The exact cause of this disease is not known.
Typical symptoms during flare-ups include abdominal cramps, an urge to move the bowels, and diarrhea (typically bloody).
The diagnosis is based on a sigmoidoscopy or sometimes a colonoscopy.
People who have had ulcerative colitis for a long time may develop colon cancer.
Treatment is aimed at controlling the inflammation, reducing symptoms, and replacing any lost fluids and nutrients.
(See also Overview of Inflammatory Bowel Disease (IBD) Overview of Inflammatory Bowel Disease (IBD) In inflammatory bowel diseases, the intestine (bowel) becomes inflamed, often causing recurring abdominal pain and diarrhea. The two primary types of inflammatory bowel disease (IBD) are Crohn... read more .)
Ulcerative colitis may start at any age but usually begins before age 30, usually between the ages of 14 and 24. A small group of people have their first attack between the ages of 50 and 70.
Ulcerative colitis usually starts in the rectum (ulcerative proctitis). It may stay confined to the rectum or over time extend to involve the entire colon. In some people, most of the large intestine is affected at once.
Ulcerative colitis usually does not affect the full thickness of the wall of the large intestine and hardly ever affects the small intestine. The affected parts of the intestine have shallow ulcers (sores). Unlike Crohn disease Crohn Disease Crohn disease is an inflammatory bowel disease where chronic inflammation typically involves the lower part of the small intestine, the large intestine, or both and may affect any part of the... read more , ulcerative colitis does not cause fistulas or abscesses.
The cause of ulcerative colitis is not known for certain, but heredity and an overactive immune response in the intestine seem to be contributing factors. Cigarette smoking, which seems to contribute to the development and periodic flare-ups of Crohn disease, seems to decrease the risk of ulcerative colitis. However, smoking in order to reduce the risk of ulcerative colitis is ill-advised in light of the many health problems that smoking can cause.
Symptoms of Ulcerative Colitis
The symptoms of ulcerative colitis occur in flare-ups. Sometimes, a flare-up is sudden and severe, causing violent diarrhea that typically contains mucus and blood, high fever, abdominal pain, and occasionally peritonitis Peritonitis Abdominal pain is common and often minor. Severe abdominal pain that comes on quickly, however, almost always indicates a significant problem. The pain may be the only sign of the need for surgery... read more (inflammation of the lining of the abdominal cavity). During such flare-ups, the person is profoundly ill. More often, a flare-up begins gradually, and the person has an urgency to have a bowel movement (defecate), mild cramps in the lower abdomen, and visible blood and mucus in the stool. A flare-up can last days or weeks and can recur at any time.
When the disease is limited to the rectum and the sigmoid colon, the stool may be normal or hard and dry. However, mucus containing large numbers of red and white blood cells is discharged from the rectum during or between bowel movements. People may or may not have mild general symptoms of illness, such as fever.
If the disease extends farther up the large intestine, the stool is looser, and the person may have more than 10 bowel movements a day. Often, the person has severe abdominal cramps and distressing, painful spasms that accompany the urge to defecate. There is no relief at night. The stool may be watery or contain mucus. Frequently, the stool consists almost entirely of blood and pus. The person also may have a fever and a poor appetite and may lose weight.
Complications of ulcerative colitis
The main complications of ulcerative colitis include
Fulminant colitis (toxic colitis)
Bleeding, the most common complication, often causes iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia results from low or depleted stores of iron, which is needed to produce red blood cells. Excessive bleeding is the most common cause. People may be weak, short of breath... read more .
Fulminant colitis (also called toxic colitis) is a particularly severe complication. In nearly 10% of people who have ulcerative colitis, a rapidly progressing first attack becomes very severe, with massive bleeding, rupture (perforation) of the colon, or widespread infection. Damage to the nerves and muscles of the bowel wall causes ileus (a condition in which the normal contractile movements of the intestinal wall temporarily stop), and thus the intestinal contents are not propelled along their way. Abdominal expansion (distention) develops.
