may affect the blood and endocrine system. uc increases the risk of blood clots in both arteries and veins; painful swelling of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism (blood clots in the lungs). the risk of blood clots is about threefold higher in individuals with ibd. the risk of venous thromboembolism is high in ulcerative colitis due to hypercoagulability from inflammation, especially with active or extensive disease. additional risk factors may include surgery, hospitalization, pregnancy, the use of corticosteroids and tofacitinib, a jak inhibitor. the immune system may also attack red blood cells, leading to autoimmune hemolytic anemia. in addition to autoimmune destruction, anemia may occur due to chronic blood loss from rectal bleeding and bone marrow suppression due to inflammation (anemia of chronic disease). anemic patients can present asymptomatically. however, 75% of individuals exhibit symptoms such as shortness of breath, fatigue, and tachycardia (racing heart). about 1/3rd of patients show signs of jaundice (yellowing of the skin) or darkened urine from loss of bilirubin in urine. a smaller percentage may present with chest pain or a concurrent immune cytopenia, most commonly immune thrombocytopenia (itp) (cite waha). osteoporosis may occur related to systemic inflammation, which increases the risk of bone fractures. clubbing, a deformity of the ends of the fingers, may occur. amyloidosis may occur, especially with severe and poorly controlled disease, which usually presents with protein in the urine (proteinuria) and nephritic syndrome. primary sclerosing cholangitis ulcerative colitis has a significant association with primary sclerosing cholangitis (psc), a progressive inflammatory disorder of small and large bile ducts. up to 70-90% of people with primary sclerosing cholangitis have ulcerative colitis. as many as 5% of people with ulcerative colitis may progress to develop primary sclerosing cholangitis. psc is more common in men, and often begins between 30 and 40 years of age. it can present asymptomatically or exhibit symptoms of itchiness (pruritis) and fatigue. other symptoms include systemic signs such as fever and night sweats. such symptoms are often associated with a bacterial episodic version of psc. upon physical exam, one may discern enlarged liver contours (hepatomegaly) or enlarged spleen (splenomegaly) as well as areas of excoriation. yellow coloring of the skin, or jaundice, may also be present due to excess of bile byproduct buildup (bilirubin) from the biliary tract. in diagnosis, lab results often reveal a pattern indicative of biliary disease (cholestatic pattern). this is often displayed by markedly elevated alkaline phosphatase levels and milder or no elevation in liver enzyme levels. xray results often show bile ducts with thicker walls, areas of dilation or narrowing. in some cases, primary sclerosing cholangitis occurs several years before the bowel symptoms of ulcerative colitis develop. psc does not parallel the onset, extent, duration, or activity of the colonic inflammation in ulcerative colitis. in addition, colectomy does not have an impact on the course of primary sclerosing cholangitis in individuals with uc. psc is associated with an increased risk of colorectal cancer and cholangiocarcinoma (bile duct cancer). psc is a progressive condition, and may result in cirrhosis of the liver. no specific therapy has been proven to affect the long term course of psc. other liver-related manifestations of uc include fatty liver disease and autoimmune liver disease. causes risk factors crohn's diseaseulcerative colitis smokinghigher risk for smokerslower risk for smokers ageusual onset between 15 and 30 yearspeak incidence between 15 and 25 years ulcerative colitis is an autoimmune disease characterized by t-cells infiltrating the colon. no direct causes for uc are known, but factors such as genetics, environment, and an overactive immune system play a role. uc is associated with comorbidities that produce symptoms in many areas of the body outside the digestive system. genetic factors a genetic component to the cause of uc can be hypothesized based on aggregation of uc in families, variation of prevalence between different ethnicities, genetic markers and linkages. in addition, the identical twin concordance rate is 10%, whereas the dizygotic twin concordance rate is only 3%. between 8 and 14% of people with ulcerative colitis have a family history of inflammatory bowel disease. in addition, people with a first degree relative with uc have a four-fold increase in their risk of developing the disease. twelve regions of the genome may be linked to uc, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, but none of these loci has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. for example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease. some of the putative regions encode transporter proteins such as octn1 and octn2. other potential regions involve cell scaffolding proteins such as the maguk family. human leukocyte antigen associations may even be at work. in fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates. multiple autoimmune disorders are associated with ulcerative colitis, including celiac disease, psoriasis, lupus erythematosus, rheumatoid arthritis, episcleritis, and scleritis. ulcerative colitis is also associated with acute intermittent porphyria. environmental factors many hypotheses have been raised for environmental factors contributing to the pathogenesis of ulcerative colitis, including diet, breastfeeding and medications. breastfeeding may have a protective effect in the development of ulcerative colitis. one study of isotretinoin found a small increase in the rate of uc. as the colon is exposed to many dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and crohn's disease. however, current research does