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Ulcerative colitis[edit]

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Ulcerative colitis
Endoscopic image of a colon affected by ulcerative colitis. The internal surface of the colon is blotchy and broken in places.
Specialty Gastroenterology
Symptoms Abdominal pain, diarrhea mixed with blood, weight loss, fever, anemia
Complications Megacolon, inflammation of the eye, joints, or liver, colon cancer
Usual onset 15–30 years or > 60 years
Duration Long term
Causes Unknown
Diagnostic method Colonoscopy with tissue biopsies
Differential diagnosis Dysentery, Crohn's disease, ischemic colitis
Treatment Dietary changes, medication, surgery
Medication Sulfasalazine, mesalazine, steroids, immunosuppressants such as azathioprine, biological therapy
Frequency Up to 5 per 1000 people
Deaths 47,400 together with Crohn's (2015)

Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are 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. Complications may include megacolon, inflammation of the eye, joints, or liver, and colon cancer.

The cause of UC is unknown. Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors. Rates tend to be higher in the developed world with some proposing this to be the result of less exposure to intestinal infections, or to a Western diet and lifestyle. The removal of the appendix at an early age may be protective. 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.

Dietary changes, such as maintaining a high-calorie diet or lactose-free diet, may improve symptoms. Several medications are used to treat symptoms and bring about and maintain remission, including aminosalicylates such as mesalazine or sulfasalazine, steroids, immunosuppressants such as azathioprine, and biologic 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. Removal of the colon and rectum can cure the disease.

Together with Crohn's disease, about 11.2 million people were affected as of 2015. Each year it newly occurs in 1 to 20 per 100,000 people, and 5 to 500 per 100,000 individuals are affected. The disease is more common in North America and Europe than other regions. Often it begins in people aged 15 to 30 years, or among those over 60. Males and females appear to be affected in equal proportions. It has also become more common since the 1950s. Together, ulcerative colitis and Crohn's disease affect about a million people in the United States. With appropriate treatment the risk of death appears the same as that of the general population. The first description of ulcerative colitis occurred around the 1850s.

Contents[edit]

Signs and symptoms[edit][edit]

Signs and symptoms
Crohn's disease Ulcerative colitis
Defecation Often porridge-like,

sometimes steatorrhea

Often mucus-like

and with blood

Tenesmus Less common More common
Fever Common Indicates severe disease
Fistulae Common Seldom
Weight loss Often More seldom

The clinical presentation of ulcerative colitis depends on the extent of the disease process. Patients usually present with severe abdominal pain and tenderness, abdominal guarding, fever, leukocytosis, or high level of white blood cells, and abdominal distention[1]. 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.  Colicky, or abrupt, sharp, localized, abdominal pain is usually described in patients with this diagnosis[1].

The most common symptom of active ulcerative colitis is bloody diarrhea[2].  Urgency and tenesmus, which is a constant feeling of the need to empty the bowel accompanied by involuntary straining efforts, pain, and cramping with little or no fecal output, are also classic signs of UC[3]. The inflammation caused by the disease along with the chronic bleeding from the GI tract leads to increased rates of anemia, especially in the elderly[1]. Although rare[3], patients may also have weight loss due to malabsorption[1]. A patient with UC can have fluid loss of about 500 to 2,000 mL over 24 hours causing severe dehydration[1]. Its pattern of remission and exacerbations sometimes requires hospitalizations in 15% of patients[1]. 

Ulcerative colitis is associated with a general inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease, such as painful arthritic knees in teenagers, which also may be seen in adults. A diagnosis of UC may not occur until the onset of intestinal manifestations, however.

Extra-intestinal features[edit][edit]

Although extra-intestinal manifestations are less common presenting features, they can occur in 20-40% of patients throughout the course of their disease[2]. Primarily, UC can affect the skin, joints, eyes, and liver[3].

