Ulcerative colitis

• 1. Introduction

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  Ulcerative colitis can stay active inside a body that feels perfectly fine. Among people with a history of the disease who report no symptoms, up to 45 percent still show objective signs of inflammation. The condition is one of two forms of inflammatory bowel disease, the other being Crohn's disease. It inflames the colon and rectum, leaves ulcers behind, and tends to come and go in waves. Nobody has pinned down a single cause. So how do doctors recognize it, separate it from its lookalikes, and bring it under control? And why does a disease of the large intestine sometimes reveal itself first in the eyes, the joints or the skin?

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• 2. Anatomy of a Flare

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  Blood is the signature symptom. An estimated 90 percent of people with ulcerative colitis experience rectal bleeding, and about the same share have loose, frequent stools. Between 75 and 90 percent feel sudden bowel urgency. The usual picture is bloody diarrhea that builds gradually and persists for weeks. Some people also leak stool, pass mucus, or wake at night to use the toilet.

  Tenesmus is the strangest of the symptoms. When the rectum is inflamed, a person feels a pressing need to empty the bowels but passes very little. Because the urge resembles the feeling of constipation, the two can be confused. Pain ranges from mild discomfort to cramping and agonizing bowel movements. Flares can add weight loss, nausea, fatigue and fever. Slow blood loss and chronic inflammation often lead to anemia, which can wear down quality of life.

  Fewer than four stools a day marks mild disease. Doctors grade severity by symptoms, blood tests, endoscopy findings and how much the illness disrupts daily life. Mild cases bring occasional urgency and bleeding, no fever or chills, and normal blood markers of inflammation. Moderate to severe disease means more than six stools daily, frequent bloody stools, moderate abdominal pain, anemia, and a low-grade fever of 38 to 39 degrees Celsius. The Mayo Score combines stool frequency, bleeding, endoscopic findings and the physician's own judgment to sort patients into mild, moderate or severe. Up to 15 percent of people already have severe disease when symptoms first appear.

  The most dangerous form is acute-severe ulcerative colitis, which strikes suddenly with heavy bleeding, diarrhea, pain and fever. Its mortality is higher than in milder forms, at 0.84 percent after three months and 1 percent after twelve. In fulminant cases the inflammation can break through the lining and slow the colon's movement. That leads to toxic megacolon, a medical emergency that is often treated with surgery. If the colon's outer membrane becomes involved, perforation can follow, and about half of people with the disease who suffer one die. Infection with C. difficile or cytomegalovirus can pile on top.

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• 3. Reach of the Disease

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  Ulcerative colitis spreads in an unbroken line. It almost always starts at the rectum and climbs upward, whereas Crohn's disease leaves healthy gaps between inflamed patches that doctors call skip lesions. Disease confined to the rectum is called proctitis. Inflammation reaching the descending colon is left-sided colitis, and anything beyond that is extensive colitis. Proctosigmoiditis covers the rectum and sigmoid colon, while pancolitis means the whole colon, from the rectum to the cecum.

  Even the small intestine is not entirely spared. About 17 percent of people with the disease have ileitis, and it appears in 20 percent of pancolitis cases. This so-called backwash ileitis, seen in 10 to 20 percent of people with pancolitis, is believed to matter little clinically.

  Outside the gut, the reported frequency of extra-intestinal problems runs from 6 to 47 percent. About 8 percent of people develop mouth problems, most often aphthous stomatitis, which causes recurring benign ulcers, and angular cheilitis, which reddens and cracks the corners of the mouth. The eyes can suffer as well. Uveitis and episcleritis are the eye conditions most often linked to the disease, and uveitis brings blurred vision and pain in bright light. Left untreated, it can cause permanent vision loss.

  Joints are affected through a pattern called seronegative arthritis. It may involve a few large joints, the vertebrae in ankylosing spondylitis, or many small joints of the hands and feet. Around 50 percent of people with inflammatory bowel disease are estimated to have migratory arthritis. Ankylosing spondylitis and sacroiliitis usually run independently of how active the bowel disease is.

  The skin tells two different stories. Erythema nodosum, the most common skin finding, appears in up to 3 percent of patients as tender red nodules measuring roughly 1 to 5 centimeters, usually on the shins. It tracks the bowel disease, so treating the colon often clears the nodules. Pyoderma gangrenosum, seen in about 1 percent of patients, behaves differently. Its deep ulcers fill with sterile pus-like material, grow steadily, and usually progress regardless of bowel inflammation.

