Ulcerative colitis is an idiopathic inflammatory condition of the large intestine (colon), which results in diffuse friability and superficial erosions on the colonic wall associated with bleeding.
It is the most prevalent form of inflammatory bowel disease worldwide.
It characteristically involves inflammation confined to the mucosa and submucosa of the colon.
Typically, the disease starts in the rectum and can extend continuously to proximal segments of the colon.
Its pathogenesis is multifactorial and involves genetic predisposition, epithelial barrier defects, dysregulated immune responses, gut microflora alterations, and environmental factors.
Ulcerative colitis usually manifests with bloody diarrhea and is diagnosed by colonoscopy and histological findings.
Treatments for ulcerative colitis include 5-aminosalicylic acid drugs (i.e., sulfasalazine, mesalamine, balsalazide), steroids (i.e., prednisone, budesonide), and immunosuppressants (i.e, tacrolimus, azathioprine). Some patients may require surgery (colectomy) for medically refractory (non-responsive) disease or to treat colonic neoplasia (tumor in the colon).
The therapeutic arsenal for ulcerative colitis is expanding, and the number of drugs with new targets are rapidly increasing.
Since there is no cure for the disease, the aim of management includes inducing and then maintaining remission, defined as resolution of symptoms and endoscopic healing.Many of them have not been evaluated for human safety, yet we encounter them daily.
In the United States, ulcerative colitis accounts for 250,000 physician visits annually, and medical costs directly associated with the disease are estimated to exceed four billion dollars annually [1, 2, 3].
Worldwide, the highest incidence and prevalence of inflammatory bowel diseases are found in Northern Europe, Australia, and North America.
Inflammatory bowel disease is closely related to a westernized environment and lifestyle.
Ulcerative colitis (UC) has an incidence of 9 to 20 cases per 100,000 people per year (number of new cases annually).
Its prevalence is 156 to 291 cases per 100,000 people per year (number of UC patients on an annual basis).
Compared to Crohn’s disease, ulcerative colitis (UC) is more frequent in adults.
When considering the children’s population, however, ulcerative colitis is less prevalent than Crohn’s disease.
The primary onset peaks between the ages of 15 and 30 years.
A second and smaller peak of incidence occurs between the ages of 50 and 70 years.
There is an increased prevalence of ulcerative colitis in non-smokers or those who recently quit smoking.
Additionally, smokers diagnosed with ulcerative colitis tend to have milder symptoms, fewer hospitalizations, and require less medication.
There is weak evidence that non-steroidal anti-inflammatory drug use is connected with the onset or relapse of ulcerative colitis.
There is also an association of inflammatory bowel disease (IBD) with the removal of an inflamed appendix (appendectomy).
Appendectomy before the age of twenty is associated with a decreased risk of incidence of ulcerative colitis (UC), whereas the opposite is true for Crohn’s disease.
Worldwide, the incidence and prevalence of ulcerative colitis have been increasing over time .
Colonic epithelial cells (colonocytes), mucous barrier, and epithelial barrier defects are strongly implicated in the pathogenesis of ulcerative colitis.
The expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a negative regulator of NF-κB-dependent inflammation, is reduced in colonocytes of UC patients suggesting a causal link [12, 13].
Existing PPAR-γ agonist drugs are prohibited, due to side-effects of cardiac and metabolic toxicity.
However, comparable, innovative 5-aminosalicylic acid (5-ASA) drugs with greater PPAR-γ agonistic activity are being developed .
Autoantibodies against colonocyte-associated tropomyosins have been documented in ulcerative colitis , but conclusive evidence classifying ulcerative colitis as an autoantibody-mediated disease is scarce.
Colonocyte-associated defects within XBP1, a key component of the endoplasmic reticulum stress response pathway, have been reported .
Alterations in trefoil factors (TFF), a family of goblet cell-derived proteins/peptides that are produced in response to mucosal injury and contribute to the integrity of the mucosal barrier, have also been documented [17, 18].