As UC 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 extra-intestinal manifestations has been reported as between 6 and 47%, and include:

Extent of involvement[edit][edit]

Ulcerative colitis is normally continuous from the rectum up the colon. UC only affects the upper layers of the intestinal wall of the large intestine[1]. The disease is classified by the extent of involvement, depending on how far the disease extends:

  • Proctitis: Involvement limited to the rectum[3]
  • Proctosigmoiditis: Involvement of the rectum and sigmoid colon, the portion of the colon adjacent to the rectum.[3]
  • Left-sided colitis: Involvement of the descending colon, which runs along the patient's left side, up to the splenic flexure and the beginning of the transverse colon; does not extend beyond the splenic flexure[3]
  • Extensive colitis: beyond the splenic flexure[3]
    • Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins

    Severity of disease[edit][edit]

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

    • Mild disease correlates with fewer than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)[3]. Mild abdominal pain or cramping may occur. Patients may believe they are constipated when in fact they are experiencing tenesmus, Rectal pain is uncommon.
    • Moderate disease correlates with more than four stools daily, but with minimal signs of toxicity[3]. Patients may display anemia (not requiring transfusions), moderate abdominal pain, and low-grade fever, 38 to 39 °C (100 to 102 °F).
    • Severe disease correlates with more than six bloody stools a day or observable massive and significant bloody bowel movement, and evidence of toxicity as demonstrated by fever, tachycardia, anemia or an elevated ESR or CRP[3].
    • Fulminant disease correlates with more than 10 bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation (expansion).[3] Patients in this category may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. If the serous membrane is involved, a colonic perforation may ensue. Unless treated, the fulminant disease will soon lead to death.

    Causes[edit][edit]

    No direct causes for UC are known, but many possible factors such as genetics and stress play a role.

    Genetic factors[edit][edit]

    It has been long speculated based from previous studies the involvement of genes as a factor resulting to UC. It is noteworthy to recall the patients with UC reported of certain family history of UC. About 240 genetic variants were reported in connection with IBD in general. These reported variants were found to participate in various factors that can cause injury to the cells to include inborn and acquired immunity, cells consuming its own, and imbalanced bacterial control. Previous studies purported the speculation on this theory. Over the years it has been perceived that IBD is hereditary. This has been a challenge to many previous studies to conclude a concrete basis on this hypothesis. As early as the 1960s, a study by Kirsner and Spencer on familial aggregation denoted that genetic and environmental factors causing IBD. Although in the same study also showed that UC and more specifically CD families is more prevalent depending on the locality and severity of the disease. It has been reported as well the high prevalence of IBD among monozygotic twins compared with dizygotic twins.[7]

    The concept of genetic factor or familial tendencies with IBD was first noted in a study in 1960s by Kirsner and Spencer. A European study in 1988 proposed the connection of genes among mono zygotic twins with UC with a 15.4% proband concordance compared to 3.9% dizygotic twins. From the same report, first degree relatives of patient with UC among Jewish people have high life time risk compared to the non Jewish people.[7]

    Twelve regions of the genome may be linked to UC, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, but none of these loci has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease.

    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. Human leukocyte antigen associations may even be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.

    Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including UC, 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 the use of potential porphyrinogenic drugs, including sulfasalazine.

    Environmental factors[edit][edit]

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

    • Diet: As the colon is exposed to many dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohn's disease. Few studies have investigated such an association; one study showed no association of refined sugar on the prevalence of ulcerative colitis. High intake of unsaturated fat and vitamin B6 may enhance the risk of developing ulcerative colitis. Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. One factor in UC inflammation is triggered by the presence of toxins called H2S (Hydrogen Sulfide). This has resulted from the dietary intake of sulfur and also the presence of SRB (Sulfur Reducing Bacteria). The occurrence of inflammation in UC typically starts from the rectum all the way to the proximal colon. One study hypothesized this occurs due to the presence of toxins destroying the gut barrier and triggers an inflammatory process, resulting in ulceration.[8]Sulfur restricted diets have been investigated in patients with UC and animal models of the disease.
    • Breastfeeding: Some reports of the protection of breastfeeding in the development of IBD contradict each other. One Italian study showed a potential protective effect.
    • One study of isotretinoin found a small increase in the rate of UC.

    Autoimmune disease[edit][edit]

    The GI tract is long that starts from the mouth down to the rectum. Part of this long tract is the large intestine or the lower GI tract that comprises the appendix, cecum, colon, and rectum. It is in the colon where the wastes materials are converted to stool.  Inside the colon are cell linings that serve as protective barriers against various irritants like food antigens and other organisms like bacteria and viruses. Also present are organisms like bacteria that are normally found in the colon. The balance inside the colon is primarily directed by its immune system. Once there is an imbalance inside the colon, this triggers an inflammatory response called inflammatory bowel disease (IBD). IBD is a relapsing and lingering inflammatory condition. Crohn's disease (CD) and ulcerative colitis(UC) are common IBD conditions.

