Ulcerative colitis (UC) is a relapsing, remitting inflammatory disease of the colonic mucosa and submucosa.

The prevalence of UC in the United States is 150200/100,000 of population. A genetic contribution to the disease is indicated by the increased incidence of UC (of 30 to 100 times that of the general poupulation) among firstdegree relative of patients with UC.

The characteristic pathology is one of chronic inflammation characterized by large numbers of lymphocytes and histiocytes in the diseased mucosa and submucosa with an

acute inflammatory infiltrate composed of neutrophils

variably present.

UC: is a form of (IBD). It is a form of colitis, of that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset.

UC is, however, a systemic disease that affects many parts

of the body outside the intestine. Because of the name, IBD is often confused with irritable bowel syndrome ("IBS"), a troublesome, but much less serious condition.

UC is an intermittent disease, with periods of exacerbated symptoms, and periods that are relatively symptom-free.

Although the symptoms of UC can sometimes diminish on

their own, the disease usually requires treatment to go into remission.

Although UC has no known cause, there is a presumed genetic component to susceptibility. The disease may be triggered in a susceptible person by environmental factors. Although dietary modification may reduce the discomfort of a person with the disease, UC is not thought to be caused by dietary factors. Although UC is treated as though it were an autoimmune disease, there is no consensus that it is such.

UC is a systemic disease that affects many parts of the body.

Sometimes the extra-intestinal manifestations of the disease

are the initial signs, such as painful, arthritic knees in a

teenager. It is, however, unlikely that the disease will be

correctly

diagnosed

until

the

onset

of

the

intestinal

manifestations.

The clinical presentation of UC depends on the extent of the

disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset. They also may have signs of weight loss, and blood on rectal examination. The disease is usually accompanied with different degrees of abdominal pain, from mild discomfort to severely painful cramps.

Extent of involvement
UC 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:
Distal colitis, potentially treatable with enemas: Proctitis: Involvement limited to the rectum.

Proctosigmoiditis:
Involvement of the rectosigmoid colon, the portion of the colon adjacent to the rectum. 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.

Extensive colitis, inflammation extending beyond the reach of enemas: Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.

Severity of disease
In addition to the extent of involvement, UC patients 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). There may be mild abdominal pain or cramping. Patients may believe they are constipated when in fact they are experiencing 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. Rectal pain is uncommon.

Moderate disease correlates with more than four stools daily, but with minimal signs of toxicity. Patients may display anemia (not requiring transfusions), moderate abdominal

pain, and low grade fever, 38 to 39 C

Severe disease, correlates with more than six bloody stools a

day, and evidence of toxicity as demonstrated by fever,

tachycardia, anemia or an elevated ESR.

Fulminant disease correlates with more than ten bowel

movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement and colonic dilation. Patients in this category may have severe inflammation extending beyond just the mucosal

layer, causing impaired colonic motility and leading to toxic

megacolon. If the serous membrane is involved, colonic perforation may ensue. Unless treated, fulminant disease will soon lead to death.

Extraintestinal features
As UC is a systemic disease, patients may present with

symptoms and complications outside the colon. These

include the following: aphthous ulcers of the mouth .

Ophthalmic .
Iritis or uveit.

Episcleritis.

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

Musculoskeletal:
Seronegative arthritis, which can be a large-joint oligoa rthritis (affecting one or two joints), or may affect many small joints of the hands and feet Ankylosing spondylitis, arthritis of the spine Sacroiliitis, arthritis of the lower spine

Cutaneous
Erythemanodosum, which is a panniculitis, or inflammation of subcutaneous tissue involving the lower extremities Pyoderma gangrenosum, which is a painful ulcerating lesion involving the skin

Deep venous thrombosis and pulmonary embolism Autoimmune hemolytic anemia

clubbing,
Primary sclerosing cholangitis, or inflammation of the
bile ducts

Similar conditions
The following conditions may present in a similar manner and should be excluded: Crohn's disease Infectious colitis, which is typically detected on stool cultures Pseudom embranous colitis, or Clostridium difficile-ssociated colitis, bacterial upsets often seen following administration of antibiotics Ischemic colitis, inadequate blood supply to the intestine, which typically affects the elderly

Radiation colitis radiotherapy

in

patients

with

previous

pelvic

Chemical colitis resulting from introduction of harsh chemicals into the colon from an enema or other procedure.

