Extraintestinal Manifestations of Ulcerative Colitis

Inflammatory bowel disease (IBD) consists predominantly of ulcerative colitis (UC) and Crohn’s disease (CD), which are clinically distinguished by intestinal localization, local features of inflammation, a profile of complications, and familial aggregation. UC is characterized by recurring episodes of continuous inflammation limited to the mucosal layer of the colon and rectum, and approximately 42% of UC patients have extraintestinal complications (Ozdil et al., 2004). This chapter highlights key features of each involved organ system including association, diagnosis, and treatment options.

frequently than men and EN rarely precedes the initial diagnosis of UC (Trost & Mcdonnell, 2005;Weinstein et al., 2005). Typical EN lesions present as painful, raised subcutaneous lesions located on extensor surfaces of the extremities (Evans & Pardi, 2007;Timani & Mutasim, 2008). However, UC patients almost always have EN lesions on the anterior surface of the legs [FIGURE 3] (Mir-Madjlessi, Taylor et al., 1985). The skin nodules are nonulcerating and resemble a bruise on the skin (Timani & Mutasim, 2008). Unlike PG, EN lesions mirror UC disease activity and worsen with colonic flares (Timani & Mutasim, 2008). The average lag time between initial UC diagnosis and appearance of EN is 5 years (Mir-Madjlessi, Taylor et al., 1985). As EN lesions and UC disease activity usually parallel each other, treatment of the underlying UC usually controls the EN lesions. Most lesions are self-limiting, thus a conservative approach to therapy is often practiced, such as leg elevation, rest, non-steroidal anti-inflammatory drugs (NSAIDs), and potassium iodide (Horio et al., 1981;Marshall & Irvine, 1997;Schulz & Whiting, 1976). In situations where lesions occur during quiescent phases of UC, treatment with oral steroids is effective. Studies have shown that time to remission in patients with EN is approximately 5 weeks which is significantly shorter than that seen in PG (Timani & Mutasim, 2008;Tromm et al., 2001).

Pyoderma Gangrenosum
The incidence of PG in patients with UC varies between 1.4 and 5% (Areias & Garcia E Silva, 1987;Mccallum & Kinmont, 1968). PG is more commonly seen in patients with UC as opposed to CD, and as with EN, there is a slight female predilection (Bernstein et al., 2001b;Greenstein et al., 1976). PG was initially described in 1930 as necrotic ulcers with expanding borders of erythema (Newell & Malkinson, 1982). The onset of noninfectious pustules and nodules eventually expand outwards to develop painful shallow and deep ulcers (Callen, 1998;Farhi & Wallach, 2008). PG usually occurs on the legs, but can also appear anywhere on the skin [FIGURE 4]. Pathergy, a phenomenon in which skin lesions develop secondary to local trauma, has been reported in approximately 30% of cases of PG (Blitz & Rudikoff, 2001;Callen, 1998). The average lag time between initial UC diagnosis and appearance of PG is 10 years (Mir-Madjlessi, Taylor et al., 1985). Diagnosis of PG is usually clinical, but skin biopsy may be necessary for confirmation. PG is classified as a type of neutrophilic dermatosis in which the inflammatory infiltrate seen on microscopic examination shows dense dermal neutrophilic infiltrates without any evidence of infection (Cohen, 2009;Timani & Mutasim, 2008). Unlike EN, there is no temporal relationship between onset of UC flares and the course of PG lesions (Thornton et al., 1980). In general, the PG lesions are more severe and refractory to therapy than EN. Treatment of the underlying UC activity does not always resolve the PG lesions and about 30% of patients require additional treatment (Mir-Madjlessi, Taylor et al., 1985). The mainstay of treating PG has been a combination of topical, intralesional, and systemic medications, but no specific therapy has proven to be universally effective (Cohen, 2009;Timani & Mutasim, 2008). Treatments with the best clinical evidence include systemic corticosteroids and Fig. 5. Aphthous stomatitis in a UC patient Pyostomatitis Vegetans. Pyostomatitis vegetans, a rare disorder of the oral mucosa, has been shown to be a specific marker for IBD, especially UC (Storwick et al., 1994;Timani & Mutasim, 2008). Lesions are hyperplastic folds of the mucosa with small abscesses and erosions and often manifest before the diagnosis of UC (Hansen et al., 1983). Pyostomatitis vegetans is usually resistant to treatments such as topical steroids, antibiotic mouthwashes, or hydrogen peroxide. Systemic steroids and immunosuppressants have been employed with variable success, but were not always successful in maintaining remission (Timani & Mutasim, 2008). In one case report, topical fluocinonide gel resulted in temporary state of remission, but total colectomy was necessary to achieve complete remission (Calobrisi et al., 1995).

Miscellaneous skin disorders
Studies report an increased risk of psoriasis with UC. In one study, of 88 patients with UC, 5.7% had psoriasis, compared to 1.5% in the control group, suggesting some type of genetic relationship between the two (Yates et al., 1982). Another study found an association between UC and hidradenitis suppurativa [FIGURE 6].

Hepatopancreatobiliary complications
There are multiple types of hepatic, biliary, and pancreatic complications associated with UC. Pancreatic complications are less common than hepatobiliary complications, but will be discussed in this section as well given its anatomic location.