The argument that gut barrier function defects are the primary drivers of disease is supported by the fact that patients with active UC have depleted colonic goblet cells (mucus-secreting cells) and a permeable mucus barrier .
This makes sense, since the glycoproteinogenic make-up of mucus protects the intestinal mucosa and often times serves as substrate for colonic bacteria, especially in the chronic absence of dietary carbohydrate ingestion.
The epithelial barrier of UC patients has a defect in colonic mucin (the chief component of mucus- a “slimy” material that coats most epithelial surfaces), and possibly in tight junctions, leading to increased uptake of luminal antigens (which can set-off an immune response).
The lamina propria (connective tissue beneath the gastrointestinal tract epithelium) and colonocytes of UC patients also show an increased number of activated and mature dendritic cells, which include large numbers of Toll-like receptors (TLR), specifically TLR2 and TLR4.
It is unclear if that non-physiologic increase in the expression of Toll-like receptors (TLR) is a cause or consequence of mucosal inflammation .
Similarly, TLR4 polymorphisms have been reported in patients with ulcerative colitis and Crohn’s disease, but their effects on disease pathogenesis are not known .
In addition, activated neutrophils tend to accumulate in the blood and colonic tissue of patients with active ulcerative colitis, compared with healthy controls .
Innate lymphoid cell activation might be fundamental in the pathogenesis of inflammatory bowel disease (IBD).
Type 3 innate lymphoid cells (ILC3), in particular, are major mediators of chronic intestinal inflammation .
Furthermore, innate lymphoid cells (ILCs) isolated from patients with active ulcerative colitis show increased gene expression of key ILC3 cytokines (IL17A and IL22), transcription factors (RORC and AHR), and cytokine receptors (including IL23R) .
The possibility that innate lymphoid cells (ILCs) might be drivers of disease pathogenesis has led to a number of potential novel therapeutic targets.
Additionally, current evidence implicates both innate and adaptive cellular immunity as key factors to the pathogenesis of ulcerative colitis (UC).
There seems to be an abnormal T-helper (Th) cell response in patients with ulcerative colitis, specifically Th2, which exerts a cytotoxic (cell- poisoning) effect against epithelial cells.
This causes destruction of the colonic mucosal epithelium.
Earlier evidence suggested that ulcerative colitis (UC) is a modified T-helper-2 (Th2) disease, while Crohn’s disease is Th1 driven.
In support, colonic lamina propria cells from patients with UC were found to contain Th2-polarised T cells that produce interleukin-5 (IL-5) .
Additionally, interleukin-4 (IL-4) and interleukin-13 (IL-13) mRNA levels were significantly increased in rectal biopsies from patients with ulcerative colitis compared with healthy controls .
Subsequent data have further suggested IL-13 playing a role in the onset of ulcerative colitis. IL-13, produced by non-classical natural killer T cells (possibly a member of the ILC family), is a key mediator of epithelial cytotoxicity and gut barrier dysfunction present in UC [27, 28].
Other immune-related factors that represent a role in UC pathophysiology include tumor necrosis factor-alpha (TNF-alpha), Interleukin 13 (IL-13), and natural killer T-cells (NK cells).
Levels of immunoglobulins- IgM, IgA, and IgG are also elevated, however, a disproportionate increase in IgG1 antibodies is found in patients diagnosed with ulcerative colitis.
The main symptoms include colon inflammation and bloody diarrhea, with or without mucus.
Ulcerative colitis patients can develop structural and functional damage to their colon, including benign strictures (abnormally narrow sections of the bowel, which can create a back-up of feces), colonic dysmotility (i.e., constipation), and anorectal dysfunction (pelvic floor muscle dysfunction- weakened muscles that support and control the bladder and bowel) .
Most patients with ulcerative colitis (UC) have a relapsing and remitting disease course with periodic flares .
