Extraintestinal symptoms of ulcerative colitis.
Inflammatory bowel disease is a group of chronic disorders of the gastrointestinal tract, including Lesniowski-Crohn disease, ulcerative colitis, and indeterminate colitis. The most frequently occurring symptoms in patients with IBD, including ulcerative colitis, involve abdominal discomfort, recurring and often bloody diarrhoea, weight loss, and the resulting anaemia and/or cachexia. Extraintestinal manifestations of ulcerative colitis may precede the diagnosis of inflammatory bowel disease, they may also occur during remission (pyoderma gangrenosum, uveitis, spondylitis, and PSC) or accompany an exacerbation of the disease (erythema nodosum, episcleritis, aphthae, and some forms of peripheral spondyloarthritis). This study focuses on the most common extraintestinal manifestations and complications in ulcerative colitis in paediatric patients.
- ulcerative colitis
- parenteral symptoms
Inflammatory bowel disease is a group of chronic disorders of the gastrointestinal tract, including Lesniowski-Crohn disease, ulcerative colitis, and indeterminate colitis. The course of these disorders is characterised by alternating periods of remission, which may last even a few years, and exacerbation. Chronic inflammatory bowel diseases develop as a result of coexisting genetic, immunological and environmental factors, and the immune system, which is linked to the digestive system and constitutes a vast proportion of the whole defence mechanism of our body. Among the most frequently occurring symptoms in patients with IBD, including ulcerative colitis, are abdominal discomfort, recurring and often bloody diarrhoea, weight loss, and the resulting anaemia and/or cachexia. The aspects of extraintestinal symptoms of inflammatory bowel diseases are not discussed often, and yet in as many as 40–50% of patients, at least one extraintestinal manifestation of IBD occurs with even 25% of patients reporting two or more symptoms not related to the digestive system. The causes of the occurrence of extraintestinal symptoms in the course of ulcerative colitis have been widely discussed. Increased permeability of the intestinal wall allows for the contents of the bacterial wall (endotoxins) and other components to enter the bloodstream, which may cause inflammation. Extraintestinal manifestations of ulcerative colitis may precede the diagnosis of inflammatory bowel disease, occur during remission (pyoderma gangrenosum, uveitis, spondylitis, and primary sclerosing cholangitis) or accompany an exacerbation (erythema nodosum, episcleritis, aphthae, and some forms of peripheral spondyloarthritis). The course of inflammatory bowel diseases in children is more severe than in adults. Extraintestinal manifestations may precede intestinal ones by months or years and may lead to false diagnoses and delayed treatment. Patients with extraintestinal manifestations often first consult other specialists, such as ophthalmologists, orthopaedic surgeons, or rheumatologists, before being diagnosed with a gastroenterological disorder. Ankylosing spondylitis or primary sclerosing cholangitis, which co-occur in patients with ulcerative colitis pose a greater health problem for some patients than the main intestinal disease(Table 1) [1, 2, 3, 4, 5, 6].
|The skeletal system||Osteopenia/osteoporosis|
|The liver and bile ducts||Steatosis|
Primary sclerosing cholangitis
Bile duct cancer
|Joints||Arthritis of the large joints|
|The skin||Erythema nodosum|
|The vascular system||Vein thrombosis|
|Intestinal complications of ulcerative colitis||Frequency of occurence|
Gastrointestinal complications are as follows:
Toxic megacolon (megacolon toxicum): a potentially lethal complication was observed in 3–4% of all patients with ulcerative colitis. Toxic megacolon usually occurs in patients whose whole area of the large intestine (pancolitis) has been affected shortly after the onset of the disease. Pathophysiological factors include inflammation-induced severe damage to the intestinal wall, electrolyte imbalance, and hypoproteinemia. Antidiarrheals and a barium enema may additionally contribute to the development of the complication. The removed intestine is characterised by significant thinning, fragility of the walls, and segmental mucosal atrophy. Histopathological examination shows significant hyperaemia, infiltration of all layers of the intestinal walls, and multiple small microperforations. Diagnostic criteria for megacolon toxicum involve radiological symptoms of large bowel distension, clinical symptoms (fever, HR >120/min and leukocytosis), and at least one of the following symptoms—dehydration, impaired consciousness, and decreased RR. The physical examination reveals increased tension and tenderness of the abdominal wall to palpation, as well as absent or subdued peristaltic sounds. In some cases, peritoneal symptoms occur, which may indicate an intestinal perforation. The diagnosis of toxic megacolon is based on the clinical picture and X-ray picture of the abdomen, which will show extensive distension of the colon filled with gas. A radiological criterion for megacolon is the transverse colon exceeding 6 cm in diameter in the body’s midline. Laboratory tests show leukocytosis, anaemia, hypoalbuminaemia, and hypokalemia.
