of blood clots; painful swelling of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism. respiratory laryngeal involvement in inflammatory bowel disease is extremely rare. only 12 cases of laryngeal involvement in crohn disease have been reported as of 2019. moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported as of that date. 9 patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of crohn's disease. considering extraintestinal manifestations of cd, those involving the lung are relatively rare. however, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. the most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. there are a number of mechanisms by which the lungs may become involved in cd. these include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs. a complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonary vasculitis, apical fibrosis, bronchiectasis, bronchitis, bronchiolitis, tracheal stenosis, granulomatous lung disease, and abnormal pulmonary function. musculoskeletal crohn's disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy. this group of diseases is characterized by inflammation of one or more joints (arthritis) or muscle insertions (enthesitis). the arthritis in crohn's disease can be divided into two types. the first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows. the second type symmetrically involves five or more of the small joints of the hands and feet. the arthritis may also involve the spine, leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved. the symptoms of arthritis include painful, warm, swollen, stiff joints, and loss of joint mobility or function. crohn's disease increases the risk of osteoporosis or thinning of the bones. individuals with osteoporosis are at increased risk of bone fractures. dermatological a single lesion of erythema nodosum crohn's disease may also involve the skin, blood, and endocrine system. erythema nodosum is the most common type of skin problem, occurring in around 8% of people with crohn's disease, producing raised, tender red nodules usually appearing on the shins. erythema nodosum is due to inflammation of the underlying subcutaneous tissue, and is characterized by septal panniculitis. pyoderma gangrenosum is a less common skin problem, occurring in under 2%, and is typically a painful ulcerating nodule. clubbing, a deformity of the ends of the fingers, may also be a result of crohn's disease. other very rare dermatological manifestations include: pyostomatitis vegetans, psoriasis, erythema multiforme, epidermolysis bullosa acquista (described in a case report), and metastatic cd (the spread of crohn's inflammation to the skin). it is unknown if sweet's syndrome is connected to crohn's disease. neurological crohn's disease can also cause neurological complications (reportedly in up to 15%). the most common of these are seizures, stroke, myopathy, peripheral neuropathy, headache, and depression. central and peripheral neurological disorders are described in patients with ibd and include peripheral neuropathies, myopathies, focal central nervous system defects, convulsions, confusional episodes, meningitis, syncope, optic neuritis, and sensorineural loss. autoimmune mechanisms are proposed for involvement with ibd. nutritional deficiencies associated with neurological manifestations, such as vitamin b12 deficiency, should be investigated. spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space. psychiatric and psychological crohn's disease is linked to many psychological disorders, including depression and anxiety, denial of your disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image. endocrinological or hematological autoimmune hemolytic anemia, a condition in which the immune system attacks the red blood cells, is also more common in crohn's disease and may cause fatigue, a pale appearance, and other symptoms common in anemia. secondary amyloidosis (aa) is another rare but serious complication of inflammatory bowel disease (ibd), generally seen in crohn's disease. at least 1% of patients with crohn's disease develop amyloidosis. in the literature, the time lapse between the onset of crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years. leukocytosis and thrombocytopenia are usually due to immunosuppressant treatments or sulfasalazine. plasma erythropoietin levels often are lower in patients with ibd than expected, in conjunction with severe anemia. thrombocytosis and thromboembolic events resulting from a hypercoagulable state in patients with ibd can lead to pulmonary embolism or thrombosis elsewhere in the body. thrombosis has been reported in 1.8% of patients with uc and 3.1% of patients with cd. thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with uc and one with cd described in case reports. in rare cases, hypercoagulation disorders and portal vein thrombosis have been described. malnutrition symptoms people with crohn's disease may develop anemia due to vitamin b12, folate, iron deficiency, or due to anemia of chronic disease. the most common is iron deficiency anemia from chronic blood loss, reduced dietary intake, and persistent inflammation leading to increased hepcidin levels, restricting iron absorption in the duodenum. as crohn's disease most commonly affects the terminal ileum where the vitamin b12/intrinsic factor complex is absorbed, b12 deficiency may be seen. this is particularly common after surgery to remove the ileum. involvement of the duodenum and jejunum can impair the absorption of many other nutrients including folate. people with crohn's often also have issues with small bowel bacterial overgrowth syndrome, which can produce micronutrient deficiencies. intestinal damage crohn's disease can lead to several mechanical complications within the intestines, including obstruction, fistulae, and abscesses. obstruction typically occurs from strictures or adhesions that narrow the lumen, blocking the passage of the intestinal contents. a fistula can develop between two loops of bowel, between the bowel and bladder, between the bowel and vagina, and between the bowel and skin. abscesses are walled-off concentrations of infection, which can occur in the abdomen or in