    Over the years there are various studies hypothesizing the causation of UC. To date, it remained to have no known cause, although several factors were pointed out that could trigger its onset, relapse, and exacerbation. The presence of the overactive immune system in the colon has been theorized that could trigger UC. The colon's inner lining is protected with epithelial cells called colonocytes and mucous barrier cells. The development of UC (pathogenesis) is when there is damage in the inner lining of the colon causes an immense inflammatory response resulting to ulcerations which can extend from the rectum all the way to the proximal part of the colon. [9][10]

    Several studies denoted the imbalance of the colon's immune system as a factor that can trigger UC. The cell linings inside the colon are protective in nature against harmful irritants. Present as well in the colon are organisms which is their natural habitat. Because of the complexity of the gastrointestinal tract's immune system in order to maintain balance, it utilizes both it is natural and acquired immunity to balance inside the colon. The over-reaction of the gut's immune systems to harmful irritants causes its own immunity to injure the protective lining of the intestines, thus producing inflammation and resulting in symptoms. The innate immunity releases neutrophils as protection, which in turn causes the release of toxins and free radicals causing injury to the lining of the colon. There are also high amounts of cytokines in UC which is brought about by the activation of the T helper cells which causes further damage to the protective epithelial barrier.[9][10][11][12][13]

    In another study, UC is caused by atypical T helper cell (Th) type 2. The non-classic natural killer T cells and cytokines like the tumor killer necrosis factor (TNF) were also reported as part of the pathogenesis in UC.[12]

    Alternative theories[edit][edit]

    One study reported few environmental factors that may contribute to getting UC, although the chance is minimal. These factors are medications like non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. There is also a slim chance of getting UC with high-fat diet. Stress and being in any emotional distress were also contributing factor although stress is more seen during flare-ups.

    Risk factors
    Crohn's disease Ulcerative colitis
    Smoking Higher risk for smokers Lower risk for smokers
    Age Usual onset between

    15 and 30 years

    		Peak incidence between

    15 and 25 years

    Infection by mycobacterium avium, subspecies paratuberculosis, has been proposed as the ultimate cause of both ulcerative colitis and Crohn's disease.

    Pathophysiology[edit][edit]

    The characteristic chronic inflammation of the colon and rectum that develops in ulcerative colitis (UC) is typically idiopathic in origin. However, the onset of UC is associated with flares of refractory inflammation as a result of abnormal immune function.[1] Genetically susceptible individuals express an altered systemic response to bacterial colonization, specifically in the colon.[14] Genetic mutation of host cellular structure and immune response can expose an individual to the mucosal damage evident in UC. For example, alteration of a host’s innate immunity can occur via a structurally deficient colonic epithelial tissue layer. This genetic mutation allows bacteria to bypass the protective epithelium of colonic mucosa and activate antigen-presenting cells called dendritic cells. Similarly, particular genes can also influence an exaggerated host adaptive immune response to various microbes in the colon.[14]

    Despite multiple causes, the underlying biochemical processes that contribute to the overreactive immune response apparent in UC are relatively well-understood. The pathophysiology of this autoimmune disease is extremely complex and involves a comprehensive understanding of innate and adaptive immunity in the human body.

    Innate immunity represents the human body’s first line protection against various antigens, including malignant cells, allergens, microbes, and other foreign substances. Antigens enter the human body via contact with the epithelial cells of the skin and mucosa. These tissues contain the body’s natural microbial population, which is called normal flora. Normal flora consists of benign microorganisms that assist in preventing antigen infiltration of the epithelium. In addition, innate immunity recruits the specialized white blood cells of monocytes and lymphocytes. These consist of macrophages (specialized white blood cells) and natural killer cells, respectively.[1]

    Macrophages initiate the cascade inflammatory response noted in an acute provocation of the host immune system. A macrophage is a type of antigen-presenting cell (APC), which mediates this inflammatory response through phagocytosis. Macrophages engulf antigens and induce apoptosis, which is programmed cell death.[15] Macrophages also secrete protective enzymes and molecules to neutralize antigens directly and indirectly through inflammatory mediators. Hydrolytic enzymes, oxidative molecules, and various cytokines overlap in function to activate direct and indirect destruction of antigens. Inflammatory mediators or cytokines, such as tumor necrosis factor-alpha (TNFα), interleukins, and prostaglandins, play an essential role in acute and chronic inflammation. Inflammatory mediators are responsible for the biochemical reactions in inflammation, such as white blood cell aggregation, proliferation, activation, and differentiation.[1]

    Natural killer cells provide a direct response to antigens, possessing the ability to incite immediate damage.