Perforation of the large intestine may further complicate toxic megacolon but it may also occur independently in a severe course of the disease. It occurs in severe, often first flares of ulcerative colitis and most often affects the left half of the colon. The clinical presentation is dominated by the symptoms of acute abdomen and peritonitis. The presence of free gas trapped within the peritoneal cavity visible in the abdominal X-ray picture or CT scan is the most reliable confirmation of the perforation.
Intestinal bleeding: caused by significant inflammatory lesions in the rectal and colonic mucosae. It is a life-threatening condition that can only be averted by colectomy.
Intestinal stricture: observed in 12% of patients with UC after 5–25 years with the condition, typically in the sigmoid colon or the rectum. However, it may occur at any time during the course of the disease. A severe course of the disease gradually leads to fibrosis and strictures in the lumen of the intestines. It is caused by the hypertrophy and thickening of the muscularis mucosa with accompanying fibrotic lesions. Their length does not usually exceed 3 cm but may reach 20–30 cm. The diagnosis of this complication based on clinical symptoms is difficult. Symptoms of strictures involve constipation, abdominal distension, sometimes more severe diarrhoea, or faecal incontinence. In the endoscopic and radiological examination, the lesions may imitate those of colorectal cancer.
Colorectal cancer: the most serious, if remote, consequence of ulcerative colitis is colorectal cancer. Risk factors include prolonged ulcerative colitis (over 8 years), large affected area of the large intestine, and the onset of the disease in childhood. An early diagnosis is difficult. Colonoscopy, together with multiple biopsies of all parts of the large intestine play the greatest role in diagnostics. These examinations also contribute to the detection of the characteristic precancerous lesions in the form of intestinal epithelial dysplasia. Low- or high-grade dysplasia is observed in flat, macroscopically insignificantly changed, or normal mucosa or in small irregularities or polypoid elevations in the mucosa, endoscopically detectable.
Perirectal lesions occur in 5–18% of patients with ulcerative colitis. They include thrombosed or prolapsed haemorrhoids, skin maceration, fissures, abscesses, and/or perianal fistulas. The majority of these lesions are secondary to diarrhoea and are characterised as acute bacterial complications. The diagnosis is based on a thorough physical examination. The main type of the internal fistula in IBD is rectovaginal fistula.
Gastrointestinal amyloidosis is characterised by the depositing of protein substances (amyloid) in the gastrointestinal wall leading to its thickening and disorders of the motor activity of the gastrointestinal tract [1, 2, 3, 4, 5, 6] (Table 2).
Malnutrition is a significant complication in children with inflammatory bowel disease that results in delayed growth and puberty. Fatigue and loss of appetite are sometimes also observed. They may imitate anorexia nervosa.
3. Hepatic lesions
Liver-related symptoms may present as hypertransaminasemia caused by the disease or as a result of the treatment (sulfasalazine, steroids, azathioprine, and parenteral nutrition). Other serious complications include autoimmune hepatitis and primary sclerosing cholangitis. Liver-related symptoms are observed in about 50% of patients with ulcerative colitis.