When ulcerative colitis flares are associated with proximal disease extension (inflammation extending proximally from proctitis to left-sided colitis), patients are more likely to need immunosuppressants, biological drugs, or surgery [31, 32].
Factors that typically exacerbate ulcerative colitis (UC) include smoking cessation and non-steroidal anti-inflammatory drug use (NSAIDs).
Age of onset seems to affect the disease course, since patients diagnosed after the age of 60 tend to have milder symptoms compared with younger patients .
Ulcerative colitis that is associated with primary sclerosing cholangitis (PSC), typically manifests itself differently; it tends to be more extensive, milder, and associated with rectal sparing, and so-called backwash ileitis (where the entire colon is inflamed), compared with patients suffering from ulcerative colitis without co-existing primary sclerosing cholangitis.
Other symptoms of UC include urgency or tenesmus (cramping rectal pain), abdominal pain, malaise, weight loss, and fever, depending on the progression and severity of the disease.
The risk for surgery in ulcerative colitis has decreased over the past decades, but is still substantial with the chance of needing surgery within 5 years being 11.6%, and 10 years being 15.6% .
Increased risk factors for surgery (colectomy) include being diagnosed prior to the age of 40, extensive disease, need for systemic steroids, and elevated inflammatory markers (ESR, CRP, leukocytosis).
Patients with ulcerative colitis are also at increased risk of colorectal cancer, but over time this risk has decreased and might be approaching the general population.
Concerning mortality rates, UC patients do not appear to have an overall increased mortality risk compared with the general population, but are more likely to have a disability preventing them from working [37, 38, 39].
There are some extraintestinal symptoms (conditions that affect other parts of the body, apart from the GI system) also present in 10% to 30% of patients with ulcerative colitis (UC).
Extraintestinal manifestations associated with ulcerative colitis include episcleritis (painless eye redness), scleritis (inflammation of the sclera- the white part of the eye), and uveitis (inflammation of the uvea- the middle layer of tissue in the eye wall), peripheral arthropathies (joint pain disorders), erythema nodosum (swollen fat under the skin, causing red bumps and patches), and pyoderma gangrenosum (non-infectious condition that causes large, painful sores/ulcers to develop on the skin, most often on the legs).
Extraintestinal manifestations co-existing with inflammatory bowel diease (IBD), independent of colitis activity, include
- Axial arthropathies (joint disorders affecting the axial joints- joints of the spine, chest, and pelvis)
- Sacroiliitis (inflammation of the sacroiliac joints)
- Ankylosing spondylitis (autoimmune disease that causes spinal pain and stiffness, and over time can cause fusion to some of the small bones in the spine, resulting in a hunched-forward posture).
A significant liver/hepatic extraintestinal manifestation of ulcerative colitis (UC) includes primary sclerosing cholangitis (PSC), associated with a greater risk of colorectal cancer.
Primary sclerosing cholangitis (PSC) is a chronic, progressive disease of the liver and gallbladder marked by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder.
Diagnosis of ulcerative colitis is made clinically with supportive findings on endoscopy, biopsy, and by negative stool examination for infectious agents.
Because colonic infections can produce clinical findings indistinguishable from idiopathic ulcerative colitis, microbiologic examinations for bacterial infection and parasitic infestation (stool culture and Clostridium difficile assay) should be included in the initial evaluation [40, 41].
Patients might present with anemia, iron deficiency, leucocytosis (abnormally high white cell count in the blood), or thrombocytosis ( excessive number of platelets in the blood).
Radiologic examinations are not imperative for the diagnosis, but may be useful.
Patients with longstanding ulcerative colitis may show a “stove-pipe” sign during a double-contrast barium enema.
A “lead-pipe” or “stove-pipe” appearance suggests chronic ulcerative colitis that has resulted in a loss of colonic haustra (small pouches that give the colon its segmented appearance), due to the colon becoming a rigid foreshortened tube.