Primary Sclerosing Cholangitis (PSC)
PSC is a chronic cholestatic liver disease that is caused by progressive inflammatory destruction of intra-and extra-hepatic bile ducts, which leads to multifocal biliary strictures, resulting in liver cirrhosis and failure. PSC is believed to be the result of a combination of genetic and immunological factors, resulting in immune dysfunction and improper targeting of the biliary system by lymphocytes and autoantibodies (Bergquist et al., 2008;Karlsen et al., 2007;Saarinen et al., 2000). Multiple autoantibodies including ANA, RF and atypical p-ANCA have been described in UC and PSC patients (Chapman et al., 2010;Terjung & Spengler, 2009). Atypical p-ANCA is detected by indirect immunofluorescence staining on ethanol fixed neutrophils in a perinuclear or nuclear pattern whereas classical ANCA targets myeloperoxidase and proteinase 3 in a perinuclear pattern (Terjung et al., 1998). Atypical p-ANCA is detectable in approximately 70% of PSC patients with or without UC and is also described in autoimmune hepatitis in patients with IBD (Duerr et al., 1991;Saxon et al., 1990;Terjung & Spengler, 2009). Atypical p-ANCA recognizes both beta isoform 5 in human neutrophils and bacterial cell division protein FtsZ, which is highly conserved across bacterial microflora in the gut (Terjung et al., 2010). This evidence supports the theory of a combined pathogenesis of PSC or autoimmune hepatitis in UC. It is proposed that an altered immune response to bacterial antigen in the gut lumen results in a "leaky gut" and stimulation of pattern recognition receptors (cross-recognition between bacterial antigen in the gut and host components, such as beta isoform 5 in neutrophils) which gives rise to autoimmunity phenomenon. (Terjung & Spengler, 2009). PSC typically affects young to middle aged males (male to female ratio of 2:1) and while only 5% of patients with UC will develop PSC, about 70% to 80% of cases of PSC occur in patients with UC (Charatcharoenwitthaya & Lindor, 2006;Lundqvist & Broome, 1997). The onset of PSC can precede or follow the onset of UC, and may not be related to UC disease activity (Larsen et al., 2010). An isolated alkaline phosphatase level may be the only finding during the early stages of the disease, but PSC usually manifests with chronic intermittent obstructive jaundice. As the disease progresses, serum bilirubin will rise (Lee & Kaplan, 1995). In the latter course of the disease, the prothrombin time will be prolonged and serum albumin level will decrease, signaling progression to hepatic failure. Other symptoms such as right upper quadrant abdominal pain, pruritus, fatigue, fever, and weight loss are variably present. However, PSC should be suspected in asymptomatic patients with an isolated elevation of serum alkaline phosphatase (Larsen, Bendtzen et al., 2010). Symptomatic patients manifest with icterus, jaundice, hepatomegaly and splenomegaly (Chapman, Fevery et al., 2010;Farrant et al., 1991;Wiesner et al., 1989). Pericholangitis, described by studies as PSC of the small bile ducts, is another complication of UC. A study of 107 patients with UC showed that 35% patients had "small duct" PSC compared to 17% with "large duct" PSC, but histologic examinations were indistinguishable from each other (Wee & Ludwig, 1985). These findings imply that rather than being separate disorders, PSC and pericholangitis merely affect different areas of the same disease process. Pericholangitis (or small-duct PSC) is now referred to patients with biochemical and histologic characteristics of PSC, but with normal appearing cholangiograms (Wee & Ludwig, 1985). Small-duct PSC is more often associated with Crohn's disease whereas largeduct PSC (classical PSC) is more often associated with UC (Bjornsson et al., 2008;Loftus, 1997;Rasmussen et al., 1997). Compared to large-duct PSC, small-duct PSC has a relatively favorable prognosis with longer transplant-free survival. Approximately 25% of patients with small-duct PSC progress to large-duct PSC, but usually does not develop into cholangiocarcinoma unless it progresses to large-duct PSC (Bjornsson, Olsson et al., 2008). The gold standard for diagnosis is endoscopic retrograde cholangiopancreatography (ERCP) and typical radiographic findings include multifocal strictures and dilatation of the intraand/or extra-hepatic biliary tracts, producing a "beaded pattern" (Lee & Kaplan, 1995;Maccarty et al., 1983). Recently, magnetic resonance cholangiopancreatography (MRCP) has emerged as a non-invasive alternative in diagnosing suspected PSC (Chapman, Fevery et al., 2010). ERCP may be more preferable over MRCP in diagnosing early stage PSC having a specificity and sensitivity near 100% (Angulo et al., 2000;Berstad et al., 2006;Moff et al., 2006). However, ERCP does carry potential for significant risks and complications (Larsen, Bendtzen et al., 2010). Hence, there has been an increased use of MRCP as an initial diagnostic tool, followed by ERCP as needed. If the diagnosis is in doubt, liver biopsy can assist in the confirmation of diagnosis as well as staging of disease (Charatcharoenwitthaya & Lindor, 2006). However, the classic pathognomonic finding of "onion-skin lesions" or periductal concentric fibrosis is rarely seen (Chapman, Fevery et al., 2010). Liver biopsy can be essential in the diagnosis of small-duct PSC, but is not required for the diagnosis of largeduct PSC (Burak et al., 2003;Chapman, Fevery et al., 2010). Multiple studies show that using ursodeoxycholic acid (UDCA) at moderate to high dosages has been shown to improve liver histology and liver biochemistry (Smith & Befeler, 2007). Even though UDCA has not been demonstrated to improve either symptoms or mortality, it has been shown to reduce the incidence of colonic dysplasia, colorectal carcinoma and cholangiocarcinoma (Pardi et al., 2003). Focus should be on starting these patients early enough to delay progression to cirrhosis, cholangiocarcinoma, and death. This is especially important as UDCA is not as effective in patients with end stage PSC. During treatment with UDCA, stenosis of bile ducts may occur and endoscopic intervention with dilatation has been showed to be effective (Stiehl, 2004). At the present time, liver transplantation is the only effective treatment especially for end-stage PSC or PSC with cholangiocarcinoma (Chapman, Fevery et al., 2010;Navaneethan & Shen, 2010). Orthotopic liver transplantation is the established treatment in PSC with 85% to 90% of 5-year survival rate (Gow & Chapman, 2000). However, 20 to 25% of transplanted patients develop recurrent PSC 5 to 10 years after transplant (Alabraba et al., 2009;Campsen et al., 2008;Graziadei et al., 1999;Navaneethan & Shen, 2010).

Malignancies
PSC has been shown to be complicated by malignancies including cholangiocarcinoma (CCA), bile duct carcinoma, gall bladder carcinoma, and hepatocellular carcinoma. Studies have shown that patients with UC and PSC are more prone to develop cholangiocarcinoma, colorectal cancer, gallbladder cancer and hepatocellular carcinoma (Broome et al., 1995;Florin et al., 2004;Kitiyakara & Chapman, 2008). Typically CCA presents as an intraductal tumor, and at times can be quite difficult to differentiate from a benign PSC stricture [FIGURE 7]. Evidence supporting diagnosis of CCA include high levels of CA 19-9, cross sectional liver imaging with long, confluent strictures and ERCP with brush biopsy of strictures, in addition to overall clinical presentation (Chapman, Fevery et al., 2010;Charatcharoenwitthaya et al., 2008;Levy et al., 2005). The relative risk of bile duct carcinoma in UC patients is 31.3 compared to the general population and the prognosis is quite poor with a mean survival of less than one year. PSC and pericholangitis are common pre-existing lesions in UC patients with bile duct carcinoma (Mir-Madjlessi et al., 1987). A case report recommended that in patients with UC and PSC with abnormal gallbladders, liver biopsy and cholecystectomy should be performed (Dorudi et al., 1991). Another case report documented an association between fibrolamellar hepatocellular carcinoma and UC complicated by PSC (Snook et al., 1989).

Primary Biliary Cirrhosis (PBC)
PBC is autoimmune in nature with the unique presence of anti-mitochondrial antibodies (AMA) on laboratory testing. Studies have reported that in patients with UC, there is a 30 fold risk of primary biliary cirrhosis compared to the general population (Koulentaki et al., 1999). UC patients with PBC, as compared to patients without UC, are younger and more likely to be male. The mainstay treatment of PBC includes cholestyramine to relieve itching by reducing the amount of bile acid in the blood, UDCA to increase bile flow to reduce inflammation in bile ducts, fat soluble vitamins for nutritional supplementation, and ERCP for bile drainage. Ultimately, advanced PBC with liver failure and portal hypertension requires liver transplantation.

Autoimmune Hepatitis (AIH)
Autoimmune chronic active hepatitis (CAH) has been observed in UC patients with and without PSC (Rabinovitz et al., 1992;Snook, Kelly et al., 1989). In addition to laboratory tests showing the presence of autoantibodies, such ANA and anti-smooth muscle muscle antibody (ASMA) and abnormal liver function tests, liver biopsy may be necessary to confirm the diagnosis (Alvarez et al., 1999). In patients with both UC and autoimmune hepatitis, up to 42% have abnormal cholangiographic findings indicating the coexistence or overlap of PSC (Perdigoto et al., 1992). UC patients with both AIH and PSC respond relatively poorly to immunosuppression and progress more rapidly to cirrhosis. Autoimmune CAH responds to steroids, but in the presence of PSC, dual therapy with steroids and azathioprine is indicated (Perdigoto, Carpenter et al., 1992;Rabinovitz, Demetris et al., 1992). Thus, in patients with UC complicated by autoimmune CAH, cholangiography is necessary to rule out PSC to dictate further therapy.