As fulminant colitis worsens, the large intestine loses muscle tone and within days—or even hours—it starts to expand (a condition sometimes referred to as toxic megacolon). This complication may cause a high fever and abdominal pain. Sometimes there is a perforation of the large intestine and the person develops peritonitis Peritonitis Abdominal pain is common and often minor. Severe abdominal pain that comes on quickly, however, almost always indicates a significant problem. The pain may be the only sign of the need for surgery... read more . X-rays of the abdomen may show expansion of the bowel and the presence of gas inside the wall of the paralyzed sections of intestine.
Colon cancer Colorectal Cancer Family history and some dietary factors (low fiber, high fat) increase a person’s risk of colorectal cancer. Typical symptoms include bleeding during a bowel movement, fatigue, and weakness... read more starts to become more common about 7 years from when ulcerative colitis started in people with extensive colitis. The risk of colon cancer is highest when the entire large intestine is affected and increases the longer the person has had ulcerative colitis. After 20 years of disease, about 7 to 10% of people will have developed cancer, and after 35 years of disease, as high as 30% of people will have developed cancer. However, people who have both inflammatory bowel disease and inflammation of the bile ducts (primary sclerosing cholangitis Primary Sclerosing Cholangitis Primary sclerosing cholangitis is inflammation with progressive scarring and narrowing of the bile ducts in and outside the liver. Eventually, the ducts become blocked and then obliterated.... read more ) are at a higher risk of colon cancer starting from the time when the colitis is diagnosed.
Colonoscopy Endoscopy Endoscopy is an examination of internal structures using a flexible viewing tube (endoscope). In addition to examinations, doctors can use endoscopy to do biopsies and give treatment. Endoscopes... read more (examination of the large intestine using a flexible viewing tube) every 1 to 2 years is advised for people who have had ulcerative colitis for more than 8 to 10 years or who have primary sclerosing cholangitis. During colonoscopy, tissue samples are taken from areas throughout the large intestine for examination under a microscope to detect the early warning signs of cancer (dysplasia). This removal and examination of tissue is called a biopsy. In a newer type of colonoscopy called chromoendoscopy, dyes are inserted into the colon during colonoscopy to highlight cancerous (malignant) and precancerous areas and may better help doctors identify areas for biopsy.
Other complications can occur, as in Crohn disease. When ulcerative colitis causes a flare-up of gastrointestinal symptoms, people also may have the following:
Inflammation of the joints (arthritis)
When ulcerative colitis is not causing a flare-up of gastrointestinal symptoms, people still may have complications that occur entirely without relation to the bowel disease such as the following:
Inflammation of the pelvic joints (sacroiliitis)
Although people with ulcerative colitis commonly have minor liver dysfunction, only about 1 to 3% have symptoms of liver disease, which vary from mild to severe. Severe liver disease can include inflammation of the liver (chronic active hepatitis Overview of Chronic Hepatitis Chronic hepatitis is inflammation of the liver that lasts at least 6 months. Common causes include hepatitis B and C viruses and certain drugs. Most people have no symptoms, but some have vague... read more ), inflammation of the bile ducts (primary sclerosing cholangitis Primary Sclerosing Cholangitis Primary sclerosing cholangitis is inflammation with progressive scarring and narrowing of the bile ducts in and outside the liver. Eventually, the ducts become blocked and then obliterated.... read more ), which narrow and eventually close, and replacement of functional liver tissue with scar tissue (cirrhosis Cirrhosis of the Liver Cirrhosis is the widespread distortion of the liver's internal structure that occurs when a large amount of normal liver tissue is permanently replaced with nonfunctioning scar tissue. The scar... read more ). Inflammation of the bile ducts may appear many years before any intestinal symptoms of ulcerative colitis. The inflammation greatly increases the risk of cancer of the bile ducts and also seems to be associated with a sharp increase in the risk of colon cancer.
Diagnosis of Ulcerative Colitis
Doctors suspect ulcerative colitis in a person with recurring bloody diarrhea accompanied by cramps and a strong urge to defecate, particularly if the person has other complications, such as arthritis or liver problems, and a history of similar attacks.
Doctors examine the stool to look for parasites, rule out bacterial infections, and assess inflammation.