Endoscopic procedures, such as colonoscopy or proctosigmoidoscopy, may reveal loss of typical vascular pattern, granularity, brittleness, and ulceration, which involve the distal rectum and proceed proximally in a symmetric, continuous, and circumferential pattern.
The disease can range from disease confined to the rectum and sigmoid colon (proctitis) to disease of the entire colon (pancolitis).
Population-based studies show that, upon presentation, proctitis is found in 30% to 60% of patients, left-sided colitis is found in 16% to 45%, and pancolitis is found in 14% to 35%.
Laboratory evaluation will usually reveal an increase in inflammatory markers (ESR, CRP, leukocytosis), especially during an acute flare.
Regardless of the disease stage, 60% to 70% of ulcerative colitis patients are positive for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA).
P-ANCA is also found in small numbers in patients with Crohn’s disease.
In addition to P-ANCA, anti-saccharomyces cerevisiae antibodies (ASCA) are found in both Crohn’s disease and ulcerative colitis, but are more prevalent in Crohn’s disease, therefore testing for both P-ANCA and ASCA has some utility in distinguishing types.
Testing for carcinoembryonic antigen (CEA) can also be helpful in ulcerative colitis as higher levels usually indicate a flare.
Testing for fecal calprotectin also has some utility in the diagnosis of ulcerative colitis, though it is non-specific.
Fecal calprotectin is a very sensitive inflammatory marker and correlates with increased neutrophils in the intestine (intestinal inflammation).
Therefore, it can help rule out inflammatory bowel disease.
Studies show that less than 1% of patients with low fecal calprotectin are likely to suffer from inflammatory bowel disease (IBD).
An endoscopy (colonoscopy) must be performed at some point, which will reveal:
- Fragile mucosa
- Granular mucosa
- Loss of vascular pattern
- Presence of erosions and pseudopolyposis (presence of polyps- projecting masses of newly formed scar tissue that develops from an intestinal wound during the healing phase)
Multiple biopsies should be obtained to confirm the diagnosis.
When a diagnosis of ulcerative colitis is made, the most common classification system used to determine the extent and severity of the disease is the Montreal classification system.
Extent (E) is determined by endoscopic evaluation and includes E1 (Proctitis- affecting the rectum), E2 (left-sided or distal colitis- affecting a proportion of the colorectum distal to the splenic flexure), and E3 (pancolitis- affecting the entire colon).
Symptoms and systemic findings determine severity (S). Severity (S) ranges from S0 (remission) to S3 (severe).
Treatment / Management
The treatment options for patients with ulcerative colitis are based on both the extent of the disease and the severity.
The prognosis (outcome) during the first decade after diagnosis is typically generally good, and most patients go into remission.
Rectal application of medical therapy, via suppository or enema, is usually appropriate for isolated distal disease (proctitis).
However, a rectal application is many times used in combination with systemic therapy to help target the distal colon and therefore decrease tenesmus (cramping rectal pain, usually accompanied by feeling of incomplete evacuation after bowel movements) [7, 44, 45].
First-line therapy in mild to moderate disease is sulfasalazine and 5-aminosalicylates, given orally or rectally, which have a remission rate of about 50%.
Glucocorticoids, orally or rectally, can be added for those who fail to achieve remission within two weeks.
Except for glucocorticoids, all of these medications can be used in the maintenance of remission.
Additionally, there is some evidence that probiotics are useful in attaining remission.
Fecal microbiota transplantation (FMT) also shows great potential in the treatment of ulcerative colitis, as it helps establish healthy gut microbiota diversity.
If patients are non-responsive to glucocorticoids, thiopurines or biological drugs can be added to therapy.
Thiopurines are immunosuppressants, such as azathioprine or 6-mercaptopurine.
Biological drugs include anti-tumor necrosis factor-alpha (TNF-alpha) drugs, such as infliximab, adalimumab, and golimumab.