the perianal area. crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae. symptoms caused by intestinal stenosis, or the tightening and narrowing of the bowel, are also common in crohn's disease. abdominal pain is often most severe in areas of the bowel with stenosis. persistent vomiting and nausea may indicate stenosis from small bowel obstruction or disease involving the stomach, pylorus, or duodenum. intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease. granuloma is considered the hallmark of microscopic diagnosis in crohn's disease (cd), but granulomas can be detected in only 21–60% of cd patients. cancer crohn's disease also increases the risk of cancer in the area of inflammation. for example, individuals with crohn's disease involving the small bowel are at higher risk for small intestinal cancer. similarly, people with crohn's colitis have a relative risk of 5.6 for developing colon cancer. screening for colon cancer with colonoscopy is recommended for anyone who has had crohn's colitis for at least eight years. some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in crohn's involving the colon; two agents have been suggested, folate and mesalamine preparations. also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers. some cancers, such as acute myelocytic leukaemia have been described in cases of crohn's disease. hepatosplenic t-cell lymphoma (hstcl) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. tnf-α inhibitor treatments (infliximab, adalimumab, certolizumab, natalizumab, and etanercept) are thought to be the cause of this rare disease. endoscopic image of colon cancer identified in the sigmoid colon on screening colonoscopy for crohn's disease major complications major complications of crohn's disease include bowel obstruction, abscesses, free perforation, and hemorrhage, which in rare cases may be fatal. other complications individuals with crohn's disease are at risk of malnutrition for many reasons, including decreased food intake and malabsorption. the risk increases following resection of the small bowel. such individuals may require oral supplements to increase their caloric intake, or in severe cases, total parenteral nutrition (tpn). most people with moderate or severe crohn's disease are referred to a dietitian for assistance in nutrition. small intestinal bacterial overgrowth (sibo) is characterized by excessive proliferation of colonic bacterial species in the small bowel. potential causes of sibo include fistulae, strictures, or motility disturbances. hence, patients with crohn's disease are especially predisposed to develop sibo. as result, cd patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism, flatulence, and abdominal pain, mimicking acute flare in these patients. pregnancy crohn's disease can be problematic during pregnancy, and some medications can cause adverse outcomes for the fetus or mother. consultation with an obstetrician and gastroenterologist about crohn's disease and all medications facilitates preventive measures. in some cases, remission occurs during pregnancy. certain medications can also lower sperm count or otherwise adversely affect a man's fertility. ostomy-related complications common complications of an ostomy (a common surgery in crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis. etiology the etiology of crohn's disease is unknown. many theories have been disputed, with four main theories hypothesized to be the primary mechanism of crohn's disease. in autoimmune diseases, antibodies and t lymphocytes are the primary mode of inflammation. these cells and bodies are part of the adaptive immune system, or the part of the immune system that learns to fight foreign bodies when first identified. autoinflammatory diseases are diseases where the innate immune system, or the immune system we are genetically coded with, is designed to attack our own cells. crohn's disease likely has involvement of both the adaptive and innate immune systems. autoinflammatory theory crohn's disease can be described as a multifactorial autoinflammatory disease. the etiopathogenesis of crohn's disease is still unknown. in any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. in this respect interestingly enough, as for blau's disease (a monogenic autoinflammatory disease), the nod2 gene mutations have been linked to crohn's disease. however, in crohn's disease, nod2 mutations act as a risk factor, being more common among crohn's disease patients than the background population, while in blau's disease nod2 mutations are linked directly to this syndrome, as it is an autosomal-dominant disease. all this new knowledge in the pathogenesis of crohn's disease allows us to put this multifactorial disease in the group of autoinflammatory syndromes. some examples of how the innate immune system affects bowel inflammation have been described. a meta-analysis of cd genome-wide association studies revealed 71 distinct cd-susceptibility loci. interestingly, three very important cd-susceptibility genes (the intracellular pathogen-recognition receptor, nod2; the autophagy-related 16-like 1, atg16l1 and the immunity-related gtpase m, irgm) are involved in innate immune responses against gut microbiota, while one (the x-box binding protein 1) is involved in regulation of the immune pathway via mhc class ii, resulting in autoinflammatory inflammation. studies have also found that increased ilc3 can overexpress major histocompatibility complex (mhc) ii. mhc class ii can induce cd4+ t cell apoptosis, thus avoiding the t cell response to normal bowel micro bacteria. further studies of ibd patients compared with non-ibd patients found that the expression of mhc ii by ilc3 was significantly reduced in ibd patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. this can also make the intestines more susceptible to environmental factors, such as food or bacteria. the thinking is, that because crohn's disease has strong innate immune system involvement and has nod2 mutations as a predisposition, crohn's disease is more likely an autoinflammatory disease than an autoimmune disease. immunodeficiency theory a substantial body of data has emerged in recent years to suggest that