not show a link between diet and the development of ulcerative colitis. few studies have investigated such an association; one study showed no association of refined sugar on the number of people affected of ulcerative colitis. high intake of unsaturated fat and vitamin b6 may enhance the risk of developing ulcerative colitis. other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. specifically, sulfur has been investigated as being involved in the cause of ulcerative colitis, but this is controversial. sulfur restricted diets have been investigated in people with uc and animal models of the disease. the theory of sulfur as an etiological factor is related to the gut microbiota and mucosal sulfide detoxification in addition to the diet. as a result of a class-action lawsuit and community settlement with dupont, three epidemiologists conducted studies on the population surrounding a chemical plant that was exposed to pfoa at levels greater than in the general population. the studies concluded that there was an association between pfoa exposure and six health outcomes, one of which being ulcerative colitis. alternative theories levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis, which could indicate higher levels of hydrogen sulfide in the intestine. an alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine. infection by mycobacterium avium, subspecies paratuberculosis, has been proposed as the ultimate cause of both ulcerative colitis and crohn's disease. pathophysiology pathophysiology crohn's diseaseulcerative colitis cytokine responseassociated with th17vaguely associated with th2 an increased amount of colonic sulfate-reducing bacteria has been observed in some people with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see intestinal mucosal barrier). n-butyrate, a short-chain fatty acid, gets oxidized through the beta oxidation pathway into carbon dioxide and ketone bodies. it has been shown that n-butyrate helps supply nutrients to this epithelial barrier. studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-coa dehydrogenase, an enzyme within the pathway. furthermore, it has been suggested that the protective benefit of smoking in ulcerative colitis is due to the hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway. an unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for people in remission. diagnosis endoscopic image of ulcerative colitis affecting the left side of the colon. the image shows confluent superficial ulceration and loss of mucosal architecture. crohn's disease may be similar in appearance, a fact that can make diagnosing uc a challenge. h&e stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis the initial diagnostic workup for ulcerative colitis consists of a complete history and physical examination, assessment of signs and symptoms, laboratory tests and endoscopy. severe uc can exhibit high erythrocyte sedimentation rate (esr), decreased albumin (a protein produced by the liver), and various changes in electrolytes. as discussed previously, uc patients often also display elevated alkaline phosphatase. inflammation in the intestine may also cause higher levels of fecal calprotectin or lactoferrin. specific testing may include the following: a complete blood count is done to check for anemia; thrombocytosis, a high platelet count, is occasionally seen electrolyte studies and kidney function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and kidney injury. liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis. imaging such as x-ray or ct scan to evaluate for possible perforation or toxic megacolon stool culture and clostridioides difficile stool assay to rule out infectious colitis inflammatory markers, such as erythrocyte sedimentation rate or c-reactive protein lower endoscopy to evaluate the rectum and distal large intestine (sigmoidoscopy) or entire colon and end of the small intestine (colonoscopy) for ulcers and inflammation although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease. the simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. endoscopic colonic pseudopolyps of a person with intractable uc, colectomy specimen the best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. the physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. however, a complete colonoscopy with entry into the terminal ileum should be performed to rule out crohn's disease, and assess extent and severity of disease. endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. when present, ulcerations may be confluent. pseudopolyps may be observed. ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. perianal disease is rare. the degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). histologic biopsy sample (h&e stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts. crypt abscess. h&e stain. biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of uc and differentiate it from crohn's disease, which is managed differently clinically. histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). unlike the transmural inflammation seen in crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. laboratory tests blood and stool tests serve primarily to assess disease severity, level of inflammation and rule out causes of infectious colitis. all individuals with suspected ulcerative colitis should have stool testing to rule out infection. a complete blood count may demonstrate anemia, leukocytosis, or thrombocytosis. anemia may be caused by inflammation or bleeding. chronic blood loss may lead to iron deficiency as a cause for anemia, particularly microcytic anemia (small red blood cells), which can be evaluated with a serum ferritin, iron, total iron-binding capacity and transferrin saturation. anemia may be due to a complication of treatment from azathioprine, which can cause low blood counts, or sulfasalazine, which can result