    Conversely, the adaptive immune system requires prior exposure to an antigen before acquiring the ability to invoke an immediate and specific immune response. The precise and reactive characteristics of adaptive immunity are dependent upon antigen interaction with a human cell, specifically the lymphocyte. Human leukocyte antigens (HLAs) are endogenous to the human body and present on all cell surfaces.[16] The lymphocyte differentiates during maturation to develop diverse cellular functions to recognize, distinguish, and react to exogenous or endogenous antigens.[1] The process of tolerance also occurs during lymphocyte maturation. Tolerance involves the multiple mechanisms used to destroy self-reactive lymphocytes.[15]

    Lymphocytes maturating from the thymus gland are called T lymphocytes (T cells). Mature lymphocytes generated from the bone marrow, spleen, and lymph nodes are called B lymphocytes.[1] Cluster of differentiation (CD) antigens are a type of HLA that develop on the surface of mature T cells and assist in their categorization and roles in adaptive immunity. CD4 cells (T helper cells) mediate both cellular and antibody immune responses. CD8 cells (cytotoxic T cells) neutralize antigens directly via cytolysis and apoptosis, which results in cell death. Antigen-presenting cells (APCs) include macrophages and dendritic cells. The APC’s initial contact and processing of antigens are required to activate T cells. The activation of this adaptive immune pathway is codependent upon the release of proinflammatory mediators by APCs and T cells.[16]

    The pathophysiology of adaptive cell-mediated immunity is critical to understanding the pathogenic features of ulcerative colitis. Ulcerative colitis is a type of cell-mediated hypersensitivity reaction. This reaction is precipitated by immune dysfunction, which causes host tissue injury in susceptible individuals.[15] In ulcerative colitis, self-reactive T cells produce a hypersensitive inflammatory reaction to HLAs, in this case, designated autoantigens.

    Regardless of the causative antigen, in UC, constant stimulation of T cells results in the dysregulation of proinflammatory mediators.[17] In acute inflammation, these “intermediary intercellular protein signals”[17] maintain homeostasis of various immune system processes. During chronic inflammation, the systemic maintenance of immunosuppressive and proinflammatory mediators active during the immune response is disrupted.[18] In UC, chronic inflammation is caused by disproportionately active proinflammatory mediators, such as TNFα, which lose their protective properties of cellular regeneration and healing necessary in acute tissue injury.[1] The aggregation of byproducts produced by the proinflammatory cellular and chemical cascade induces colonic epithelial cell damage. These byproducts include cytokines, free radicals, proteases, angiogenesis growth factors, and fibroblast activators.[1] Other adverse effects of chronic intestinal inflammation include altered cellular differentiation, degeneration of secretory cells of the mucosal barrier, increased mucosal barrier permeability to antigens, mucosal dysfunction, necrosis, and cell death.[18]

    Diagnosis[edit][edit]

    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:

    Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.

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

    Endoscopic[edit][edit]

    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:

    • Loss of the vascular appearance of the colon
    • Erythema (or redness of the mucosa) and friability of the mucosa
    • Superficial ulceration, which may be confluent, and
    • Pseudopolyps.

    Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. 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[edit][edit]

    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[edit][edit]

    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:

    • Crohn's disease
    • Infectious colitis, which is typically detected on stool cultures
    • Ischemic colitis, inadequate blood supply to the intestine, which typically affects the elderly
    • Radiation colitis in patients with previous pelvic radiotherapy
    • Chemical colitis resulting from the introduction of harsh chemicals into the colon from an enema or other procedure.
    • Malignancy – Cancer may present as acute flare of colitis or vice versa. It is important to rule out malignancy especially when the colitis is refractory to the treatment.

    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 their courses and treatments may differ. 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
    Involvement around

    the anus

    		Common Seldom
    Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate
    Distribution of disease Patchy areas of inflammation (skip lesions) Continuous area of inflammation
    Endoscopy Deep geographic and serpiginous (snake-like) ulcers Continuous ulcer
    Depth of inflammation May be transmural, deep into tissues Shallow, mucosal
    Stenosis Common Seldom
    Granulomas on biopsy May have non-necrotizing non-peri-intestinal crypt granulomas Non-peri-intestinal crypt granulomas not seen

    Management[edit][edit]

    Main article: Management of ulcerative colitis

    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. 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 remission, which involves relief of symptoms and mucosal healing of the colon's lining, and then longer term treatment to maintain remission and prevent complications. Acute severe ulcerative colitis requires hospitalisation, exclusion of infections, and corticosteroids.