Sigmoidoscopy Endoscopy Endoscopy is an examination of internal structures using a flexible viewing tube (endoscope). In addition to examinations, doctors can use endoscopy to do biopsies and give treatment. Endoscopes... read more (an examination of the sigmoid colon using a flexible viewing tube) confirms the diagnosis of ulcerative colitis. This procedure permits a doctor to directly observe the severity of the inflammation, take samples of mucus or stool for culture, and remove tissue samples of affected areas for examination under a microscope (called a biopsy). Even during symptom-free intervals, the intestine rarely appears entirely normal, and tissue samples removed for examination under a microscope usually show chronic inflammation. A colonoscopy is usually not necessary, but doctors may need to do a colonoscopy if the inflammation extends beyond the reach of the sigmoidoscope.
Blood tests do not confirm the diagnosis of ulcerative colitis but may reveal that the person has anemia, increased numbers of white blood cells (occurs with inflammation), a low level of the protein albumin, and an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein level, which also indicate active inflammation. A doctor may also do liver tests.
X-rays of the abdomen taken after barium is given by enema (called a barium enema X-Ray Studies of the Digestive Tract X-rays often are used to evaluate digestive problems. Standard x-rays ( plain x-rays) can show some blockages or paralysis of the digestive tract, or abnormal air patterns in the abdominal cavity... read more ) may indicate the severity and extent of the disease but are not done when the disease is active, such as during a flare-up, because of the risk of causing a perforation. Other x-rays of the abdomen may also be taken.
Recurring or severe symptoms of ulcerative colitis
Doctors examine people when their typical symptoms return, but they do not always do tests. If symptoms have been more frequent or longer-lasting than usual, doctors may do sigmoidoscopy or colonoscopy and a blood count. Doctors may do other tests to look for infection or parasites.
When symptoms are severe, people are hospitalized. Doctors take x-rays to look for a dilated or perforated intestine.
Prognosis for Ulcerative Colitis
Ulcerative colitis is usually chronic, with repeated flare-ups and remissions (periods of no symptoms). In about 10% of people, an initial attack progresses rapidly and results in serious complications. Another 10% of people recover completely after a single attack. The remaining people have some degree of recurring disease.
People who have disease only in their rectum (ulcerative proctitis) have the best prognosis. Severe complications are unlikely. However, in about 20 to 30% of people, the disease eventually spreads to the large intestine (thus evolving into ulcerative colitis). In people who have proctitis that has not spread, surgery is rarely required, cancer rates are not increased, and life expectancy is normal.
The long-term survival rate for people with colon cancer caused by ulcerative colitis is about 50%. Most people survive if the diagnosis is made during the early stages and the colon is removed in time.
Treatment of Ulcerative Colitis
Dietary management and loperamide
Biologic and related agents
Ulcerative colitis treatment aims to control the inflammation, reduce symptoms, and replace any lost fluids and nutrients.
Specific treatment depends on the severity of people's symptoms.
General management of ulcerative colitis
Iron supplements may offset anemia caused by ongoing blood loss in the stool.
Usually, if the large intestine is swollen, people should eat a low-fiber diet (in particular, avoiding foods such as nuts, corn hulls, raw fruits, and vegetables) to reduce injury to the inflamed lining of the large intestine.
A diet free of dairy products may decrease symptoms and is worth trying but does not need to be continued if no benefit is noted.
All people who have ulcerative colitis should take calcium and vitamin D supplements.
Small doses of loperamide are taken for relatively mild diarrhea. For more intense diarrhea, higher doses of loperamide may be needed. In severe cases, however, a doctor must closely monitor the person taking these antidiarrheal drugs because of the risk of fulminant colitis.
Routine health maintenance measures Health maintenance In inflammatory bowel diseases, the intestine (bowel) becomes inflamed, often causing recurring abdominal pain and diarrhea. The two primary types of inflammatory bowel disease (IBD) are Crohn... read more , particularly vaccinations and cancer screening, are important.
Aminosalicylates are drugs used to treat inflammation caused by inflammatory bowel disease. Drugs such as sulfasalazine, olsalazine, mesalamine, and balsalazide are types of aminosalicylates and are used to reduce the inflammation of ulcerative colitis and to prevent flare-ups of symptoms. These drugs usually are taken by mouth (orally), but mesalamine can also be given as an enema or a suppository (rectally). Whether given orally or rectally, these drugs are at best moderately effective for treating mild or moderately active disease, but they are more effective for preventing symptoms from reappearing (maintaining remission).
