Ulcerative colitis

Ulcerative colitis

Endoscopic image of a colon affected by ulcerative colitis. The internal surface of the colon is blotchy and broken in places.
Classification and external resources
Specialty gastroenterology
ICD-10 K51
ICD-9-CM 556
OMIM 191390
DiseasesDB 13495
MedlinePlus 000250
eMedicine med/2336
Patient UK Ulcerative colitis
MeSH D003093

Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum.[1][2] The primary symptom of active disease is abdominal pain and diarrhea mixed with blood. Weight loss, fever, and anemia may also occur. Often symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares.[1] Complications may include megacolon, inflammation of the eye, joints, or liver, and colon cancer.[1][3]

The cause of UC is unknown.[1] Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors.[1][4] Rates tend to be higher in the developed world with some proposing this to be the result of less exposure to intestinal infections, or a Western diet and lifestyle.[2][5] The removal of the appendix at an early age may be protective.[5] Diagnosis is typically by colonoscopy with tissue biopsies. It is a kind of inflammatory bowel disease (IBD) along with Crohn's disease and microscopic colitis.[1]

Dietary changes may improve symptoms. A number of medications are used to treat symptoms and bring about and maintain remission. These include aminosalicylates such as sulfasalazine, steroids, immunosuppressants such as azathioprine, and biological therapy. Removal of the colon by surgery may be necessary if the disease is severe, does not respond to treatment, or if complications such as colon cancer develop.[1] Removal of the colon and rectum can cure the disease.[1][5]

The first description of ulcerative colitis occurred around the 1850s.[5] Each year it newly occurs in 1 to 20 people per 100,000 and 5 to 500 per 100,000 individuals are affected.[2][5] The disease is more common in North America and Europe.[5] Often it begins between 15 and 30 years of age or among those over 60.[1] Males and females appear to be affected equally.[2] It has also become more common since the 1950s.[2][5] Together, ulcerative colitis and Crohn's disease affect approximately 500,000 to 2 million people in the United States.[6] With appropriate treatment the risk of death appears the same as that of the general population.[3]

A video explaining ulcerative colitis.
Video explanation

Signs and symptoms

Signs and symptoms
Crohn's disease Ulcerative colitis
Defecation Often porridge-like,[7]
sometimes steatorrhea 		Often mucus-like
and with blood[7]
Tenesmus Less common[7] More common[7]
Fever Common[7] Indicates severe disease[7]
Fistulae Common[8] Seldom
Weight loss Often More seldom

Gastrointestinal

The clinical presentation[9] of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset that persists for an extended period (weeks). They may also have weight loss and blood on rectal examination. The inflammation caused by the disease along with the chronic blood from the GI tract leads to increased rates of anemia. The disease may be accompanied by different degrees of abdominal pain, from mild discomfort to painful bowel movements or painful abdominal cramping with bowel movements.

Ulcerative colitis is associated with a general inflammatory process that affects many parts of the body. Sometimes these associated extra-intestinal symptoms are the initial signs of the disease, such as painful arthritic knees in a teenager and may be seen in adults also. The presence of the disease may not be confirmed immediately, however, until the onset of intestinal manifestations.

Extent of involvement

Diagram of the human intestine

Ulcerative colitis is normally continuous from the rectum up the colon. The disease is classified by the extent of involvement, depending on how far up the colon the disease extends:

Severity of disease

Colonic pseudopolyps of a patient with intractable ulcerative colitis. Colectomy specimen.

In addition to the extent of involvement, people may also be characterized by the severity of their disease.[10]

Extraintestinal features

Patients with ulcerative colitis can occasionally have aphthous ulcers involving the tongue, lips, palate and pharynx

As ulcerative colitis is believed to have a systemic (i.e., autoimmune) origin, patients may present with comorbidities leading to symptoms and complications outside the colon. The frequency of such extraintestinal manifestations has been reported as anywhere between 6 and 47 percent.[11] These include the following:

Causes

There are no direct known causes for ulcerative colitis, but there are many possible factors such as genetics and stress.