Comparison to Crohn's Disease

The most common disease that mimics the symptoms of UC is Crohn's disease, as both are IBD 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.

Comparisons of various factors in Crohn's disease and ulcerative colitis

Crohn's Disease
Involves terminal ileum Commonly

Ulcerative Colitis
Seldom

Involves colon? Involves rectum? Peri-anal involvement

Bile duct involvement? Distribution of Disease

Usually Seldom Commonl

Not associated Patchy areas of inflammation

Always Usually Seldom

Higher rate of Primary sclerosing cholangitis Continuous area of inflammation

Endoscopy
Depth of inflammation

Linear and serpiginous (snake-like) ulcers

May be transmural, deep into tissues

Continuous ulcer
Shallow, mucosal

Comparisons of various factors in Crohn's disease and UC (Cont.)

Fistulae, abnormal passageways between organs Biopsy Commonly Seldom

Can have granulomata

Crypt abscesses and cryptitis

Surgical cure ?

Smoking

Usually cured by removal of colon, can be followed by po uchitis Higher risk for smokers Lower risk for smokers

Often returns following removal of affected part

Autoimmune disease

Generally regarded as an autoimmune disease Lower than ulcerative colitis

No consensus

Cancer risk?

Higher than Crohn's

Endoscopic
The best test for diagnosis of UC remains endoscopy. Full colonoscopy to the cecum and entry into the terminal ileum is attempted only if 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 UC 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.

UC is usually continuous from the rectum, with the

rectum almost universally being involved. There is rarely

peri-anal 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

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.

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

Histologic
Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's diseas, Microbiological samples are typically taken at the time of endoscopy.

The pathology in UC 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 management.

Course and complications

Progression or remission
Patients with UC 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 disease

UC and colorectal cancer

There is a significantly increased risk of colorectal cancer

in patients with UC after 10 years if involvement is beyond

the splenicflexure. Those 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

Primary sclerosing cholangitis (PSC)

UC has a significant association with (PSC), a progressive

inflammatory disorder of small and large bile ducts. As

many as 5% of patients with UC may progress to develop

(PSC).

Mortality
The effect of UC on mortality is unclear, but it is thought that the disease primarily affects quality of life, and not lifespan.

Treatment
Standard treatment for UC depends on 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

maintan the remission.

Current treatments have been effective for many patients with UC but have numerous limitations for patients with modeate to severe disease.

Drugs used
Aminosalicylates are the mainstay of UC pharmacotherapy for induction and

maintenance of remission for patietns with mild to

moderate disease. Sulfasalazine has been a major agent in the therapy of

mild to moderate UC for over 50 years. In 1977 Mastan

S.Kalsi et al determined that 5-aminosalicyclic acid (5-ASA and mesalazine) was the therapeutically active compound in sulfasalazine. 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.

Mesalazine,

also

known

as

5-aminosalicylic

acid,

mesalamine, or 5-ASA. (Asacol, Pentasa, Mezavant, Lialda, and Salofalk). Sulfasalazine, also known as Azulfidine. Balsalazide - Disodium , also known as Colazal.

Olsalazine, also known as Dipentum.

Corticosteroids
It is often required for the one-third of patients who fail to respond to 5-ASAs, But it is not useful for maintenance of remission and carry significnat undesirable side effects, as osteoporosis, glucose intolerance, and increased risk of infection.