  Blood clots are another hazard. Inflammation makes the blood more prone to clotting, and the risk is about threefold higher in people with inflammatory bowel disease. Painful swelling of the lower legs can signal a clot in a deep vein, and difficulty breathing can signal one in the lungs. Prolonged steroid treatment can thin the bones, and severe, poorly controlled disease can lead to amyloidosis.

  The liver carries the most serious link. Between 70 and 90 percent of people with primary sclerosing cholangitis, a progressive inflammation of the bile ducts, have ulcerative colitis. As many as 5 percent of people with ulcerative colitis go on to develop it. It is more common in men and often begins between ages 30 and 40, sometimes years before any bowel symptoms. Removing the colon does not change its course. It raises the risk of colorectal cancer and of cholangiocarcinoma, a bile duct cancer, and it can progress to cirrhosis. No specific therapy has been proven to alter its long-term course.

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• 4. Suspected Causes

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  Among identical twins, the disease is shared in 10 percent of pairs, compared with only 3 percent of non-identical pairs. Between 8 and 14 percent of patients have a relative with inflammatory bowel disease. Having a first-degree relative with ulcerative colitis raises a person's own risk fourfold. Researchers have linked twelve regions of the genome to the disease, including chromosomes 16, 12, 6, 14, 5, 19, 1 and 3. None has been consistently shown to be at fault, which suggests many genes working together. The link on chromosome 6, involving human leukocyte antigens, may be the most convincing.

  Rates run higher in developed countries. Some attribute this to less childhood exposure to intestinal infections, and others to a Western diet and lifestyle. Breastfeeding may protect against the disease. So may an appendix removal before age 20 for appendicitis, and so does current tobacco use, though former smokers face a higher risk. One study of the acne drug isotretinoin found a small rise in cases. Few studies have examined diet, and research has not established a link. Still, high intake of unsaturated fat and vitamin B6 may raise risk, and meat protein and alcohol may influence onset or relapse.

  An industrial case study adds a stranger clue. After a class-action lawsuit and settlement with DuPont, three epidemiologists studied people living around a chemical plant who had been exposed to PFOA at above-average levels. They tied that exposure to six health outcomes, and ulcerative colitis was one of them.

  Hydrogen sulfide is a leading chemical suspect. Some patients carry more sulfate-reducing bacteria, and these produce the toxic gas. The cells lining the colon depend on the short-chain fatty acid n-butyrate for nourishment. Hydrogen sulfide is proposed to disrupt the pathway that processes it by interfering with an enzyme, short-chain acetyl-CoA dehydrogenase. The same theory offers an explanation for smoking's protective effect. Hydrogen cyanide in cigarette smoke may react with hydrogen sulfide to form the nontoxic isothiocyanate. Another study suggested that sulfur in red meat and alcohol raises the chance of relapse in remission. A separate proposal blames infection with Mycobacterium avium, subspecies paratuberculosis, for both ulcerative colitis and Crohn's disease.

  The immune explanation starts with sentinel cells. Dendritic cells and macrophages normally engulf dangerous microbes and show fragments of them to T-cells. In ulcerative colitis they instead engulf bacteria from the ordinary gut microbiome and release the signal TNFα, which recruits inflammatory cells. The TNF inhibitors infliximab, adalimumab and golimumab block this step. The sentinel cells then travel to the mesenteric lymph nodes and release IL-12 and IL-23. These signals push naive T-cells to become Th1 and Th17 cells. Ustekinumab blocks both IL-12 and IL-23, while guselkumab, mirikizumab and risankizumab block IL-23.

  The T-cells then reach the gut wall by binding an adhesion protein called MAdCAM-1, which vedolizumab blocks. Ozanimod and etrasimod instead act on the sphingosine-1-phosphate receptor to stop the cells leaving the lymph vessels. Once in the intestinal lining, JAK-STAT signaling inside the T-cells drives release of inflammatory cytokines. Tofacitinib, filgotinib and upadacitinib inhibit that pathway.