People with moderately severe disease usually take corticosteroids in fairly high doses, which frequently induces a dramatic remission. After corticosteroids control the inflammation of ulcerative colitis, sulfasalazine, olsalazine, or mesalamine, or an immunomodulating drug Immunomodulating drugs Ulcerative colitis is a chronic inflammatory bowel disease in which the large intestine (colon) becomes inflamed and ulcerated (pitted or eroded), leading to flare-ups (bouts or attacks) of... read more , a biologic agent Biologic and related agents Ulcerative colitis is a chronic inflammatory bowel disease in which the large intestine (colon) becomes inflamed and ulcerated (pitted or eroded), leading to flare-ups (bouts or attacks) of... read more , or tofacitinib or ozanimod is often is given to maintain the improvement. Gradually, the prednisone dosage is decreased, and ultimately the prednisone is discontinued.
Budesonide is another corticosteroid that may be used. It has fewer side effects than prednisone but does not work as quickly and is typically given to people whose disease is less severe.
When mild or moderate ulcerative colitis is limited to the lower part of the left side of the large intestine (sigmoid colon) and the rectum, enemas or suppositories with a corticosteroid or mesalamine may be helpful. Corticosteroid treatment is reduced and gradually stopped over several weeks.
If the disease becomes severe, the person is hospitalized, and corticosteroids and fluids are given by vein (intravenously). People may still be given mesalamine. People with heavy rectal bleeding may require blood transfusions.
Immunomodulating drugs modify the action of the body's immune system, decreasing its activity. Drugs such as azathioprine and mercaptopurine have been used to maintain remissions in people with ulcerative colitis who would otherwise need long-term corticosteroid treatment. These drugs inhibit the function of T cells, which are an important component of the immune system. However, these drugs are slow to act, and a benefit may not be seen for 1 to 3 months. They also have potentially serious side effects that require close monitoring by the doctor.
Cyclosporine has been given to some people who have severe flare-ups and have not responded to corticosteroids. Most of these people respond initially to the cyclosporine, but some may still ultimately require surgery.
Tacrolimus is given by mouth. This drug has been given as short-term treatment to people whose ulcerative colitis is difficult to manage while they begin treatment with azathioprine and mercaptopurine. Tacrolimus may help maintain remission.
Biologic and related agents
Biologic agents are medicines that are created by living organisms.
Infliximab, which is derived from monoclonal antibodies to tumor necrosis factor (called a tumor necrosis factor inhibitor or TNF inhibitor) and given intravenously, is beneficial for some people with ulcerative colitis. This drug may be given to people who do not respond to corticosteroids or who develop symptoms whenever corticosteroid doses are lowered, despite the optimal use of other immunomodulating drugs. Infliximab, adalimumab, and golimumab are beneficial for people whose ulcerative colitis is difficult to treat or for people who depend on corticosteroids.
Side effects that may occur with infliximab include worsening of an existing uncontrolled bacterial infection, reactivation of tuberculosis or hepatitis B, and an increase in the risk of some types of cancer. Some people have reactions such as fever, chills, nausea, headache, itching, or rash during the infusion (called infusion reactions). Before starting treatment with infliximab or other TNF inhibitors such as adalimumab and golimumab, people must be tested for tuberculosis and hepatitis B infections.
Vedolizumab is a drug for people who have moderate to severe ulcerative colitis that has not responded to TNF inhibitors or other immunomodulating drugs or who are unable to tolerate these drugs. The most serious side effect it causes is increased susceptibility to infection. Vedolizumab has a theoretical risk of a serious brain infection called progressive multifocal leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy is a rare infection of the brain that is caused by the JC (John Cunningham) virus. People with a weakened immune system are most likely to get the... read more (PML) because this infection has been reported with the use of a related drug called natalizumab.
Ustekinumab is another kind of biologic agent given to people who have moderate to severe ulcerative colitis that has not responded to TNF inhibitors or other immunomodulating drugs or who are unable to tolerate these drugs. The first dose is given by vein and then by injections under the skin every 8 weeks. Side effects include injection site reactions (pain, redness, swelling), cold-like symptoms, chills, and headache.