Infliximab (Remicade) is the most widely used for ulcerative colitis and can be used in severe cases during hospital admissions.
The newest class of biological drugs include anti-adhesion molecule inhibitors, such as vedolizumab (Entyvio), which blocks alpha-4-beta-7 integrin.
Adhesion molecules play an integral role in the migration of leukocytes into inflamed bowel tissue, which in itself is central to the pathogenesis of IBD.
The disruption of adhesion molecule interactions may prove to be effective in UC, due to decreased T-cell recruitment, inhibition of co-stimulatory signals in local T-cell activation, or a combination of both.
Since patients with ulcerative colitis have reduced expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in their colonic cells (colonocytes), future treatments may include PPAR-gamma agonistic activity.
PPAR-gamma is a negative regulator of NF-KB-dependent inflammation.
Drugs with a similar action to 5-aminosalicylic acid (5-ASA) compounds are currently under development, and exhibit greater PPAR-gamma activity.
Cardiotoxicity and metabolic toxicity are limiting factors in the use of already-existing PPAR-gamma agonists.
Colectomy (surgical removal of the colon) can be curative in patients with ulcerative colitis, since the disease is restricted to the colon.
Indications for surgery are failure of medical therapy, intractable fulminant colitis (the most severe form of uncomplicated acute colitis), toxic megacolon (serious colon distension with an inability to remove gas or feces from the body, usually caused by advanced IBD or infections, such as Clostridium difficile colitis), perforation (holes on the walls of the colon), uncontrollable bleeding, intolerable side effects of medications, strictures, unresectable high-grade or multifocal dysplasia, cancer, or growth retardation in children.
From a surgical standpoint, the procedure of choice is proctocolectomy with ileal pouch-anal anastomosis (IPAA), also known as J-pouch surgery.
However, in patients who are ineligible for IPAA, proctocolectomy with ileostomy (surgery that makes a temporary or permanent opening in the bowel, called a stoma) is a viable alternative.
Because of the increased risk of colon cancer, colonoscopy is recommended at regular intervals.
All patients require maintenance therapy and diet modifications to prevent relapse.
Oral aminosalicylates (i.e., mesalazine, sulfasalazine, olsalazine) are the drugs of choice, but others may respond to azathioprine (Imuran) and 6-mercaptopurine (Purinethol).
There are no specific official diet recommendations for patients with ulcerative colitis, but many develop lactose intolerance.
Unlike Crohn’s disease, which can occur anywhere between the mouth and the anus, in UC there is no role for elemental or parenteral nutrition.
Ulcerative colitis is a chronic, idiopathic inflammatory disease of the colon with multifactorial etiology, including reduced microflora diversity , autoimmunity , defects in epithelial barrier immunity, and genetic susceptibility.
It is the most common form of inflammatory bowel disease worldwide. It is characterized by relapsing and remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon.
The goal of therapy is to induce and maintain clinical and endoscopic remission .
Aminosalicylates are the main choice of treatment for mild to moderate ulcerative colitis, topical and systemic steroids are used to treat ulcerative colitis flares, while immunosuppressants and biological drugs are used in moderate to severe disease.
Surgery (colectomy), which is indicated in cases of non-responsive acute severe ulcerative colitis, uncontrolled hemorrhage, perforation, colorectal carcinoma, and dysplastic lesions not amenable to endoscopic removal, is needed in up to 15% of patients, and it is a sign that other treatment options have proven ineffective.
Concerning the risk for malignancies, it is estimated that about 5% of UC patients will develop colorectal cancer over time.
Since ulcerative colitis is a chronic condition with no identified cure, it requires constant, lifetime monitoring, and management.
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About George Kelly
George Kelly M.Sc is a Sports Nutritionist, Functional Nutritional Therapy Practitioner (FNTP), and Metabolic Type expert. He is the CEO and lead author of Metabolic Body.