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• 5. Reading the Evidence

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  A normal CRP blood test does not clear a patient. Twenty-five percent of people with inflammation confirmed on endoscopy have a normal CRP level. The markers CRP and ESR also rise in many other conditions, including infection. Perinuclear antineutrophil cytoplasmic antibodies, or pANCA, turn up in 70 percent of cases. Antibodies against Saccharomyces cerevisiae are more often positive in Crohn's disease. Because these serologic tests are so inaccurate, they do not help much in diagnosis.

  Stool testing does better. Fecal calprotectin is 88 percent sensitive and 79 percent specific for ulcerative colitis, and it helps separate irritable bowel syndrome, which is not inflammatory, from a flare. If the level is low, the likelihood of inflammatory bowel disease is under 1 percent. Lactoferrin is another nonspecific marker. Everyone with suspected ulcerative colitis should have stool testing to rule out infection, including a Clostridioides difficile assay.

  Blood work looks at the damage. A complete blood count may show anemia, leukocytosis or thrombocytosis. Chronic bleeding can cause iron deficiency with small red blood cells. Azathioprine can lower blood counts, and sulfasalazine can cause folate deficiency. Chronic diarrhea can lower potassium and magnesium and injure the kidneys, so electrolytes and kidney function are checked. Liver tests screen for primary sclerosing cholangitis. Low vitamin D is associated with the disease, though its significance is unclear. In 1998, the simple clinical colitis activity index was created to gauge symptom severity.

  Endoscopy remains the best test. A flexible sigmoidoscopy may come first, and the physician may limit the exam when colitis is severe to reduce the risk of perforation. A full colonoscopy reaching the terminal ileum is still needed to rule out Crohn's disease and measure extent. The camera looks for redness, fragile mucosa, shallow ulcers, loss of the colon's normal vascular pattern, and sometimes pseudopolyps. The rectum is almost universally involved.

  Biopsies taken during the exam show distorted crypt architecture, crypt abscesses, and lymphocytes, plasma cells and granulocytes in the mucosa. In ulcerative colitis the inflammation stays within the mucosa. Crohn's disease, managed differently, shows transmural inflammation instead.

  Imaging plays a supporting role. X-ray or CT can reveal perforation or toxic megacolon. In severe disease, an abdominal X-ray may show thumbprinting, a sign of swelling from displaced fluid. A barium enema must be avoided in very severe cases, since it can slow or stop stool passage and cause ileus and toxic megacolon. Bowel ultrasound is cost-effective, well tolerated and non-invasive, and some studies show it accurately gauges disease activity. MRI is needed to diagnose underlying primary sclerosing cholangitis.

  Crohn's disease is the most common mimic. Perianal disease, meaning anal fissures, abscesses and fistulas, points toward Crohn's. When the two cannot be told apart, the disease is classed as indeterminate colitis. Infectious colitis is sorted out with tissue cultures and stool studies. A few cases of intestinal infection with the parasite Entamoeba histolytica were misdiagnosed as ulcerative colitis, and corticosteroids led to poor outcomes. Radiation colitis and diversion colitis can look similar too. After a transplant, graft versus host disease can cause prolonged diarrhea, a rash, and crypt cell necrosis on biopsy.

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• 6. Medicines

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  Treatment runs in two phases. Physicians first aim to induce remission, which means relieving symptoms and healing the lining of the colon. They then switch to longer-term drugs that maintain remission and prevent complications. The medicines overlap but are not identical. During acute stages, a low-fiber diet may be recommended.

  Sulfasalazine has anchored treatment of mild to moderate disease for over 50 years. In 1977, researchers showed that its active ingredient was 5-aminosalicylic acid, also called mesalazine or mesalamine. Newer 5-ASA drugs deliver that compound to the large intestine while avoiding side effects tied to the sulfapyridine portion of sulfasalazine. Mesalazine is the first-line maintenance drug, and the first choice for disease limited to the left colon or rectum. Suppositories, foam or liquid enemas treat the rectum, sigmoid or descending colon, and work best alongside oral doses. Prodrugs like sulfasalazine carry a greater potential for serious side effects and have not proven superior in large trials.

  Corticosteroids such as prednisone are added when mesalazine alone fails, but they are not used long term because the risks then outweigh the benefits. Immunosuppressants such as azathioprine and biologic drugs are reserved for severe disease or for patients who cannot reach remission otherwise. A formulation of budesonide was approved by the U.S. Food and Drug Administration in January 2013. Cyclosporine is effective for severe disease, and tacrolimus has shown benefits. Methotrexate has not been shown to produce remission.