Tofacitinib is a drug given by mouth twice a day for adults with moderate to severe ulcerative colitis. This drug is a Janus kinase (JAK) inhibitor that is not actually a biologic agent because it is created by chemical processes rather than living organisms. However, it shares many characteristics with biologic agents, including many of their side effects. It interferes with the communication between cells that coordinate inflammation by inhibiting an enzyme (Janus kinase, or JAK). Serious side effects include increased susceptibility to infection and pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism is the blocking of an artery of the lung (pulmonary artery) by a collection of solid material brought through the bloodstream (embolus)—usually a blood clot (thrombus) or... read more (the blocking of an artery of the lung by a blood clot).
Ozanimod is a drug given by mouth for adults with moderate to severe active ulcerative colitis. This drug should not be used by people who have had a heart attack, chest pain (unstable angina), stroke or mini-stroke (transient ischemic attack or TIA), or certain types of heart failure in the last 6 months. This drug also should not be taken by people who have or have had a history of certain types of an irregular or abnormal heartbeat (arrhythmia) that is not corrected by a pacemaker, by people with severe untreated sleep apnea, or by people who take a monoamine oxidase inhibitor (MAOI—such as selegiline, phenelzine, and linezolid). Ozanimod can increase the risk of infections, slow the heart rate, lower the number of white blood cells, and cause liver damage.
Severity of symptoms
People with proctitis, or colitis that affects only the part of the colon near the rectum, are given mesalamine enemas. Corticosteroid and budesonide enemas are given to people who are not helped by or cannot tolerate mesalamine.
People with moderate or extensive disease are given mesalamine by mouth in addition to mesalamine enemas. People with severe symptoms and those who still have symptoms while using mesalamine usually take oral corticosteroids such as prednisone. Prednisone in fairly high doses frequently induces a dramatic remission. After prednisone controls the inflammation of ulcerative colitis, sulfasalazine, olsalazine, or mesalamine often is given to maintain the improvement. Gradually, the prednisone dosage is decreased, and ultimately the prednisone is discontinued because prolonged corticosteroid treatment almost always causes side effects.
People whose symptoms return when prednisone is decreased are sometimes given an immunomodulating drug (azathioprine or mercaptopurine). Additionally, some people benefit from infliximab, adalimumab, vedolizumab, golimumab, ustekinumab, tofacitinib, or ozanimod.
People with severe colitis are hospitalized, and high-dose corticosteroids and fluids are given intravenously. Doctors may continue to give mesalamine. People with heavy rectal bleeding may require blood transfusions. People who do not respond to these treatments within 3 to 7 days may be given intravenous infliximab, vedolizumab, or cyclosporine or may need surgery to remove their colon. People who have severe or difficult to treat colitis but who do not need to be hospitalized may be given tacrolimus.
Fulminant colitis (toxic colitis)
People whose disease occurs suddenly, rapidly, and with great pain or who may have toxic megacolon are hospitalized. All antidiarrheal drugs are stopped, no food or drugs are given by mouth, and doctors pass a tube through the nose and into the stomach or small intestine to remove contents from the stomach or small intestine. People are given intravenous fluids and electrolytes and high-dose intravenous corticosteroids or cyclosporine. Doctors also give antibiotics. People may be given infliximab.
People are monitored closely for signs of infection or a perforation. People whose condition does not improve in 24 to 48 hours need immediate surgery to remove all or most of the large intestine.
To prevent symptoms from reappearing (that is, to maintain remission), people continue to take mesalamine by mouth or as an enema indefinitely because stopping this maintenance regimen often allows the disease to return (called relapse). Studies suggest that a combination of oral and rectal mesalamine treatment is significantly more effective than either treatment alone.
People who cannot stop taking corticosteroids are given immunomodulating drugs (azathioprine or mercaptopurine), TNF inhibitors (infliximab, adalimumab, or golimumab), tofacitinib, vedolizumab, ustekinumab, or ozanimod or a combination of immunomodulating drugs and TNF inhibitors.
About 30% of people with extensive ulcerative colitis require surgery. Emergency surgery may be necessary for sudden life-threatening attacks with massive bleeding, perforation, or fulminant colitis.