Genetic factors

A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following:[12]

There are 12 regions of the genome that may be linked to ulcerative colitis, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3,[14] but none of these loci have been consistently shown to be at fault, suggesting that the disorder arises from the combination of multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease.[15]

Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. There may even be human leukocyte antigen associations at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.[14]

Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including ulcerative colitis, Crohn's disease, celiac disease, dermatitis herpetiformis, diabetes, systemic and discoid lupus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, Sjogren's disease and scleritis. Physicians should be on high alert for porphyrias in families with autoimmune disorders and care must be taken with potential porphyrinogenic drugs, including sulfasalazine.

Environmental factors

Many hypotheses have been raised for environmental contributants to the pathogenesis of ulcerative colitis. They include the following:

Autoimmune disease

Ulcerative colitis is an autoimmune disease characterized by T-cells infiltrating the colon.[26] In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis usually involves the rectum and is confined to the colon, with occasional involvement of the ileum. This so-called "backwash ileitis" can occur in 10–20% of patients with pancolitis and is believed to be of little clinical significance.[27] Ulcerative colitis can also be associated with comorbidities that produce symptoms in many areas of the body outside the digestive system. Surgical removal of the large intestine often cures the disease.[10]

Alternative theories

Risk factors
Crohn's disease Ulcerative colitis
Smoking Higher risk for smokers Lower risk for smokers[28]
Age Usual onset between
15 and 30 years[29] 		Peak incidence between
15 and 25 years

Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis. This could mean that there are higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine.[30]

Pathophysiology

Pathophysiology
Crohn's disease Ulcerative colitis
Cytokine response Associated with Th17[31] Vaguely associated with Th2

An increased amount of colonic sulfate-reducing bacteria has been observed in some patients with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. Human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see intestinal mucosal barrier). N-butyrate, a short-chain fatty acid, gets oxidized through the beta oxidation pathway into carbon dioxide and ketone bodies. It has been shown that N-butyrate helps supply nutrients to this epithelial barrier. Studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-CoA dehydrogenase, an enzyme within the pathway. Furthermore, it has been suggested that the protective benefit of smoking in ulcerative colitis is due to the hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway.[32] An unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for patients in remission.[30]

Ulcerative colitis patients typically present with rectal bleeding, diarrhea, tenesmus (urgent desire to evacuate the bowels but with the passage of little stool), and lower abdominal pain. The severity of disease at clinical presentation is important in determining the appropriate therapy. Patients with mildly active disease will have fewer than 4 bowel movements daily and no signs of toxicity. Individuals with moderate-severity UC have more frequent bowel movements with bleeding. Approximately 70% of patients with ulcerative colitis will have moderately active disease at presentation. Patients with severely active disease will have signs of toxicity with fever, tachycardia, and anemia. Patients with fulminant or toxic colitis or toxic megacolon often have more than 10 bowel movements in a day, continuous bleeding, abdominal distention and tenderness, and radiologic evidence of edema and, in some cases, bowel dilation. These people most often require immediate colectomy because 10% have perforated colon at the time of surgery.

Diagnosis

H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis

The initial diagnostic workup for ulcerative colitis includes the following:[10][33]

Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.[10] Factors may include: recent cessation of tobacco smoking; recent administration of large doses of iron or vitamin B6; hydrogen peroxide in enemas or other procedures.

The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms.[34][35]

Endoscopic

Biopsy sample (H&E stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.

The best test for diagnosis of ulcerative colitis remains endoscopy. Full colonoscopy to the cecum and entry into the terminal ileum is attempted only if the diagnosis of UC is unclear. Otherwise, a flexible sigmoidoscopy is sufficient to support the diagnosis. The physician may elect to limit the extent of the exam if severe colitis is encountered to minimize the risk of perforation of the colon. Endoscopic findings in ulcerative colitis include the following:

Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. There is rarely perianal disease, but cases have been reported. The degree of involvement endoscopically ranges from proctitis or inflammation of the rectum, to left sided colitis, to pancolitis, which is inflammation involving the ascending colon.