The clinical manifestation is not characteristic. In 40–60%, there are no clinical symptoms, and the observed abnormal parameters of cholestasis and damage to the liver suggest primary sclerosing cholangitis.
In some patients, the skin and the sclera turn yellow, and other symptoms involve itching, fatigue, loss of body weight, weakness, epigastric pain, andor episodes of fever. PSC is a progressive condition leading to cirrhosis and liver failure. A total of 50% of patients with primary sclerosing cholangitis require a liver transplant within 10–15 years of diagnosis. A total of 50–80% of patients with PSC have a co-existing inflammatory bowel disease (ulcerative colitis more often than Lesniowski-Crohn’s disease). Lesions more often affect the right colon, with the rectum remaining unaffected (free). Interestingly, only 2–4% of patients with ulcerative colitis, and 1.4–3% of those with Lesniowski-Crohn’s disease have co-existing PSC. Other autoimmune conditions often co-exist in patients with PSC. They are type 1 diabetes mellitus, coeliac disease, autoimmune pancreatitis and Hashimoto thyroiditis, glomerulonephritis, and/or arthritis.
4. Pancreatic complications
5. Skin lesions
Skin lesions are observed in about 3–10% of patients with ulcerative colitis.
6. Rheumatoid symptoms
7. Opthalmological manifestations (1%)
Ophthalmological manifestations concern mainly patients with ulcerative colitis, with the whole area of the large intestine affected and accompanying lesions in the joints. They occur in 6–60% of patients with IBD, almost twice as frequently in men as in women. These complications are typically one-sided, and their presence is linked with the activity of the primary condition. The most common ones involve watering eyes, burning eyes, pain in the eyes, light sensitivity, conjunctival hyperaemia, scleral hyperaemia, impaired visual acuity, or complete vision loss. Ophthalmological complications may also be asymptomatic. Inflammation may develop in any part of the eye. Episcleritis, together with uveitis is the most common ophthalmological complication of inflammatory bowel disease. Less frequent conditions include iritis scleritis, keratitis, and conjunctivitis. Among complications related to the treatment of IBD, cataract is often observed, which is probably linked to the prolonged use of glucocorticoids.
Rare opthalmological complications are as follows:
8. Haematological complications
Anaemia concerns almost 30% of patients with IBD. It significantly affects the quality of life. Chronic blood loss, impaired absorption, and the impact of cytokines play an important role. Similarly, the applied treatment, involving sulfasalazine, methotrexate, and azathioprine also contributes to the condition. In the treatment of anaemia linked to ulcerative colitis, an early therapeutic intervention that is suited to the deficiencies and activity of the intestinal disease is extremely important.
Hypochromic anaemia is caused by microhaemorrhages within the gastrointestinal tract and ongoing inflammation. Anaemia caused by B12/folic acid deficiency includes autoimmune haemolytic anaemia and thrombocytopenia/thrombocytosis [1, 2, 3, 4, 5, 6, 25, 26, 27].
Reduced bone mineral density has a complex mechanism and is related to deficiencies in protein and calories, abnormal absorption of calcium, vitamin D deficiency, glucocorticoid therapy, and the adverse impact of proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-1Beta, and IL-6) on the bone tissue metabolism. Osteoporosis occurs in approximately 15% of patients with inflammatory bowel disease. Osteoporosis and osteopenia develop particularly often in patients with co-existing sclerosing cholangitis, probably as a result of the abnormal transportation and absorption of bile acids. It has been shown that patients with IBD statistically significantly more often experience fractures of long bones and the corpus vertebrae. Densitometry is a screening test and should be performed in particular in groups of patients with severe IBD, especially treated with glucocorticoids [1, 2, 3, 4, 5, 6].