Sometimes surgery is needed even when there is no emergency reason for surgery. These situations include chronic colitis that is disabling or that constantly requires high doses of corticosteroids, cancer, and narrowing of the large intestine or growth retardation in children.
Complete removal of the large intestine, rectum, and anus (total proctocolectomy) permanently cures ulcerative colitis, restores life expectancy to normal, and eliminates the risk of colon cancer. However, inflammation develops in the small intestine in about 25% of people after surgery even though their small intestine was not previously affected. Because the rectum and anus are removed, people must have a permanent ileostomy. In an ileostomy, a surgeon brings the end of the lowest portion of the small intestine (ileum) out through an opening in the abdominal wall (stoma). People who have an ileostomy must always wear a plastic bag (ileostomy bag) over the opening to collect the stool that comes out. An ileostomy used to be the traditional price of this cure.
However, various alternative procedures are now available, and the most common one is a procedure called proctocolectomy with ileal pouch-anal anastomosis (IPAA). In this procedure, the large intestine and most of the rectum are removed, and a small reservoir (pouch) is created out of the small intestine and attached to the remaining rectum just above the anus. Because the muscles of the anus (anal sphincter) are not removed, this procedure allows people to remain in control of their bowels (continence). However, because a small amount of tissue of the rectum can remain, the risk of cancer is significantly decreased but not eliminated. A common complication of IPAA is inflammation of the reservoir (called pouchitis). To treat pouchitis, doctors give antibiotics. Most cases of pouchitis can be controlled with drugs, but a small percentage cannot. For these cases, doctors create an ileostomy to correct the problem.
For people with ulcerative proctitis, surgery is rarely needed, and life expectancy is normal. In some people, though, the symptoms may be very difficult to treat.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Crohn's and Colitis Foundation of America: General information on Crohn disease and ulcerative colitis, including access to support services
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)—Ulcerative Colitis: General information on ulcerative colitis, including information about research and clinical trials
United Ostomy Associations of America (UOAA): Information and support resources for people who live with an ostomy
Drugs Mentioned In This Article
|Generic Name||Select Brand Names|
|Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20|
|Anti-Diarrheal, Imodium A-D, Imodium A-D EZ Chews , K-Pek II|
|Calcidol, Calciferol, D3 Vitamin, DECARA, Deltalin, Dialyvite Vitamin D, Dialyvite Vitamin D3, Drisdol, D-Vita, Enfamil D-Vi-Sol, Ergo D, Fiber with Vitamin D3 Gummies Gluten-Free, Happy Sunshine Vitamin D3, MAXIMUM D3, PureMark Naturals Vitamin D, Replesta, Replesta Children's, Super Happy SUNSHINE Vitamin D3, Thera-D 2000, Thera-D 4000, Thera-D Rapid Repletion, THERA-D SPORT, UpSpring Baby Vitamin D, UpSpring Baby Vitamin D3, YumVs, YumVs Kids ZERO, YumVs ZERO|
|Azulfidine, Azulfidine En-Tabs, Sulfazine , Sulfazine EC|
|Apriso, Asacol, Asacol HD, Canasa, Delzicol, Lialda, Pentasa, Rowasa, sfRowasa|
|Xeljanz, Xeljanz Oral, Xeljanz XR|
|Deltasone, Predone, RAYOS, Sterapred, Sterapred DS|
|Entocort EC, Ortikos, Pulmicort, Pulmicort Flexhaler, Rhinocort, Rhinocort Aqua, Rhinocort Children's Allergy, TARPEYO, UCERIS, UCERIS Rectal|
|Cequa, Gengraf , Neoral, Restasis, Sandimmune, SangCya, Verkazia|
|ASTAGRAF XL, ENVARSUS, HECORIA, Prograf, Protopic|
|AVSOLA, INFLECTRA, Remicade, RENFLEXIS|
|AMJEVITA , CYLTEZO, HADLIMA, Hulio, Hulio PEN, Humira, Hyrimoz, Idacio, YUFLYMA, YUSIMRY|
|Simponi, SIMPONI ARIA|
|Carbex, Eldepryl, EMSAM, Zelapar|
|Zyvox, Zyvox Powder, Zyvox Solution|