    For acute stages of the disease, a low fiber diet may be recommended.

    Medication[edit][edit]

    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 immunosuppressive 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. Such treatments are used less commonly due to their possible risk factors, including but not limited to increased risk of cancers in teenagers and adults, 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. Tofacitinib was approved for treatment of moderately to severely active ulcerative colitis in 2018 in the US, the first oral medication indicated for long term use in this condition. The evidence on methotrexate does not show a benefit in producing remission in people with ulcerative colitis. Off-label use of drugs such as ciclosporin and tacrolimus has shown some benefits. Fexofenadine, an antihistamine drug used in treatment of allergies, has shown promise in a combination therapy in some studies. 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[edit][edit]

    Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, it was shown that 5-aminosalicylic acid (5-ASA, mesalazine/mesalamine) was the therapeutically active component in sulfasalazine. Many 5-ASA drugs have been developed with the aim of delivering the active compound to the large intestine to maintain therapeutic efficacy but with reduction of the side effects associated with the sulfapyridine moiety in sulfasalazine. Oral 5-ASA drugs are particularly effective in inducing and in maintaining remission in mild to moderate ulcerative colitis. Rectal suppository, foam or liquid enema formulations of 5-ASA are used for colitis affecting the rectum, sigmoid or descending colon, and have been shown to be effective especially when combined with oral treatment.

    Biologics[edit][edit]

    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. 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, 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[edit][edit]

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

    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. 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[edit][edit]

    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 anemia with blood tests repeated every three months in active disease and annually in quiescent disease. 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. Others require oral iron to be used first, as patients eventually respond and many will tolerate the side effects. All guidelines advise that parenteral iron should be administered in cases of severe anemia (a hemoglobin level less than 100 g/L).

    Surgery[edit][edit]

    Management
    Crohn's disease Ulcerative colitis
    Mesalazine Less useful More useful
    Antibiotics Effective in long-term Generally not useful
    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.

    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[edit][edit]

    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. Results from small trials have been tentatively positive.

    Bacterial recolonization[edit][edit]

    • In a number of randomized clinical trials, probiotics have demonstrated the potential to be helpful in the treatment of ulcerative colitis. Specific types of probiotics such as Escherichia coli Nissle have been shown to induce remission in some patients for up to a year. Another type of probiotic that is said to have a similar effect is Lactobacillus acidophilus.[citation needed] The probiotics are said to work by calming some of the ongoing inflammation that causes the disease, which in turn allows the body to mobilize dendritic cells, otherwise known as messenger immune cells. These cells then are able to produce other T-cells that further aid in restoring balance in the intestines by rebalancing systematic inflammation.
    • Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas. Ulcerative colitis typically requires a more prolonged bacteriotherapy treatment than Clostridium difficile infection to be successful, possibly due to the time needed to heal the ulcerated epithelium. The response of ulcerative colitis is potentially very favorable with one study reporting 67.7% of sufferers experiencing complete remission. It suggests that the cause of ulcerative colitis may be a previous infection by a still unknown pathogen. This initial infection resolves itself naturally, but somehow causes an imbalance in the colonic bacterial flora, leading to a cycle of inflammation which can be broken by "recolonizing" the colon with bacteria from a healthy bowel. There have been several reported cases of patients who have remained in remission for up to 13 years.

    Alternative medicine[edit][edit]