  The TNF inhibitors infliximab, adalimumab and golimumab are commonly used once steroids stop working. Tofacitinib and vedolizumab can also produce good remission rates. Biologics may start early in a step-down approach, or after other treatments fail in a step-up approach, and the strategy is individualized. Unlike aminosalicylates, they can cause serious side effects, including a higher risk of cancers outside the intestine, heart failure, and weakened immunity that can reawaken latent infections such as tuberculosis. Patients are therefore closely monitored and often tested for hepatitis and tuberculosis every year. In 2018, tofacitinib became the first oral medication approved in the United States for long-term use in moderately to severely active disease. Etrasimod, a once-daily oral drug, followed in October 2023 after two randomized trials showed it effective as both induction and maintenance therapy.

  Immunosuppression brings its own risks. Many patients are more exposed to opportunistic infections, and many of these, such as hepatitis B, influenza, chickenpox, herpes zoster, pneumococcal pneumonia and human papilloma virus, are preventable with vaccines. Several guidelines advise checking vaccination status before treatment starts. Patients on Janus kinase inhibitors showed a higher risk of shingles. Even so, vaccination rates in people with inflammatory bowel disease are suboptimal and may fall below those of the general population.

  Anemia needs its own watch. Guidelines suggest blood tests every three months in active disease and yearly in quiescent disease. Good disease control usually improves anemia of chronic disease, but true iron deficiency needs supplements. Some experts favor injected iron first because people respond faster, with fewer stomach side effects and no problem sticking to a regimen. Others start with oral iron, since patients eventually respond and many tolerate it. Anticholinergic drugs can calm abdominal cramps by slowing colonic movement, but they are contraindicated in moderate to severe disease because they can trigger toxic megacolon.

  Some treatments sit outside the standard playbook. Smokers are less likely than non-smokers to develop the disease, and in a few people with a smoking history, resuming low-dose smoking improved active symptoms, though it is not recommended. In a United Kingdom double-blind trial, 48.6 percent of patients using a nicotine patch alongside standard treatment had complete resolution of symptoms. A trial in the United States found significant improvement in 39 percent of patch users versus 9 percent on placebo. Nicotine therapy is still generally not recommended because of side effects and inconsistent results.

  Probiotics have a modest record. A Cochrane review found low-certainty evidence that probiotic supplements may raise the chance of clinical remission. People receiving them were 73 percent more likely to reach remission and over twice as likely to report improvement. Remission was 22 percent more likely when probiotics were combined with 5-aminosalicylic acid. The strain Escherichia coli Nissle has induced remission in some people for up to a year. Fecal microbiota transplant, delivered by enema, needs a longer course for ulcerative colitis than for Clostridioides difficile infection. One study reported complete remission in 67.7 percent of patients.

  Curcumin, the compound in turmeric, may help maintain remission when taken with mesalamine or sulfasalazine, though its effect alone is unknown. For abdominal pain, people have tried a low-FODMAP diet, relaxation training, yoga, a kefir diet and stellate ganglion block, and it is unclear whether any is safe or effective. Cannabis and cannabis oil remain uncertain, since studies have not settled their effectiveness or safety.

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• 7. The Surgical Option

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  Removing the large intestine can cure the digestive side of ulcerative colitis, though symptoms outside the gut may persist. Surgery is necessary for exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. It is also indicated for severe colitis or toxic megacolon. People whose symptoms are disabling and unresponsive to drugs may choose it to improve their quality of life.

  The most complete operation is a proctocolectomy, removing the entire large intestine. It results in a permanent ileostomy, in which the terminal ileum is pulled through the abdomen to form a stoma. Intestinal contents empty into a removable ostomy bag secured by adhesive.

  The ileal pouch-anal anastomosis, or IPAA, is an alternative for disease affecting most of the large bowel. In the three-step version, the first operation is a sub-total colectomy that removes the large bowel but leaves the rectum, with a temporary ileostomy. The second step removes most of the remaining rectal stump and fashions the end of the small intestine into a pouch, commonly called a j-pouch, attached to the anus. A loop ileostomy lets the joins heal. The final take-down surgery reverses the ileostomy, ending the need for a bag. Done in two steps, a proctocolectomy is combined with the pouch and loop ileostomy. A six- to twelve-month gap is typically recommended between the first two steps, and at least two to three months before take-down.