Histologic

Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's disease, which is managed differently clinically. Microbiological samples are typically taken at the time of endoscopy. The pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis), frank crypt abscesses, and hemorrhage or inflammatory cells in the lamina propria. In cases where the clinical picture is unclear, the histomorphologic analysis often plays a pivotal role in determining the diagnosis and thus the management. By contrast, a biopsy analysis may be indeterminate, and thus the clinical progression of the disease must inform its treatment.

Differential diagnosis

Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration and loss of mucosal architecture. Crohn's disease may be similar in appearance, a fact that can make diagnosing UC a challenge.

The following conditions may present in a similar manner as ulcerative colitis, and should be excluded:

The most common disease that mimics the symptoms of ulcerative colitis is Crohn's disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.

Diagnostic findings
Crohn's disease Ulcerative colitis
Terminal ileum involvement Commonly Seldom
Colon involvement Usually Always
Rectum involvement Seldom Usually[28]
Involvement around
the anus 		Common[8] Seldom
Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate[36]
Distribution of disease Patchy areas of inflammation (skip lesions) Continuous area of inflammation[28]
Endoscopy Deep geographic and serpiginous (snake-like) ulcers Continuous ulcer
Depth of inflammation May be transmural, deep into tissues[8][14] Shallow, mucosal
Stenosis Common Seldom
Granulomas on biopsy May have non-necrotizing non-peri-intestinal crypt granulomas[8][37][38] Non-peri-intestinal crypt granulomas not seen[28]

Management

Standard treatment for ulcerative colitis depends on the extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer term treatment to maintain the remission and prevent complications. Acute severe ulcerative colitis requires hospitalisation, exclusion of infections, and corticosteroids.[39]

Medication

Ulcerative colitis can be treated with a number of medications, including 5-ASA drugs such as sulfasalazine and mesalazine. Corticosteroids such as prednisone can also be used due to their immunosuppressing and short-term healing properties, but because their risks outweigh their benefits, they are not used long-term in treatment. Immunosuppressive medications such as azathioprine and biological agents such as infliximab and adalimumab are given only if people cannot achieve remission with 5-ASA and corticosteroids. This is because of their possible risk factors, including but not limited to increased risk of cancers in teenagers and adults,[40] tuberculosis, and new or worsening heart failure (these side effects are rare). A formulation of budesonide was approved by the FDA for treatment of active ulcerative colitis in January 2013.[41] The evidence on methotrexate does not show a benefit in producing remission in people with ulcerative colitis.[42] Off-label use of drugs such as ciclosporin and tacrolimus has shown some benefits.[43][44] Fexofenadine, an antihistamine drug used in treatment of allergies, has shown promise in a combination therapy in some studies.[45][46] Opportunely, low gastrointestinal absorption (or high absorbed drug gastrointestinal secretion) of fexofenadine results in higher concentration at the site of inflammation. Thus, the drug may locally decrease histamine secretion by involved gastrointestinal mast cells and alleviate the inflammation.

Aminosalicylates

Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, Mastan S. Kalsi et al. determined that 5-aminosalicylic acid (5-ASA and mesalazine) was the therapeutically active component in sulfasalazine.[47] Since then, many 5-ASA compounds have been developed with the aim of maintaining efficacy but reducing the common side effects associated with the sulfapyridine moiety in sulfasalazine.[48]

Biologics

Biologic treatments such as the TNF inhibitors infliximab, adalimumab, and golimumab are commonly used to treat people with UC who are no longer responding to corticosteroids. Tofacitinib, vedolizumab, and etrolizumab can also produce good clinical remission and response rates in UC.[4] Usually, these medications are only used if other options have been exhausted (i.e., the person has received and not responded favorably to high-dose corticosteroids and immunomodulators such as azathioprine and mesalazine).

