Bowel problems occur in 27% to 62% of patients with spinal cord injuries (SCI), most commonly constipation, distention, abdominal pain, rectal bleeding, hemorrhoids, bowel accidents, and autonomic hyperreflexia. The acute abdomen, with a mortality of 9.5%, does not present with rigidity or absent bowel sounds but rather with dull/poorly-localized pain, vomiting, or restlessness, with tenderness, fever, and leukocytosis in up to 50% of patients. Fecal impaction may present with anorexia and nausea. Methods used for bowel care include laxatives, anal massage, manual evacuation, and enemas. Randomized, double-blind studies demonstrated the effectiveness of neostigmine, which increases cholinergic tone, combined with glycopyrrolate, an anticholinergic agent with minimal activity in the colon that reduces extracolonic side-effects. Improved bowel function occurs with anterior sacral root stimulators which may be combined with an S2 to S4 posterior sacral rhizotomy which interrupts the reflex arc by cutting the posterior roots carrying the spasticity-causing sensory nerves. For severe constipation, a colostomy reduces time for bowel care, providing a clean environment so decubitus ulcers may heal. Gallstones occur in 17% to 31% of patients, and acalculous cholecystitis in 3.7% of patients with acute SCI. A high index of suspicion is needed to properly diagnose bowel problems in SCI.

Gastrointestinal (GI) manifestations of leukemia occur in up to 25% of patients at autopsy, generally during relapse. Its presence varies with the type of leukemia and has been decreasing over time due to improved chemotherapy. Gross leukemic lesions are most common in the stomach, ileum, and proximal colon. Leukemia in the esophagus and stomach includes hemorrhagic lesions from petechiae to ulcers, leukemic infiltrates, pseudomembranous esophagitis, and fungal esophagitis. Lesions in the small and large bowel are usually hemorrhagic or infiltrative. Infiltration of lymphoreticular organs, mainly spleen, liver, and lymph nodes, is more prominent in chronic than acute leukemia. Neutropenic enterocolitis, a necrotizing process involving the cecum, ascending colon, and terminal ileum, is increasing in incidence due to greater intensity of chemotherapy. Distension of bowel leads to mucosal breaches, permitting entry of organisms that grow profusely in the absence of neutrophils. Ischemic necrosis follows, leading to perforation and/or peritonitis. Patients present with fever, abdominal pain, diarrhea, nausea, vomiting, abdominal distension and tenderness. Ultrasound and computed tomography scans show thickening of the bowel wall. Treatment is supportive with surgery for necrosis and perforation. The main GI causes of death in leukemia are hemorrhage, infection, and necrotizing enterocolitis.

In this review of the gastrointestinal (GI) and hepatic manifestations of systemic lupus erythematosus (SLE), 180 articles from the English literature, found using a medline search from January 1965 to December 2010, were examined. Vasculitis may cause ulcerations, bleeding, stricture formation, and perforation from ischemia and infarction. Otherwise, GI symptoms, occurring in about 50% of patients, are usually mild. Esophageal dysmotility may result in heartburn, regurgitation, and dysphagia. Occasionally, pneumatosis cystoides intestinalis may develop, sometimes associated with benign pneumoperitoneum. Patients are prone to salmonella bacteremia, presenting more commonly with fever and abdominal pain than with diarrhea. Intestinal pseudoobstruction usually is found with active lupus serology, preferentially involving small rather than the large bowel. Protein-losing enteropathy, characterized by diarrhea, edema, and hypoalbuminemia, can be the initial presentation of SLE. Malabsorption with a prevalence of 9.5% is occasionally associated with celiac disease. Pancreatitis, with an annual incidence of 0.4 to 1/1000, has an overall mortality of 27% that is decreased with corticosteroid therapy. Acute and chronic ascites may be due to lupus peritonitis or to associated diseases, such as pancreatitis, nephrotic syndrome, heart failure, or infections. Abnormal liver function tests may be due to steatosis from lupus or from corticosteroid therapy. Only about 10% of patients with autoimmune hepatitis have lupus. Up to 4.7% of patients with SLE have chronic active hepatitis correlating strongly with the presence of antibody to ribosomal P protein. SLE can involve the entire GI tract and the liver. Treatment with corticosteroids, cytotoxic agents, and/or immunosuppressants is often successful.