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

    • Melatonin may be beneficial according to in vitro research, animal studies, and a preliminary human study.
    • Dietary fiber, meaning indigestible plant matter, has been recommended for decades in the maintenance of bowel function. Of peculiar note is fiber from brassica, which seems to contain soluble constituents capable of reversing ulcers along the entire human digestive tract before it is cooked.
    • Fish oil, and eicosapentaenoic acid (EPA) derived from fish oil, inhibits leukotriene activity, the latter which may be a key factor of inflammation. As an IBD therapy, there are no conclusive studies in support and no recommended dosage. But dosages of EPA between 180 and 1500 mg/day are recommended for other conditions, most commonly cardiac. Fish oil also contains vitamin D, of which many people with IBD are deficient.
    • Short chain fatty acid (butyrate) enema. The epithelial cells in the colon uses butyrate from the contents of the intestine as an energy source. The amount of butyrate available decreases toward the rectum. Inadequate butyrate levels in the lower intestine have been suggested as a contributing factor for the disease. This might be addressed through butyrate enemas. The results however are not conclusive.[citation needed]
    • Herbal medications are used by patients with ulcerative colitis. Compounds that contain sulfhydryl may have an effect in ulcerative colitis (under a similar hypothesis that the sulfa moiety of sulfasalazine may have activity in addition to the active 5-ASA component). One randomized control trial evaluated the over-the-counter medication S-methylmethionine and found a significant decreased rate of relapse when the medication was used in conjunction with oral sulfasalazine.
    • Helminthic therapy is the use of intestinal parasitic nematodes to treat ulcerative colitis, and is based on the premises of the hygiene hypothesis. Studies have shown that helminths ameliorate and are more effective than daily corticosteroids at blocking chemically induced colitis in mice, and a trial of intentional helminth infection of rhesus monkeys with idiopathic chronic diarrhea (a condition similar to ulcerative colitis in humans) resulted in remission of symptoms in 4 out of 5 of the animals treated. A randomised controlled trial of Trichuris suis ova in humans found the therapy to be safe and effective, and further human trials are ongoing.
    • Curcumin (turmeric) therapy, in conjunction with taking the medications mesalamine or sulfasalazine, may be effective and safe for maintaining remission in people with quiescent ulcerative colitis. The effect of curcumin therapy alone on quiescent ulcerative colitis is unknown.

    Prognosis[edit][edit]

    Complications
    Crohn's

    disease

    		Ulcerative

    colitis

    Nutrient deficiency Higher risk
    Colon cancer risk Slight Considerable
    Prevalence of extraintestinal complications
    Iritis/uveitis Females 2.2% 3.2%
    Males 1.3% 0.9%
    Primary sclerosingcholangitis Females 0.3% 1%
    Males 0.4% 3%
    Ankylosingspondylitis Females 0.7% 0.8%
    Males 2.7% 1.5%
    Pyodermagangrenosum Females 1.2% 0.8%
    Males 1.3% 0.7%
    Erythema nodosum Females 1.9% 2%
    Males 0.6% 0.7%

    Progression or remission[edit][edit]

    This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2012) (Learn how and when to remove this template message)

    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[edit][edit]

    The risk of colorectal cancer is significantly increased in patients with ulcerative colitis after ten years if involvement is beyond the splenic flexure. Those patients with only proctitis or rectosigmoiditis usually have no increased risk. 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.

    Primary sclerosing cholangitis[edit][edit]

    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.

    Mortality[edit][edit]

    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. It is thought that the disease primarily affects quality of life, and not lifespan.

    Other long-term features[edit][edit]

    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.

    Epidemiology[edit][edit]

    The geographic distribution of UC and Crohn's disease is similar worldwide, with the highest number of new cases a year of UC found in Canada, New Zealand and the United Kingdom. It begins most commonly between the ages of 15 and 25. A second peak of onset is the 6th decade of life. In general, higher rates are seen in northern locations compared to southern locations in Europe and the United States.

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

    United States[edit][edit]

    As of 2004, the number of new cases of UC in the United States is between 2.2 and 14.3 per 100,000 per year. The number of people affected in the United States is between 37 and 246 per 100,000.

    Canada[edit][edit]

    In Canada, between 1998 and 2000, the number of new cases per year was 12.9 per 100,000 population or 4,500 new cases. The number of people affected was estimated to be 211 per 100,000 or 104,000.

    United Kingdom[edit][edit]

    In the United Kingdom 10 per 100,000 people newly develop the condition a year while the number of people affected is 243 per 100,000. Approximately 146,000 people in the United Kingdom have been diagnosed with UC.

    Research[edit][edit]

    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. 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.

    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. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. 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. This suggests that ICAM-1 is a potential therapeutic target in the treatment of ulcerative colitis.

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

    A series of drugs in development looks to disrupt the inflammation process by selectively targeting an ion channel in the inflammation signaling cascade known as KCa3.1. In a preclinical study in rats and mice, inhibition of KCa3.1 disrupted the production of Th1 cytokines IL-2 and TNF-∝ and decreased colon inflammation as effectively as sulfasalazine.