Other hepatic complications
Fatty liver or hepatic steatosis can be observed in UC patients and appears to correlate with disease severity or duration and may contribute to abnormal liver function tests (Riegler et al., 1998). The ultrasound findings of fatty liver show hepatomegaly and a dysechogenic pattern (De Fazio et al., 1992). Causes of fatty liver include malnutrition, protein loss, and steroid use. Patients are usually asymptomatic and treatment is geared towards treatment of the underlying UC and improving nutritional status (Navaneethan & Shen, 2010). Hepatic amyloidosis is an extremely rare complication of UC (0.07% vs. 0.9% in CD) and control of gut inflammation can reduce amyloid deposition severity (Greenstein et al., 1992;Navaneethan & Shen, 2010;Wester et al., 2001). Because of the rarity and asymptomatic nature of this complication, the need for liver biopsy remains unclear and should be made on a case-by-case basis. Hepatic and/or splenic abscesses are rare complications of IBD and even more rare in UC. They are diagnosed by ultrasound or CT scan showing non-enhancing hypodense lesions in the liver and/or spleen. Clinical suspicion of hepatosplenic abscesses should be considered in febrile patients with IBD whose presentations are inconsistent with IBD exacerbation. The treatments of hepatosplenic abscesses include drainage, broad-spectrum antibiotics, and treatment of underlying IBD with sulfasalazine and/or steroids. The pathogenesis of hepatosplenic abscess in UC is unclear at this time with possible mechanisms including infectious and immunologic etiologies (Navaneethan & Shen, 2010).

Portal vein thrombosis
Portal vein thrombosis is considered an EIM of UC and is thought to be secondary to coagulation abnormalities caused by chronic bowel inflammation. Ulceration of the mucosa barrier can increase the chance of gut microbial translocation and thus portal vein thrombosis (Navaneethan & Shen, 2010). Portal vein thrombosis has also been observed in UC patients who were status post proctocolectomy (Navaneethan & Shen, 2010).

Pancreatic complications
Patients with UC have increased chances of developing both acute and chronic pancreatitis (Keljo & Sugerman, 1997). Causes include idiopathic, gallstones, PSC, and medication side effects from drugs such as 5-ASA, mesalamine, corticosteroids, azathioprine, and 6mercaptopurine. Medication induced pancreatitis does not lead to chronic pancreatitis and treatment involves cessation of the insulting drug (Bank & Wright, 1984). On the other hand, the etiology of chronic pancreatitis is unknown. Chronic pancreatitis with UC is usually painless, but is associated with pancreatic duct strictures and severe pancreatic exocrine insufficiency (Pena et al., 2000). Autoimmune pancreatitis (AIP) is a less common complication of UC compared to druginduced or gallstone pancreatitis (Navaneethan & Shen, 2010). It affects elderly individuals and can present with obstructive jaundice. Steroids have become the standard treatment of AIP for obstructive jaundice, abdominal pain, and prevention of future episodes of pancreatitis (Finkelberg et al., 2006;Kamisawa et al., 2009). Failure to respond to steroids raises the possibility of pancreatic cancer and warrants further work up for malignancy.

Arthritis
Peripheral Arthritis: Arthritis, located peripherally or axially, can precede, occur concurrently, or follow the diagnosis of UC (Bourikas & Papadakis, 2009). The type of articular involvement in UC is inflammatory and is associated with pain, heat, swelling, and decreased joint mobility. Similar to rheumatoid arthritis (RA), the pain and stiffness of arthritis in UC is worse in the morning and improves with physical activity. However, unlike RA arthritis, UC arthritis is typically seronegative, non-deforming, and non-erosive. The peripheral arthropathy seen with UC can be classified into two types: Type 1 and Type 2 (Atzeni et al., 2009;Bourikas & Papadakis, 2009;Brakenhoff et al., 2010;Jose & Heyman, 2008). Type 1 is pauci-articular, asymmetrical in distribution, and typically affects less than 5 large joints, such as the knees, elbows, and ankles. The risk of developing peripheral arthritis is higher in UC patients and increases with colonic involvement (Bourikas & Papadakis, 2009;Jose & Heyman, 2008). The risk of developing type 1 peripheral arthritis is also increased with the presence of other EIMs, such as EN, PG, abscesses, stomatitis, and uveitis (Jose & Heyman, 2008). With the exception of small joints or type 2 polyarticular arthritis, the arthritis usually correlates with UC disease activity (Atzeni, Ardizzone et al., 2009). This type of arthritis is sometimes referred to as colitic arthritis, affects up to 20% of UC patients, and usually presents as an acute self-limiting episode that lasts less than 10 weeks with a median of 5 weeks (Bourikas & Papadakis, 2009;Das, 1999;Jose & Heyman, 2008). However, about 20% to 40% will experience recurrent episodes of arthritis. Type 2 arthropathy is typically polyarticular, involving 5 or more joints including the small joints of the hands, and most commonly affects the MCP joints of the hands. This type of polyarticular arthritis with IBD is associated with uveitis, but not with other EIMs of IBD.
Unlike type 1 arthritis, symptoms of type 2 arthritis are independent of bowel disease activity and can persist for months to years with a median of 3 years (Bourikas & Papadakis, 2009;Jose & Heyman, 2008). Genetic factors implicated in the association between peripheral arthritis and UC include: HLA-B27, HLA-B35, HLA-DR, and HLA-B44 (Brakenhoff, Van Der Heijde et al., 2010). Axial Arthritis: Axial arthritis, referred as type 3 arthritis, includes both AS and isolated sacroiliitis. This axial type of arthropathy occurs less frequently than peripheral arthritis, and as with type 2 arthropathy, does not parallel the underlying IBD in clinical course (Bourikas & Papadakis, 2009;Brakenhoff, Van Der Heijde et al., 2010;Jose & Heyman, 2008). In fact, studies have shown that axial arthropathy often precedes UC diagnosis by several years (Bourikas & Papadakis, 2009). In fact, studies have shown that AS occurs in approximately 5% to 10% of patients with IBD and patients are typically young and HLA-B27 positive [FIGURES 8 AND 9]. Presentation involves a severe onset of back pain with morning stiffness that is exacerbated by activity. Spondyloarthritis commonly coincides with periarticular involvement including synovitis, dactylitis, enthesitis, plantar fasciitis, and chest wall pain (Bourikas & Papadakis, 2009). Sacroiliitis seen with UC is often asymptomatic, but can manifest as pelvic pain that improves with movement and sacroiliac joint pain worsened with pelvic brim pressure [FIGURE 10] (Atzeni, Ardizzone et al., 2009). The treatment of UC-associated arthropathies is extrapolated from other forms of arthritis (Atzeni, Ardizzone et al., 2009). As with other types of UC EIMs, treatment of the underlying disorder with medical and/or surgical interventions can improve the peripheral arthritis seen with UC (Danese, Semeraro et al., 2005;Jose & Heyman, 2008). Symptomatic treatments include rest, physical therapy, and intra-articular steroid treatments. A short course of celecoxib (COX-2 inhibitor) for 2 weeks has been safely used to treat arthritis in UC (Sandborn et al., 2006). Patients failing to improve should be considered for second-line therapy, including sulfasalazine and immunomodulators (Danese, Semeraro et al., 2005). In patients with active colonic inflammation and peripheral arthritis, biologic agents such as infliximab should be considered (Atzeni, Ardizzone et al., 2009). In contrast to peripheral arthritis which generally responds to treatment of the colitis, medical and surgical therapy of the underlying bowel disease does not affect the disease course of axial arthropathy. Traditionally, mainstay treatments of AS included intensive physical therapy plus disease-modifying drugs such as sulfasalazine and methotrexate (Atzeni, Ardizzone et al., 2009). However, recent studies have shown that TNF-alpha inhibitor agents such as infliximab are effective in treating AS, IBD, and IBD-associated peripheral and axial arthritis (Atzeni, Ardizzone et al., 2009;Bourikas & Papadakis, 2009;Danese, Semeraro et al., 2005).