10. Nephrological complications
In patients, especially in paediatric ones, the calcium obtained from food interacts with unabsorbed fatty acids. This leads to an increase in urine oxalate excretion, and significantly increases the risk of urolithiasis. Some studies concerning IBD mention cases of glomerulonephritis caused by concentrations of immune complexes in patients affected. Recurring urinary tract infections, hydronephrosis, and renal amyloidosis are reported relatively more frequently compared to the general population.
11. Cardiological complications
12. Pulmonary complications
The following occur with a greater frequency—pulmonary vasculitis, chronic bronchitis and bronchiolitis, and bronchiectasis (more extensive and more rapidly developing compared to those of another aetiology). It is sometimes difficult to determine whether the pulmonary lesions are an extraintestinal manifestation or independent comorbidity.
Drug-induced pulmonary complications are as follows:
Eosinophilic pneumonia/pleuritis: The clinical presentation is dominated by fever, cough, dyspnoea, and respiratory distress. The HRCT test shows ground-glass areas and the BAL fluid eosinophil greater than 25%.
Methotrexate-related complications—after as little as 1 dose and up to 4 weeks following the last dose; folic acid does not protect from such complications. Imaging tests show diffuse lesions, interstitial infiltrates, fibrosis, and granulomas.
Azathioprine-related complications—rarely-interstitial pneumonia; discontinuation of the medication usually leads to improvement and the withdrawal of the symptoms.
Anti-TNFα-related complications-usually interstitial pneumonia-often in older patients, with previous lung strains and with simultaneous immunosuppressing therapy-discontinuation of treatment leads to the withdrawal of the symptoms in most patients.
Opportunistic infections. Infections with Mycobacterium tuberculosis, Pneumocystis carini, Listeria monocytogenes, Aspergillus fumigatus, Histoplasma capsulatum, and Cytomegalovirus.
The pulmonary lesions are usually either asymptomatic or oligosymptomatic. Pulmonary function tests show abnormalities in over 40% of patients. The classic thoracic X-ray in the majority of patients is non-characteristic. A High-resolution CT scan, on the other, is a helpful diagnostic tool.
13. Arterial/vein thrombosis
Occurs 3–4 times more often in patients with inflammatory bowel disease compared with the healthy population. The frequency of occurrence increases with age and concerns 2–10% of patients with IBD. Vein thrombosis is the dominant condition. The treatment involves low molecular weight heparin.
Types of thrombosis are as follows:
deep vein thrombosis.
thromboembolic lesions of intracranial vessels and/or of the eye.
The significance of these complications are mainly due to the young age of the affected patients, a large percentage of deaths and complex treatment (the use of anticoagulants in patients with gastrointestinal bleeding). It is often recurring. Vein thrombosis in the course of IBD is characterised by the atypical location of the thrombotic lesions, correlates with the activity of the intestinal disease and has a proven link with the use of glucocorticoids. Active intestinal disease with thrombocythaemia and increased activity of blood coagulation factors, as well as an increase in the concentration of homocysteine, are additional factors contributing to the development of thrombosis. Thromboprophylaxis should be adopted in patients with medium/acute exacerbation of inflammatory bowel disease .
14. Neurological complications
Vascular lesions in the central nervous system occur equally frequently in patients with ulcerative colitis and those with Crohn’s Disease. They usually develop 5–6 years following the onset of the intestinal disease and often coincide with other extraintestinal manifestations of IBD [1, 2, 3, 4, 5, 6, 35, 36].
Better awareness of the initial symptoms, the course of the disease and extraintestinal manifestations, often preceding IBD may shorten the period from the onset of the symptoms to the diagnosis.
Arthritis of the large joints, iritis, and erythema nodosum occurs mainly during the periods of the exacerbation of ulcerative colitis.
Ankylosing spondylitis and most complications in the liver and bile ducts happen independently from the activity of the intestinal disease.
Extraintestinal manifestations require differential diagnosis with conditions occurring independently from IBD and drug toxicity.
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