Unlike aminosalicylates, biologics can cause serious side effects such as an increased risk of developing extra-intestinal cancers,[40] heart failure; and weakening of the immune system, resulting in a decreased ability of the immune system to clear infections and reactivation of latent infections such as tuberculosis. For this reason, patients on these treatments are closely monitored and are often given tests for hepatitis and tuberculosis at least once a year.

Nicotine

Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers.[49][50] Studies using a transdermal nicotine patch have shown clinical and histological improvement.[51]

In one double-blind, placebo-controlled study conducted in the United Kingdom, 48.6% of patients who used the nicotine patch, in conjunction with their standard treatment, showed complete resolution of symptoms. Another randomized, double-blind, placebo-controlled, single-center clinical trial conducted in the United States showed that 39% of patients who used the patch showed significant improvement, versus 9% of those given a placebo.[52] Use of a transdermal nicotine patch without the addition of other standard treatments such as mesalazine has relapse occurrence rates similar to standard treatment without the use of nicotine.

Iron supplementation

The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this with blood tests repeated every three months in active disease and annually in quiescent disease.[53] Adequate disease control usually improves anemia of chronic disease, but iron deficiency anemia should be treated with iron supplements. The form in which treatment is administered depends both on the severity of the anemia and on the guidelines that are followed. Some advise that parenteral iron be used first because patients respond to it more quickly, it is associated with fewer gastrointestinal side effects, and it is not associated with compliance issues.[54] Others require oral iron to be used first, as patients eventually respond and many will tolerate the side effects.[53][55] All guidelines advise that parenteral iron should be administered in cases of severe anemia (a hemoglobin level less than 10).

Treatments in development

Inflammation of the colon is a characteristic symptom of ulcerative colitis, and a new series of drugs in development looks to disrupt the inflammation process by selectively targeting an ion channel. A crucial step involved in the inflammation signaling cascade involves an intermediate conductance calcium activated potassium channel (IK channel) known as KCa3.1;[56] a protein coded for in the human gene KCNN4.[57] Ongoing research seeks to prevent T-cell activation and inflammation by inhibiting the KCa3.1 channel, selectively.[58] Since there is an upregulation of IK channel activity during T cell activation,[56] inhibition of the KCa3.1 is able to disrupt the production of Th1 cytokines IL-2 and TNF-∝. Production of these cytokines decreases because inhibition of KCa3.1 reduces the efflux of K+, which in turn diminishes the influx of Ca2+. By lowering elevated intracellular Ca2+ in patients with ulcerative colitis, these novel drug candidates can inhibit the signaling cascade involved in the inflammation process[58] and help relieve many of the symptoms associated with ulcerative colitis.

Preclinical study results in 2012 indicated that these selective inhibitors decreased colon inflammation in mice and rats cloned with the human KCa3.1 protein as effectively as the standard inflammatory bowel disease treatment of sulfasalazine. However, these novel selective IK channel blockers are significantly more potent and theoretically would be able to be taken at a much more manageable dosage.[58]

Benzothiazinone, NS6180, is a novel class KCa3.1 channel inhibitor in development. Through a number of in vitro experiments, NS6180 was qualified for KCa3.1 channel inhibition. In vivo experiment of DNBS (2,4 - dinitrobenzene sulfonic acid) induced rat colitis, a frequently used animal model for inflammatory bowel disease, showed comparable efficacy and greater potency than sulfasalazine.[58]

Surgery

Management
Crohn's disease Ulcerative colitis
Mesalazine Less useful[59] More useful[59]
Antibiotics Effective in long-term[60] Generally not useful[61]
Surgery Often returns following
removal of affected part 		Usually cured by removal
of colon

Unlike in Crohn's disease, the gastrointestinal aspects of ulcerative colitis can generally be cured by surgical removal of the large intestine, though extraintestinal symptoms may persist. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.

Ulcerative colitis affects many parts of the body outside the intestinal tract. In rare cases, the extra-intestinal manifestations of the disease may require removal of the colon.[10]

Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the ileo-anal pouch procedure. This is a two- to three-step procedure in which the large bowel is removed, except for the rectal stump and anus, and a temporary ileostomy is made. The next part of the surgery can be done in one or two steps and is usually done at six- to twelve-month intervals from each prior surgery.