Periarticular Inflammation
Periarticular inflammation including enthesitis, tendonitis, clubbing, dactylitis, periostitis, fibromyalgia, and granulomatous lesions of the joints and bones, have been described in UC patients in the presence and absence of arthritis (Bourikas & Papadakis, 2009;Salvarani et al., 2000). These types of periarticular involvement usually do not alter inflammatory markers, but can severely compromise quality of life.

Metabolic bone disorders
Bone disorders such as osteoporosis, osteopenia, and osteonecrosis are associated with UC and this relationship is intensified with concomitant steroid use (Jose & Heyman, 2008). Some studies have shown that in IBD patients, the prevalence rate of osteoporosis can range from 2% to 30% and as high as 40% to 50% for osteopenia (Danese, Semeraro et al., 2005). However, there is still controversy on the exact relationship between UC and osteoporosis.
While one study found approximately 25% of UC patients to have decreased bone mineral density (BMD), another group in Norway found that unlike CD patients, UC patients had relatively normal body compositions without significantly decreased body mass index (BMI) or BMD (Jahnsen et al., 1997;Jahnsen et al., 2003;Vestergaard, 2004). The exact pathogenesis between UC and metabolic bone disorders is not entirely clear, but suggested causes include nutritional deficiency, malabsorption of calcium and vitamin D, steroid use, immobility, and elevated inflammatory cytokines (Danese, Semeraro et al., 2005). Consequently, calcium and vitamin D levels should be checked in UC patients taking steroids. Attempts to minimize steroid dosage and/or duration, substituting steroids with steroid-sparing immunomodulators, or supplementation with bisphosphonates or calcitonin can prevent bone loss and reduce morbidity in these patients (Jose & Heyman, 2008). Osteonecrosis, also known as aseptic or avascular necrosis, is characterized by bone tissue death secondary to poor vascular supply. Believed to be the result of ischemia of the juxtaarticular bone, osteonecrosis has been described in both children and adults with IBD with a prevalence of <1% of all IBD patients and up to 4% of patients taking steroids (Jose & Heyman, 2008;Madsen & Andersen, 1994). Osteonecrosis is a serious complication of UC that should be diagnosed early by magnetic resonance imaging and/or bone scan to prevent serious complications (Madsen & Andersen, 1994). Treatment includes medical management with calcium, vitamin D, bisphosphonates, hydrochlorothiazide, or antihypertensive to reduce bone edema. Surgical options include core-decompression biopsy, arthroplasty, or joint replacement (Jose & Heyman, 2008).

Localized myopathy
Muscle involvement is a rare EIM and UC patients are less affected than CD (Bourikas & Papadakis, 2009). The myopathy seen in UC patients can be a direct result of the underlying autoimmune disorder or a side effect of the IBD therapy. In most patients, diagnosis of IBD usually precedes the development of myopathy symptoms. Myopathy disorders that have been associated with UC include orbital myositis, gastrocnemius myalgia syndrome, polymyositis, and dermatomyositis (Bourikas & Papadakis, 2009). Orbital myositis in UC patients is rare and only a handful of cases have been reported (Macarez et al., 2005). It presents as acute orbital pain, diplopia, eyelid swelling, exophthalmos, and conjunctival injection. Diagnosis is made by CT or MRI that can show proptosis and extra-ocular muscle swelling. A case report documented successful results with a short course of systemic steroids and long-term mesalamine therapy (Macarez, Bazin et al., 2005). Gastrocnemius myalgia syndrome usually presents as calf tenderness and is less commonly reported in UC compared to CD. Polymyositis and dermatomyositis in UC patients usually present with proximal muscle weakness (Bourikas & Papadakis, 2009). Diagnostic work up should include CPK, ESR, muscle/skin biopsy, and EMG. Mainstay treatment of the various types of myositis should always include glucocorticoids. TNF-alpha blockers may be required for orbital myositis and azathioprine for polymyositis and dermatomyositis (Bourikas & Papadakis, 2009). A case report of an elderly woman with UC and polymyositis who was treated with corticosteroids and 5-ASA had marked improvement of her muscle weakness (Chugh et al., 1993).

Impaired growth
About 33% of patients with IBD develop symptoms during childhood and adolescence (Ballinger et al., 2001). Of this young population, approximately 28% of UC patients have evidence of growth impairment and delay with onset of bowel symptoms (Berger et al., 1975;Stawarski et al., 2006). The underlying UC causes of this chronic under-nutrition include poor oral intake from fear of colitis exacerbation, malabsorption from inflammation, and hypoalbuminemia secondary to protein-losing enteropathies (Jose & Heyman, 2008). There is evidence that inflammatory cytokines such as IL-6 and TNF-alpha account for the chronic inflammation that impairs linear growth and thus development (Ballinger, Camacho-Hubner et al., 2001). Studies have also shown that high dose daily steroid therapy is associated with diminished type 1 collagen production, which is also important for linear growth. Interestingly, low dose and alternate-day steroid regimens have less dramatic impacts on growth velocity and should be considered as treatment regimens for UC (Berger, Gribetz et al., 1975). Height, weight, puberty staging, and bone age should be regularly checked in young UC patients to prevent poor development. Optimal management of these young patients involves a balance between selecting an appropriate regimen that adequately treats the UC while minimally compromising normal growth and development. Ideally, keeping the underlying bowel disease in remission, especially during puberty, can improve the chance of reaching full growth potential. Calorie supplementation and enteral nutrition should be utilized to meet individualized nutritional goals. (Ballinger, Camacho-Hubner et al., 2001). Surgical interventions eradicating medically refractory disease activity have had more success in reversing growth retardation than high dose steroids, assuming that there was not a significant preexisting delay (Berger, Gribetz et al., 1975).