    Notable cases[edit][edit]

    Main article: List of people diagnosed with ulcerative colitis

    References[edit]

    1. ^ a b c d e f g h i j k l m n Capriotti, Theresa (2016). Pathophysiology: Introductory Concepts and Clinical Perspectives. Frizzell, Joan. Philadelphia: F.A. Davis. ISBN 9780803615717.
    2. ^ a b c d e f g h i j k Andrews, Charlie (2019). "Ulcerative colitis". InnovAiT: Education and inspiration for general practice. 12 (9): 501–506. doi:10.1177/1755738019856030. ISSN 1755-7380.
    3. ^ a b c d e f g h i j k l m n Feuerstein, Joseph D.; Cheifetz, Adam S. (2014-11-01). "Ulcerative Colitis: Epidemiology, Diagnosis, and Management". Mayo Clinic Proceedings. 89 (11): 1553–1563. doi:10.1016/j.mayocp.2014.07.002. ISSN 0025-6196. PMID 25199861.
    4. ^ "Ankylosing Spondylitis : Symptoms, Diagnosis and Treatment". Johns Hopkins Arthritis Center. Retrieved 2019-11-07.
    5. ^ "Sacroiliitis - Symptoms and causes". Mayo Clinic. Retrieved 2019-11-07.
    6. ^ "Primary Sclerosing Cholangitis - Symptoms, Causes, and Treatment". American Liver Foundation. Retrieved 2019-11-07.
    7. ^ a b Park, Sung Chul; Jeen, Yoon Tae (May 1, 2019). "Genetic Studies of Inflammatory Bowel Disease-Focusing on Asian Patients". Cells. 8 (5). doi:10.3390/cells8050404. ISSN 2073-4409. PMC 6563043. PMID 31052430.{{cite journal}}: CS1 maint: unflagged free DOI (link)
    8. ^ Teigen, Levi M.; Geng, Zhuo; Sadowsky, Michael J.; Vaughn, Byron P.; Hamilton, Matthew J.; Khoruts, Alexander (2019-04-25). "Dietary Factors in Sulfur Metabolism and Pathogenesis of Ulcerative Colitis". Nutrients. 11 (4). doi:10.3390/nu11040931. ISSN 2072-6643. PMC 6521024. PMID 31027194.{{cite journal}}: CS1 maint: unflagged free DOI (link)
    9. ^ a b "Ulcerative Colitis | NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 2019-10-16.
    10. ^ a b Ungaro, Ryan; Mehandru, Saurabh; Allen, Patrick B.; Peyrin-Biroulet, Laurent; Colombel, Jean-Frédéric (April 29, 2017). "Ulcerative colitis". Lancet (London, England). 389 (10080): 1756–1770. doi:10.1016/S0140-6736(16)32126-2. ISSN 1474-547X. PMC 6487890. PMID 27914657.
    11. ^ Kim, Duk Hwan; Cheon, Jae Hee (February 2017). "Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies". Immune Network. 17 (1): 25–40. doi:10.4110/in.2017.17.1.25. ISSN 1598-2629. PMC 5334120. PMID 28261018.
    12. ^ a b Wan, Ping; Chen, Hao; Guo, Yuan; Bai, Ai-Ping (2014-10-21). "Advances in treatment of ulcerative colitis with herbs: From bench to bedside". World Journal of Gastroenterology : WJG. 20 (39): 14099–14104. doi:10.3748/wjg.v20.i39.14099. ISSN 1007-9327. PMC 4202341. PMID 25339799.{{cite journal}}: CS1 maint: unflagged free DOI (link)
    13. ^ Chen, Wei-Xu; Ren, Li-Hua; Shi, Rui-Hua (2014-11-14). "Enteric microbiota leads to new therapeutic strategies for ulcerative colitis". World Journal of Gastroenterology : WJG. 20 (42): 15657–15663. doi:10.3748/wjg.v20.i42.15657. ISSN 1007-9327. PMC 4229530. PMID 25400449.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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    15. ^ a b c Actor, J. K. (2019). Introductory immunology : basic concepts for interdisciplinary applications (Second ed.). Academic Press. ISBN 9780128165720.
    16. ^ a b Justiz Vaillant, Angel A.; Zulfiqar, Hassam; Ramphul, Kamleshun (2019). "Delayed Hypersensitivity Reactions". StatPearls. StatPearls Publishing.
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    18. ^ a b Rogler, G.; Herfarth, H.; Hibi, T.; Nielsen, O.H., eds. (2015). Anti-tumor necrosis factor therapy in inflammatory bowel disease. ISBN 978-3-318-05474-3.
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