In the next step of the surgery, an internal pouch is made of the patient's own small bowel, and this pouch is then hooked back up internally to the rectal stump so that the patient can once again have a reasonably functioning bowel system, all internal. The temporary ileostomy can be reversed at this time so that the patient is internalized for bowel functions, or, in another step to the procedure, the pouch, and rectal stump anastamosis can be left inside the patient to heal for some time while the patient still uses the ileostomy for bowel function. Then, on a subsequent surgery, the ileostomy is reversed and the patient has internalized bowel function again.

Leukocyte apheresis

A type of leukocyte apheresis, known as granulocyte and monocyte adsorptive apheresis, still requires large-scale trials to determine whether or not it is effective.[62] Results from small trials have been tentatively positive.[63]

Bacterial recolonization

Alternative medicine

About 21% of inflammatory bowel disease patients use alternative treatments.[68] A variety of dietary treatments show promise, but they require further research before they can be recommended.[69]

Prognosis

Complications
Crohn's
disease 		Ulcerative
colitis
Nutrient deficiency Higher risk
Colon cancer risk Slight Considerable
Prevalence of extraintestinal complications[82]
Iritis/uveitis Females 2.2% 3.2%
Males 1.3% 0.9%
Primary sclerosing
cholangitis 		Females 0.3% 1%
Males 0.4% 3%
Ankylosing
spondylitis 		Females 0.7% 0.8%
Males 2.7% 1.5%
Pyoderma
gangrenosum 		Females 1.2% 0.8%
Males 1.3% 0.7%
Erythema nodosum Females 1.9% 2%
Males 0.6% 0.7%

Progression or remission

Patients with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. Patients with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. Patients with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of the disease.

Colorectal cancer

There is a significantly increased risk of colorectal cancer in patients with ulcerative colitis after ten years if involvement is beyond the splenic flexure. Those with only proctitis or rectosigmoiditis usually have no increased risk.[10] It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity, at one to two year intervals.[83]

Primary sclerosing cholangitis

Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. As many as 5% of patients with ulcerative colitis may progress to develop primary sclerosing cholangitis.[84]

Mortality

Research has not revealed any difference in overall risk of dying in patients with Ulcerative colitis from that of the background population. The cause-of-death distribution may be different from that of the background population.[85] It is thought that the disease primarily affects quality of life, and not lifespan.

Other long-term features

Changes that can be seen in chronic ulcerative colitis include granularity, loss of the vascular pattern of the mucosa, loss of haustra, effacement of the ileocecal valve, mucosal bridging, strictures and pseudopolyps.[86]

Epidemiology

The number of new cases per year of ulcerative colitis in North America is 10–12 per 100,000 per year. It begins most commonly between the ages of 15 and 25. The number of people affected is 1–3 per 1000.[87] Another frequent age of onset is the 6th decade of life.

The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide,[88] with highest incidences in the United States, Canada, the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe[89] and the United States.[90]

As with Crohn's disease, the prevalence of ulcerative colitis is greater among Ashkenazi Jews and decreases progressively in other persons of Jewish descent, non-Jewish Caucasians, Africans, Hispanics, and Asians.[27] Appendectomy prior to age 20 for appendicitis[91] and current tobacco use[92] are protective against development of ulcerative colitis (although former tobacco use is associated with a higher risk of developing ulcerative colitis.[92])

Research

Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in patients with ulcerative colitis.[93] The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the developed world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which was unexpected given that ulcerative colitis was thought to involve Th2 overproduction.[94]

Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1.[95] ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue.[95] Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of ulcerative colitis sufferers, where ICAM-1 over production correlated with disease activity.[96] This suggests that ICAM-1 is a potential therapeutic target in the treatment of ulcerative colitis.[97]

Gram positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis.[98]

Notable cases

References

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