Ocular complications
Ocular complications associated with UC were first described in 1925 in two patients with corneal inflammation and conjunctivitis (Crohn, 1925). A large study of 465 UC patients showed that 17 patients (3.6%) had ocular involvement. Of these 17 patients, 7 patients had episcleritis and 5 had iritis or anterior uveitis (Billson et al., 1967). Two patients had blepharo-keratitis and there were single cases of interstitial keratitis, choroiditis, and dacryocystitis reported in this study. Episcleritis, uveitis and conjunctivitis are the most frequent eye manifestations of IBD. Females are affected more frequently than males and eye manifestations were found to be well correlated with UC flares (Billson, De Dombal et al., 1967). Another study reported a higher incidence with 10 out of 78 UC patients (12.8%) having ocular complications (Ozdemir et al., 2000).

Episcleritis
The episclera is the connective tissue between the conjunctiva and sclera. Episcleritis is thus defined as an inflammation of the episclera and its adjacent tissues. The inflammation is usually segmental and bilateral in distribution and associated with eye discomfort, irritation, redness, and tearing [FIGURE 11]. However, there is usually no visual impairment or purulent discharge. Episcleritis responds well to topical steroids (Billson, De Dombal et al., 1967).

Uveitis
The uvea is the middle layer of the eye and is situated between the retina and sclera. It includes the iris, ciliary body, and the choroid of the eye. Uveitis refers to an inflammation of the uvea. Multiple studies and case reports have demonstrated that UC can be associated not only with anterior uveitis, but also posterior, peripheral, or even pan-uveitis (Ozdemir et al., 2000). Symptoms of uveitis include photophobia, blurred vision, pain, and conjunctival injection. Anterior uveitis or iritis is distinguished from other causes of red eye by slit lamp examination and leukocytes seen in the anterior chamber is diagnostic of anterior uveitis. Posterior uveitis can be diagnosed by one of two ways: either by direct visualization of the active chorioretinal inflammation and/or by detecting leukocytes in the vitreous humor by slit lamp or indirect ophthalmoscope. Uveitis usually responds to topical steroid treatment. Severe cases of iritis should be treated with mydriatics to dilate pupils to prevent synechia, in which there is adhesion of the iris to the cornea or lens. It has been speculated that primary treatment of the UC with systemic steroids could account for the relatively low incidence of uveitis in patients with UC (Billson, De Dombal et al., 1967).

Scleritis
UC has been associated with different types of anterior scleritis: diffuse, nodular, and posterior scleritis (Ozdemir et al., 2000). Symptoms of scleritis include deep eye pain with radiation to eyebrows, cheeks and temples, eye redness, tearing, photophobia and blurred vision. Severe cases can ultimately lead to blindness. Initial treatments include NSAIDs; oral steroids or immunosuppressants may be necessary for advanced disease. Necrotizing scleritis, the most severe form of scleritis, causes severe inflammation and pain in part of or the entire sclera. This serious disorder is associated with RA, but has also been reported in UC (Lyne & Pitkeathley, 1968). A case report documented a case of severe necrotizing scleritis in a patient with UC that was surgically treated with an amniotic membrane graft and successfully preserved the patient's vision (Lazzaro, 2010).

Optic neuritis
Optic neuritis is inflammation of optic nerve and studies have shown that optic neuritis can be the sole ocular manifestation of UC (Sedwick et al., 1984). Patients with UC who develop rapid and progressive reduction in vision should be suspected to have optic neuritis. Untreated optic neuritis can lead to permanent loss of vision and treatment of optic neuritis typically includes systemic steroid (Nakamura et al., 2005). One of the key inflammatory mediators of UC includes the cytokine tumor necrosis-alpha (TNF-α). As such, anti-TNF-α therapies are often used to treat patients with UC and are generally well tolerated (Rutgeerts et al., 2005). However, there have been reports of the development of demyelinating disease such as optic neuritis in patients receiving anti-TNFα therapy (Nash & Florin, 2005). A study of 15 patients who presented with optic neuritis following TNF-α antagonist therapy showed that 9 of these patients experienced full

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Ulcerative Colitis -Epidemiology, Pathogenesis and Complications 146 recovery, 2 had partial resolution, and 4 patients continued to be symptomatic (Simsek et al., 2007). It is recommended that patients on anti-TNF-α therapy should be monitored for signs and symptoms of optic neuritis and if symptomatic, should have the medication discontinued.

Other ocular complications
Other ocular complications include marginal keratitis and corneal ulcers, cataracts, recurrent conjunctivitis, blepharitis, retinal vasculitis, retinal vein occlusion, and neuroretinitis (Billson, De Dombal et al., 1967). In summary, routine eye examinations are recommended for UC patients. Early diagnosis and treatment of ocular involvement can prevent serious and potentially irreversible complications of UC.

Iron deficiency anemia
In addition to biochemical values (serum iron, total iron binding capacity, transferrin, ferritin), new indices of iron metabolism (for example soluble transferrin receptors or sTfR, sTfR-ferritin index, hepcidin, ferritin: transferrin receptor ratio, reticulocyte hemoglobin content or percentage of hypochromic red blood cells) may help with the assessment of IDA and ACD in IBD (Stein et al., 2010;Zhu et al., 2010). Traditionally, IDA is treated with oral iron supplementation. However in patients with UC, not only can oral iron cause more GI side effects, but it is also poorly absorbed in the gut secondary to mucosal inflammation and altered distribution. As a result, the strong oxidizing properties of the unabsorbed iron inside the gut lumen can exacerbate the UC (Zhu, Kaneshiro et al., 2010). Hence, parenteral iron therapy and erythropoietin have been advocated in the treatment of IDA in UC patients (Gomollon & Gisbert, 2009;Stein, Hartmann et al., 2010;Wilson, Reyes et al., 2004;Zhu, Kaneshiro et al., 2010).

Anemia of Chronic Disease
ACD, seen in patients with acute or chronic inflammation, is the second most common anemia in both the general and IBD population (Weiss & Goodnough, 2005). The pathogenesis of ACD is immune driven by cytokines and cells of the reticuloendothelial system. Erythropoiesis is decreased secondary to the chronic inflammation and corresponding anti-inflammatory treatments for IBD (Zhu, Kaneshiro et al., 2010). In UC, recombinant human erythropoietin is recommended for ACD and IDA if parenteral iron therapy is ineffective (Stein, Hartmann et al., 2010;Weiss & Goodnough, 2005;Zhu, Kaneshiro et al., 2010).

Autoimmune Hemolytic Anemia
The association of autoimmune hemolytic anemia (AIHA) with UC is rare, occurring in less than 1% of cases. However, AIHA should be suspected in patients with anemia, painless jaundice, and unconjugated hyperbilirubinemia (Gumaste et al., 1989;Valderrama Rojas et al., 2003). The diagnosis of AIHA includes a positive direct Coombs test that detects IgG or complement absorbed onto red blood cells. However, studies have shown that approximately 1.82% of UC patients without signs of hemolysis can have a positive direct Coombs test (Valderrama Rojas, Rodriguez Gorostiza et al., 2003). Systemic steroids are the first line of therapy, produce remission in 21% to 50% of cases, and should be continued for 3 weeks before being considered ineffective (Gumaste, Greenstein et al., 1989;Veloso et al., 1991). For cases unresponsive to steroids, immunosuppressive therapy with agents such as cyclophosphamide or azathioprine and surgical intervention including splenectomy should be considered. A case report describes a patient with UC and AIHA in which immunosuppression with steroids and azathioprine was not successful in achieving remission. Ultimately, splenectomy was performed and the patient went into remission allowing her immunosuppressants to be discontinued (Wodzinski & Lawrence, 1985). If the hemolysis is not responding to the aforementioned treatments, colectomy or total proctocolectomy are advisable and effective (Gumaste, Greenstein et al., 1989)(Sharma 2002. Thrombocytopenia with AIHA is known as Evan's syndrome. A case report describes an association of Evan's syndrome with UC that responded to immunosuppressive therapy (Ucci et al., 2003).