  The pouch removes the bag but does not restore normal bowel function. In the months after the final operation, patients typically have 8-15 bowel movements a day. Many report 4-6 after a year. Pouchitis, inflammation of the pouch with symptoms resembling ulcerative colitis, is relatively common. It can be acute, remitting or chronic, and antibiotics, steroids or biologics can treat it effectively. Other complications include fistulas, abscesses and pouch failure. Revision surgery may be needed, and in some cases the pouch must be bypassed or removed and an ileostomy recreated.

  The risk of cancer arising from a pouch is low. Annual surveillance with pouchoscopy may still be considered for people with risk factors for dysplasia. Those include a history of dysplasia or colorectal cancer, a history of primary sclerosing cholangitis, refractory pouchitis, and a severely inflamed, atrophic pouch lining.

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• 8. Living With Colitis

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  Only 15 percent of people with proctitis or left-sided colitis see the disease progress upward, and up to 20 percent can stay in remission without any therapy. The usual course alternates quiet periods with flares. A subset follows a rapid course, fails to respond to drugs, and often has surgery within the first few years. Risk factors for eventually needing a colectomy include a prior hospitalization, extensive colitis, systemic steroids, young age at diagnosis, low serum albumin, elevated CRP and ESR, and severe inflammation on colonoscopy.

  Cancer risk climbs after ten years when the disease reaches beyond the splenic flexure. People with only proctitis usually have no added risk, and those with backwash ileitis might. Screening colonoscopies with random biopsies are recommended after eight years of disease activity, repeated every one to two years. Overall mortality is similar to, or perhaps slightly above, that of the background population, though the causes of death differ. Infection with C. difficile or reactivated cytomegalovirus predicts worse outcomes.

  Food becomes a daily negotiation. Patients most often avoid spicy foods, dairy, alcohol, fruits, vegetables and carbonated drinks, mostly during remission to prevent relapse. During flares the restrictions can grow so severe that nutrition suffers. Lactose-free diets are followed by 21.3 percent of patients versus 11.6 percent of controls. Gluten-free diets are followed by 23.4 percent versus 9.3 percent, even without a coeliac diagnosis, because patients believe gluten worsens symptoms.

  Mood is part of the picture. Studies find more depression and anxiety in people with inflammatory bowel disease, and up to 65 percent of women with the disease may have depressive and anxiety disorders. A meta-analysis of mood-lifting interventions, including talk therapy, antidepressants and exercise, found they lowered inflammatory markers such as C-reactive protein and fecal calprotectin. Psychological therapies lowered inflammation more than antidepressants or exercise.

  The disease was first described around the 1850s. Samuel Wilks used the term ulcerative colitis in 1859, and it entered general medical vocabulary in 1888 when William Hale-White published a report on various cases. It was the first subtype of inflammatory bowel disease to be identified, and it has grown more common since the 1950s. Together with Crohn's disease it affected about 11.2 million people as of 2015, and 47,400 died of inflammatory bowel disease that year. Onset peaks between ages 30 and 40, with a second peak in the 6th decade of life. Men and women are equally affected.

  Geography matters. The disease is more common in North America and Europe, and rates rise toward the north within Europe and the United States. They are higher among Ashkenazi Jews, falling progressively in other people of Jewish descent, non-Jewish Caucasians, Africans, Hispanics and Asians. In the United Kingdom about 146,000 people have been diagnosed. In Canada between 1998 and 2000, new cases ran at 12.9 per 100,000 people, or 4,500 a year.

  Research keeps probing the edges. A randomized trial from Iowa found benefit from helminthic therapy with the whipworm Trichuris suis, testing the idea that missing intestinal worms in the developed world invite inflammation. As of early 2022, Roche halted its trials of etrolizumab, a drug that blocks leukocyte migration into the intestinal lining. Helminthic therapy and fecal microbiota transplant both trigger a Th2 white cell response in diseased areas, which surprised researchers, because ulcerative colitis had been thought to involve an overproduction of Th2 cells.

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