Immunosupressive drugs
It have a role in maintenance of remission in moderate to severe UC. Their relatively slow onset of action precludes their use during flares of the disease, and the use of these agents has been reported to potentially increase the risk of lymphoma in patients with IBD. It requires intense monitoring, and may cause irreversible nephrotoxicity, all of which limit its use to severe cases only.

 Mercaptopurine, also known as 6-Mercaptopurine, 6-MP

and Purinethol.

Azathioprine, also known as Imuran, Azasan or Azamun,

which metabolises to 6-MP. Methotrexate. Tacrolimus.

Biological treatment
It refers to the use of medication that is tailored to specifically target an immune or genetic mediator of disease. The, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy; many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms . (Infliximab ,Visilizumab)

Infliximab is known as a "chimeric monoclonal antibody"

(the term "chimeric" refers to the use of both mouse

(murine) and human components of the drug. The drug blocks the action of TNF (tumour necrosis factor alpha) by binding to it and preventing it from signaling the receptors for TNF on the surface of cells.

TNF is one of the key cytokines that triggers and sustains

the inflammation respone.

Visilizumab is a humanized monoclonal antibody. It is being

investigated for use as an immunosuppressive drug in

patients with UC and Crohn's disease. Visilizumab binds to

the CD3 receptor on certain activated T cells without

effecting resting T cells. It is currently under clinical

studies.

The

47

integrin

is

heterodimeric

cell

surface

glycoprotein present on the surface of subsets of circulating memory CD4+ and CD8+T cells and most B cells. It has received particular attention in the context of mucosal immune responses because of its intimate involvement in lymphocyte recruitment to normal

gastrointestinal (GI) mucosa and associated lymphoid

tissue.

This agent inhibits the binding of 47 integrin to its ligand, the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) which is highly expressed on GI mucosaassociaetd endothelium and high endothelial venules of mesenteric lymph nodes. Binding of integrin antagnosit to 47 on lymphocytes disrupts lymphocyte migration into inflamed GI mucosa, thus providing a potential therapeutic option for patients with UC.

Surgery
Failure of medical therapy leads to colectomy in (9% - 35%) of
patients with UC within 5 years. Colectomy is considered to

be an important adjunct treatment for refractory UC; however,

colectomy with ileal pouch anal anastomosis (the standard

surgical therapy) has many limitations and is associated with

its own set of complications, including high stool frequency, female infertility, and a cumulative incidence of chronic pouchitis of 50% at 10 years.

Unlike Crohn's disease, UC can generally be cured by surgical removal of the large intestine. 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.

In rare cases the extra-intestinal manifestations of the

disease may require removal of the colon.

Moderate

Severe Extensive Colitis

NO Remission High dose 5-ASA

Steroids

NO Remission

CsA AZA / 6-MP

Remission Remission

Remission

Failure

High dose maintenance

5-ASA

AZA/6-MP maintenance

Colectomy

Alternative treatments
Smoking :
Unlike Crohn's disease, UC has a lesser prevalence in smokers than non-smokers .

Dietary modification :
Dietary modification may reduce the symptoms of the disease.

Lactose intolerance is noted in many ulcerative colitis

patients. Those with suspicious symptoms should get a

lactose breath hydrogen test.

Patients with abdominal cramping or diarrhea may find relief or a reduction in symptoms by avoiding fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-

containing foods.
Many dietary approaches have purported to treat UC,

including the ElaineGottschall's specific carbohydrate diet

and the "anti-fungal diet" (Holland/Kaufmann). The use of elemental and semi-elemental formula has been successful in pediatric patients

Bacterial recolonization
Probiotics may have benefit. And promise for people with UC. Fecalbacteriotherapy involves the infusion of human probiotics through fecal enemas. It suggests that the cause of UC 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.

Intestinal parasites
IBD is less common in the developing world. Some have

suggested that this may be because intestinal parasites are

more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. The decrease in immune response could reduce or eliminate the

IBD.