Other hematologic complications
Agranulocytosis and thrombocytopenia have been reported to be associated with UC. This can be secondary to medication side effects: for example, sulfasalazine has been shown to cause agranulocytosis and mesalamine has been showed to cause thrombocytopenia (Farrell et al., 1999;Roddie et al., 1995). Immune-mediated neutropenia and thrombocytopenia have also been reported in UC (Kim et al., 1995). Idiopathic thrombocytopenic purpura (ITP), documented by various case reports to occur in patients with UC, is autoimmune in nature and treatment is similar to that of AIHA with steroids, splenectomy, and if necessary, colectomy (Mizuta et al., 2003;Yoshida et al., 1996). Various hematologic malignancies have been reported as UC complications and include: acute promyelocytic leukemia, acute myelogenous leukemia, chronic granulocytic leukemia, and myelodysplastic syndrome (Braverman & Bogoch, 1978;Fabry et al., 1980;Hebbar et al., 1997;Rosen & Teplitz, 1965). However, the pathogenesis of the association remains unclear (Fabry, Sachar et al., 1980;Hebbar, Kozlowski et al., 1997;Rosen & Teplitz, 1965;Suzuki et al., 1995).

Vascular complications
Venous thromboembolism (VTE) such as deep vein thrombosis (DVT) and pulmonary embolism (PE) are known complications of UC (Braverman & Bogoch, 1978). This is attributable to the hypercoagulable state associated with UC with patients often having active disease at time of VTE (Koutroubakis, 2005). Treatment is similar to that of patients without IBD. Arterial thrombosis is a rare complication of UC and sites of thrombosis involving radial, brachial and common carotid arterial thrombosis have been reported (Braverman & Bogoch, 1978;Mikroulis et al., 1999;Nogami et al., 2007). The pathogenesis of arterial thrombosis is related to increased fibrinogen levels, increased platelet counts, and decreased anti-thrombin III levels (Mikroulis, Antypas et al., 1999). Treatment with antithrombotic therapy can often worsen the UC and in patients who fail antithrombotic or anticoagulation therapies, colectomy is often necessary (Mikroulis, Antypas et al., 1999;Nogami, Iiai et al., 2007). UC has been reported to be associated with several vasculitides including: Takayasu's arteritis and giant cell arteritis (Jacob et al., 1990;Kawashima et al., 1999;Shibata et al., 2002). Takayasu's arteritis is a granulomatous arteritis involving the aorta and its branches. Involvement of the common carotid artery will show typical tenderness of carotid artery, an early but pathognomonic symptom of Takayasu's arteritis. MRI is helpful for the early diagnosis of Takayasu's arteritis (Kawashima, Koike et al., 1999). Giant cell arteritis is granulomatous arteritis involving medium and large-sized arteries. Giant cell arteritis, also known as temporal arteritis and cranial arteritis, usually presents with headache, blurred vision, and sometimes sensorineural deafness (Jacob, Ledingham et al., 1990). Biopsy of temporal artery is needed for definitive diagnosis of temporal arteritis. Both Takayasu's arteritis and Giant cell arteritis respond to steroids (Jacob, Ledingham et al., 1990;Kawashima, Koike et al., 1999;Shibata, Funayama et al., 2002). Early diagnosis is important as delayed treatment can lead to permanent loss of vision.

Renal and genitourinary tract complications
A significant number of UC patients can develop complications involving the kidney and genitourinary tract. These complications include urolithiasis, chronic renal disease, ureteral obstruction, fistulas, and renal cell carcinoma.

Urolithiasis
Kidney stones, usually composed of either calcium oxalate or uric acid, are more prevalent in UC patients than in the general population (Caudarella et al., 1993). UC patients, especially those who have undergone surgery, have been shown to have decreased urinary volume, pH, magnesium, and excretion of citrate, all of which are significant risk factors for renal stone formation. Dehydration from diarrhea during UC flares further increases one's chance of developing nephrolithiasis.

Chronic renal disease
A statistically significant increased risk for renal disease is found in UC but not in CD patients (Bernstein et al., 2005). Reported chronic renal diseases associated with UC include: glomerulonephritis, immunoglobulin A nephropathy, nephrotic syndrome, idiopathic interstitial nephritis, drug-induced nephritis by mesalamine, NSAID induced nephropathy, type AA renal amyloidosis, or secondary amyloidosis (Basili et al., 2002;Skhiri et al., 1998;rStokke et al., 1976;Tokuyama et al., 2010). Kidney biopsy is indicated in order to confirm the diagnosis. Nephrotic syndrome as a complication of UC has been reported to be related to an underlying complement and immune disorder and usually responds favorably to steroid treatment. A case report documents rapid improvement in renal function after colectomy (Stokke, Teisberg et al., 1976). UC patients found to have micro-or macro-hematuria should receive a renal biopsy for possible immunoglobulin A nephropathy (Trimarchi et al., 2001). Many of these diagnoses can end in renal failure and may ultimately require hemodialysis.
Ureteral obstruction in UC can be caused by kidney stone or retroperitoneal inflammation and fibrosis. Intravenous pyelography (IVP) is used to diagnose non-calculous ureteral obstruction and is found in 14% of UC patients (Fleckenstein et al., 1977). These patients are initially asymptomatic, but chronic obstruction and lead to pyelonephritis, hydronephrosis, hypertension, and eventual loss of kidney function. Because occult ureteral stenosis without gastrointestinal symptoms may be present, the possibility of IBD should be raised in patients who present with isolated ureteral stenosis (Kruglik et al., 1977). Initial management focuses on medical treatment of UC, but nephrostomy tubes or ureteral stents are indicated to relieve any obstructions.

Renal Cell Carcinoma
Renal cell carcinoma (RCC), although relatively uncommon, has been documented to occur in UC patients. While the association is unclear, possible etiologies include genetic predisposition or immunosuppression from medications. Treatment usually requires surgical intervention including nephrectomy (Satsangi et al., 1996).

