoms being controlled to an extent that is acceptable to the individual in question, with no significant effect on their life. There is no consensus about the best way to classify FI, [ 8 ]  and several methods are used.


Symptoms can be directly or indirectly related to the loss of bowel control. The direct (primary) symptom is a lack of control over bowel contents which tends to worsen without treatment. Indirect (secondary) symptoms, which are the result of leakage, include  pruritus ani  (an intense itching sensation from the anus), perianal  dermatitis  (irritation and inflammation of the skin around the anus), and urinary tract infections. [ 1 ]  Due to embarrassment, people may only mention secondary symptoms rather than acknowledge incontinence. Any major underlying cause will produce additional signs and symptoms, such as protrusion of mucosa in external  rectal prolapse . Symptoms of fecal leakage (FL) are similar and may occur after defecation. There may be loss of small amounts of brown fluid and staining of the underwear. [ 2 ]


FI can be divided into those people who experience a defecation urge before leakage (urge incontinence), and those who experience no sensation before leakage (passive incontinence or soiling). [ 8 ]  Urge incontinence is characterized by a sudden need to defecate, with little time to reach a  toilet . Urge and passive FI may be associated with weakness of the  external anal sphincter  (EAS) and  internal anal sphincter  (IAS) respectively. Urgency may also be associated with reduced rectal volume, reduced ability of the rectal walls to distend and accommodate stool, and increased rectal sensitivity. [ 5 ]


There is a continuous spectrum of different clinical presentations from incontinence of flatus (gas), through incontinence of mucus or liquid stool, to solids. The term  anal incontinence  often is used to describe  flatus incontinence [ 8 ]  (that is, involuntary loss of flatus). [ 29 ]  In other sources, the term  anal incontinence  is distinguished as involuntary loss of feces or flatus caused by loss of control of the anal sphincter; [ 29 ] [ 30 ]  whereas  fecal incontinence  may be given the definition of involuntary loss of solid or liquid feces which may also be caused by enlarged skin tags, poor hygiene, hemorrhoids, rectal prolapse, and fistula in ano. [ 29 ] [ 30 ] [ 31 ]  It may occur together with incontinence of liquids or solids, or it may present in isolation. Flatus incontinence may be the first sign of FI. [ 2 ]  Once continence to flatus is lost, it is rarely restored. [ 8 ]  Anal incontinence may be equally disabling as the other types. [ 32 ]  However, the term  anal incontinence  is also often used interchangeably as a synonym for FI generally, [ 33 ]  and use a wider definition for FI which includes
uncontrolled passage of feces or gas. [ 34 ]


Fecal leakage, fecal soiling and fecal seepage are minor degrees of FI, and describe incontinence of liquid stool, mucus, or very small amounts of solid stool. They cover a spectrum of increasing symptom severity (staining, soiling, seepage, and accidents). [ 1 ]  Rarely, minor FI in adults may be described as  encopresis . Fecal leakage is a related topic to  rectal discharge , but this term does not necessarily imply any degree of incontinence. Discharge generally refers to conditions where there is  pus  or increased mucus production, or anatomical  lesions  that prevent the anal canal from closing fully, whereas fecal leakage generally concerns disorders of IAS function and functional evacuation disorders which cause a solid fecal mass to be retained in the  rectum . Solid stool incontinence may be called complete (or major) incontinence, and anything less as partial (or minor) incontinence (i.e. incontinence of flatus (gas), liquid stool and/or mucus). [ 2 ]