Neurological complications
Both central and peripheral neurological disorders have been reported to occur in patients with UC. These include strokes, cerebral sinus thrombosis, cerebral vasculitis, acute disseminated encephalomyelitis, multiple sclerosis, peripheral neuropathies, and many other disorders (Jose & Heyman, 2008). Neurological complications of UC can be differentiated into three major categories: cerebrovascular disease, cerebral vasculitis, and immune mediated neuropathy. (Pandian et al., 2004)

Cerebrovascular disease
Compared to venous thrombotic events such as DVT and pulmonary emboli, thrombotic events occurring in the CNS are relatively rare occurring in up to 7.5% of cases (Nudelman et al., 2010). Cerebral sinus thrombosis typically presents with headache, convulsions, hemiparesis, and/or other neurologic signs and diagnosis is made by MRI angiogram (Tsujikawa et al., 2000). Because untreated cerebral sinus thrombosis can result in fatal cerebral edema and herniation, rapid diagnosis and treatment aimed to reduce intracranial pressure with a combination of steroids, diuretics, anticoagulants, and antithrombotic therapy is essential (Nudelman, Rosen et al., 2010;Tsujikawa, Urabe et al., 2000). Cerebral arterial thrombosis is also a rare complication of UC, but has been described in young patients without any other significant risk factors of cerebral vascular accidents such as hyperlipidemia, cardiac arrhythmia, or carotid artery disease (Katsanos & Tsianos, 2002). Unfortunately, due to the rarity of cases, there are no official guidelines on the treatment of strokes in patients with IBD. Case reports have documented that arterial thrombotic events in UC patients is often associated with severe pan-colonic disease and generally carries a poor prognosis (Novotny et al., 1992). Colectomy may be necessary in these patients.

Cerebral vasculitis
Cerebral vasculitis is another complication of UC and can manifest as seizures and severe headaches (Masaki et al., 1997;Nomoto et al., 2006). Diagnosis is typically made with MRI digital subtraction angiogram that shows a "beaded" appearance with multiple areas of irregularities of the intracerebral arteries. Treatment is similar to that of systemic vasculitis and usually involves steroids and/or immunosuppressants (Nelson et al., 1986;Nomoto, Nagao et al., 2006).

Immune mediated neuropathy
An association between UC and multiple sclerosis (MS) has been found both within families and within individuals (Hoffmann & Kruis, 2004). MS affects UC more than CD patients and the prevalence of MS in IBD patients is about 3.7 times more than seen in the average (Kimura et al., 2000). There are clearly common factors between IBD and MS, but more research is necessary to establish specific relationships between the two disorders (Pandian, Pawar et al., 2004). Management of these patients including diagnosis and treatment is generally similar to patients without UC (Pandian, Pawar et al., 2004). O t h e r r a r e n e u r o l o g i c a l c o m p l i c a t i o n s o f U C t h a t h a v e b e e n r e p o r t e d i n c l u d e : a c u t e disseminated encephalomyelitis, optic neuritis, sensorineural hearing loss, myelopathy, peripheral polyneuropathy, Guillain-Barre syndrome, and myasthenia gravis (Gondim et al., 2005;Kanra et al., 2002;Krystallis et al., 2010;Lossos et al., 1995;Scheid & Teich, 2007;Tan, 1974;Yesilova et al., 2006). Many of these complications are autoimmune in nature and respond to steroids and/or immunosuppressive therapy.

Pulmonary complications
A variety of pulmonary complications associated with UC have been well documented and reported in medical and scientific literature. Virtually any part of the respiratory system can be involved and the pulmonary complications can be classified into airway, parenchymal, vascular, thromboembolic, and pleural disease.

Airway disease
Almost any part of the airway ranging from the trachea to the bronchi and bronchioles, can be associated with UC with the most common complications involving the bronchi (Higenbottam et al., 1980). Bronchial involvement may present as a chronic persistent cough with mucopurulent production suggesting chronic bronchitis or bronchiectasis (Gibb et al., 1987). In general, these symptoms do not respond to antibiotics, but do respond to inhaled steroids (Higenbottam, Cochrane et al., 1980). Studies have shown that in UC patients, colonic and pulmonary flares often parallel each other, suggesting a common embryonic origin of the colonic and pulmonary epithelium (Higenbottam, Cochrane et al., 1980;Wilcox et al., 1987). Furthermore, the histopathology of sclerosing cholangitis, another EIM of UC, has been shown to be quite similar to that of the airway inflammation associated with UC (Janssen et al., 2006). Tracheal involvement can present as cough, hoarseness, dyspnea or even stridor due to inflammation and stenosis in subglottic or upper tracheal area. Depending on the severity of the inflammation and degree of respiratory compromise, systemic steroids and sometimes endotracheal intubation may be indicated (Janssen, Bierig et al., 2006;Rickli et al., 1994). Less frequently seen in UC patients is bronchiole and small airways inflammation manifested as constrictive bronchiolitis or bronchiolitis obliterans with organizing pneumonia (BOOP) (Ward et al., 1999). Constrictive bronchiolitis is defined as concentric fibrosis in the bronchiolar submucosal layer with continuous external circular scarring (Epler, 2007). BOOP is an inflammatory disease involving the terminal bronchiole and alveoli (lung parenchyma), and has been reported to be associated with UC. Symptoms seen with small airway involvement include cough, sputum production, wheezing, dyspnea, fever, flu-like symptoms, and pleuritic chest pain. These symptoms can manifest acutely or in chronic fashion and systemic steroids are indicated in the treatment of small airway inflammation.

Diagnosis
1. Routine laboratory tests: Sputum culture can rule out a respiratory infection. Observing peripheral eosinophilia on complete blood count can help differentiate inflammation from infection. Chest X-ray may show diffuse narrowing of the trachea in tracheal stenosis, thickening of the bronchial wall in bronchiectasis, or ground glass opacities in BOOP (Epler, 2001;Gibb, Dhillon et al., 1987;Janssen, Bierig et al., 2006). 2. Pulmonary function tests: An obstructive pattern is usually seen in large airway inflammation while a restrictive pattern is usually seen in small airway or parenchymal inflammation. Patients with inflammation affecting various parts of the airway and parenchyma can have mixed patterns on pulmonary function tests (Gibb, Dhillon et al., 1987). In patients with upper airway obstruction, flow-volume loops will show showing flattening of the inspiratory and expiratory limbs (Janssen, Bierig et al., 2006). A low lung diffusing capacity for carbon monoxide (DLco) can help to diagnose small airway inflammation such as BOOP or parenchymal disease such as interstitial lung disease. 3. CT scan: CT scans, especially High Resolution CT (HRCT) scans are more sensitive than plain chest films in differentiating between the pulmonary complications of UC. Irregular narrowing of the trachea or main bronchi can be seen in large airway involvement, thickened bronchial walls and dilated airways with mucoid impaction can be seen with bronchial involvement, and bilateral consolidation and peripheral (pleural-based) ground glass opacities are observed in BOOP (Epler, 2001;Garg et al., 1993;Spira et al., 1998;Wilcox, Miller et al., 1987). 4. Bronchoscopy: Bronchial epithelial biopsy can help diagnose tracheal stenosis with extensive inflammation with granulation tissue, basal reserve cell hyperplasia, thickening of the basement membrane, and submucosal inflammation (Gibb, Dhillon et al., 1987;Janssen, Bierig et al., 2006). 5. Surgery: Open lung biopsy or video-assisted thoracoscopic (VATS) procedure with biopsy may be needed to establish a diagnosis of BOOP or interstitial lung disease (Epler, 2001).

Lung parenchymal disease
BOOP, a disorder with both airway and parenchymal involvement, has been discussed under the airway disease section. Interstitial lung disease as a pulmonary complication of UC is extremely rare and is usually steroid-responsive, but cases of mortality have been reported (Marten et al., 2005). In a case report, a patient with UC was described to present with dyspnea and fatigue, but unlike BOOP, cough or fever was absent. Physical examination revealed inspiratory crackles and chest x-ray revealed reticular densities in the mid-to lower lung field bilaterally. CT scan revealed honeycombing and ground glass opacification with traction bronchiectasis and bronchiolectasis in similar lung field. Pulmonary function test revealed restriction pattern with reduced DLco and the patient ultimately developed respiratory failure requiring mechanical ventilation and passed away from acute right ventricular failure (Marten, Fend et al., 2005). Pulmonary infiltrates with eosinophilia (PIE syndrome) is a recognized pulmonary complication of UC and has been documented to occur in patients receiving and not receiving sulfasalazine/mesalamine therapy (Camus et al., 1993;Saltzman et al., 2001). Typical chest x-ray appearance of PIE is peripheral homogenous nonsegmental air-space infiltrate or a "reverse pulmonary edema" pattern (Saltzman, Rossoff et al., 2001). The patient presents with dry cough, wheezing, fever, night sweat, and malaise. Peripheral blood and bronchoalveolar lavage can demonstrate eosinophilia. Systemic steroid treatment causes prompt and sustained resolution of clinical and radiographic abnormalities (Saltzman, Rossoff et al., 2001). Necrobiotic nodules (sterile abscesses) are rare pulmonary complications of UC. Patients usually present with high fever and constitutional symptoms. The lesions show PMNs and fibrin with necrosis, a similar pattern seen in PG, a dematologic complication of IBD (Camus, Piard et al., 1993;Warwick et al., 2009). Chest X-ray can show multiple cavitary and noncavitary nodules. In 2 case reports, therapy with steroids with or without cyclophosphamide successfully produced remission without relapse (Camus, Piard et al., 1993).

Vascular thromboembolic disease
The incidence of VTE is about 3 to 4 times higher for patients with IBD in comparison with controlled age-matched groups (Bernstein et al., 2001a;Miehsler et al., 2004;Stebbing, Askin et al., 1999). The age-adjusted incidence ratios of UC compared to age-matched population was 2.8 for DVT and 3.6 for pulmonary embolism (PE) (Bernstein, Blanchard et al., 2001). IBD patients have increased risk factors for thromboembolism secondary to the underlying disease process or its associated complications including dehydration, inactivity, hospitalization, surgery, and central venous catheterization. However, up to 1/3 of VTE events occur in patients while the underlying disease process is quiescent, suggesting that there are additional risk factors unrelated to disease activity or accompanying therapies (Stebbing, Askin et al., 1999;Tsiolakidou & Koutroubakis, 2008). The following genetic factors have been suggested to increase the incidence of VTE in IBD patients: factor V Leiden, factor II (prothrombin, G20210A), methylenetetrahydrofolate reductase gene mutation (MTHFR, 6777T), plasminogen activator inhibitor type 1 (PAI-1) gene mutation and factor XIII (val34leu) (Tsiolakidou & Koutroubakis, 2008). The symptoms, diagnosis and treatment of DVT and PE in UC are similar to patients without IBD.

Pleural disease
Pleural and pericardial complications of IBD in the form of serositis, pleural effusions, pleuritis, pericarditis, pleuro-pericarditis or myo-pericarditis are uncommon (Tsiolakidou & Koutroubakis, 2008). When they do occur, they are usually diagnosed in young male patients with UC (Camus, Piard et al., 1993;Stebbing, Askin et al., 1999). The pleural effusion is almost always unilateral and exudative in nature. The symptoms and diagnosis of serositis are similar to other patients without UC and the treatment of serositis includes steroid and NSAIDs such as aspirin and Indocin (Stebbing, Askin et al., 1999).

Cardiac complications
In general, cardiovascular involvement with UC is uncommon, but complications such as intracavitary thrombosis, endocarditis, myocarditis, pericarditis, coronary artery disease, arrhythmias, and heart failure have been described in case reports (Katsanos & Tsianos, 2002).

Thrombosis
Intracavitary thrombosis, diagnosed by echocardiogram, has been reported to occur in the right atrium and left ventricle of UC patients (Saleh, 2010;Sasvary et al., 1996). Early diagnosis and treatment is essential as RA thrombus can lead to PE and LV thrombus can lead to systemic embolism.

Myocardial Involvement
Although relatively rare, myocardial involvement in UC patients compared with the general population has an incidence ratio of 2.6 (Sorensen & Fonager, 1997). A majority of cases in UC patients with myocardial involvement is complicated by pericarditis or pleural effusion. Prolonged corticosteroid use has been implicated in the cause of hypertrophic cardiomyopathy and mesalamine has been reported to cause myocarditis and perimyocarditis (Katsanos & Tsianos, 2002). Case reports of acute myocardial infarction have been documented to occur during flares (Efremidis et al., 1999). The pathogenesis behind this ischemia is presumed to be reversible vasoconstriction of varying severity decreasing blood flow to myocardial tissue (Katsanos & Tsianos, 2002).

Pericarditis
The most commonly reported cardiac complication of UC is pericarditis which can be caused by drugs (5-aminosalicylic acid, mesalamine, azathioprine), pericardio-colonic fistulas, or idiopathic mechanisms (Katsanos & Tsianos, 2002). Both acute and chronic pericarditis with and without cardiac tamponade have been reported (Cappell & Turkieh, 2008;Dubowitz & Gorard, 2001). Drug induced pericarditis typically resolves after omission of the offending drug and treatment with NSAIDs is effective. Cardiac tamponade is a rare, but life threatening complication of UC that can be diagnosed by echocardiogram or cardiac catheterization. Treatment includes emergent pericardiocentesis and pericardiectomy is indicated for recurrent pericardial effusion and chronic constrictive pericarditis (Cappell & Turkieh, 2008;Rezaie et al., 2010).

Valvular Involvement
Valvular involvement in UC is relatively common and can manifest as endocardium and aortic root involvement. Aortic and mitral valve involvement may require surgical replacement, but generally carries with good outcomes and prognosis (Katsanos & Tsianos, 2002).

Arrhythmias
Various types of cardiac arrhythmia have been reported to occur in UC, including Wenckebach, complete heart block, atrial fibrillation, supraventricular tachycardia, ventricular tachyarrhythmia, and mesalamine related sinus bradycardia (Katsanos & Tsianos, 2002). A permanent pacemaker is indicated for complete heart block (Maeder, 1996). Hypomagnesemia is frequently seen in UC due to ongoing fecal losses and this can lead to ventricular tachycardia. Treatment with magnesium infusion is effective (Levine et al., 1982). Interestingly, in patients with no prior cardiac history or electrolyte balance, QT intervals were found to be significantly higher in UC than CD, suggesting an increased risk of dangerous arrhythmias (Curione et al., 2010).

Conclusion
UC is a systemic disease, since its clinical manifestations can affect not only the bowel, but can also involve almost any organ including the skin, eyes, liver, musculoskeletal cardiovascular, hematologic, and renal systems (Table 1). These EIM can influence both morbidity and mortality. Most of the patients with IBD associated EIMs have extensive colitis and family history of the disease. With the exception of PSC, AS, PG, and type 2 arthritis, extraintestinal complications tend to follow the clinical course of IBD. Awareness and understanding of the disease manifestations extrinsic to the gastrointestinal tract are essential in the management of IBD patients.
Both, more common in CD