Background and Aims: The diagnosis of Churg-Strauss syndrome (CSS), an allergic granulomatosis involving small- and medium-sized vessels, requires the presence of at least four of six criteria including asthma, peripheral eosinophilia, and systemic vasculitis. The gastrointestinal manifestations have never been reviewed. Methods: The 75 articles in the English literature found by electronic searches from 1960 to 2011 were examined. Results: Ischemia from vasculitis causes ulcerations, perforation, annular stenosis, and/or intestinal occlusions usually involving the small bowel, presenting as an acute abdomen or intestinal angina. Colonoscopy characteristically shows shallow ulcers with erythematous halos. Endoscopic biopsies usually do not reveal vasculitis as this requires sampling of the submucosa. Intestinal resections reveal eosinophilic infiltrates, vasculitis, fibrinoid necrosis, and/ or granulomas. Unusual complications include acalculous cholecystitis and eosinophilic ascites from involvement of the peritoneum. Most patients respond to corticosteroids although mesenteric ischemia is associated with a poor outcome. Conclusion: CSS, while rare, has characteristic GI involvement.

Rheumatoid arthritis (RA), characterized by inflammation of the synovium and surrounding structures, has a prevalence of 0.5–1%. Rheumatoid vasculitis (RV) is an inflammatory condition of the small- and medium-sized vessels that affects up to 5% of patients with RA with intestinal involvement in 10–38% of these cases. Clinically apparent RV of the gastrointestinal (GI) tract, while rare, is often catastrophic, resulting in ischemic ulcers and bowel infarction. Vasculitis of the colon may present as pancolitis clinically similar to ulcerative colitis. Rectal biopsies that include submucosal vessels are positive for vasculitis in up to 40% of cases. Abnormal esophageal motility in RA may result in heartburn and dysphagia. Chronic atrophic gastritis may be associated with hypergastrinemia and hypo- or achlorhydria, promoting small bowel bacterial overgrowth. RA is the most common cause of secondary amyloidosis with GI symptoms in 22% of affected patients. Although amyloid is usually found in the liver, it is rarely evident clinically. Felty’s syndrome occurs in less than 1% of patients with RA and is characterized by neutropenia and splenomegaly. The liver may be involved with portal fibrosis or nodular regenerative hyperplasia. Liver histology is abnormal in 92% of RA patients at autopsy, although the changes are usually mild without associated hepatomegaly. Drug-induced liver disease may occur with aspirin, sulfasalazine, and methotrexate. Significant liver damage is rare if the drug is discontinued or the patient is properly monitored. RA can affect both the GI tract and the liver; changes are usually mild except with RV.

Sickle cell disease (SCD) is an autosomal recessive abnormality of the beta-globin chain of hemoglobin (Hb), resulting in poorly deformable sickled cells that cause microvascular occlusion and hemolytic anemia. The spleen is almost always affected by SCD, with microinfarcts within the first 36 months of life resulting in splenic atrophy. Acute liver disorders causing right-sided abdominal pain include acute vaso-occlusive crisis, liver infarction, and acute hepatic crisis. Chronic liver disease might be due to hemosiderosis and hepatitis and possibly to SCD itself if small, clinically silent microvascular occlusions occur chronically. Black pigment gallstones caused by elevated bilirubin excretion are common. Their small size permits them to travel into the common bile duct but cause only low-grade obstruction, so hyperbilirubinemia rather than bile duct dilatation is typical. Whether cholecystectomy should be done in asymptomatic individuals is controversial. The most common laboratory abnormality is an elevation of unconjugated bilirubin level. Bilirubin and lactate dehydrogenase levels correlate with one another, suggesting that chronic hemolysis and ineffective erythropoiesis, rather than liver disease, are the sources of hyperbilirubinemia. Abdominal pain is very common in SCD and is usually due to sickling, which resolves with supportive care. Computed tomography scans might be ordered for severe or unremitting pain. The liver typically shows sickled erythrocytes and Kupffer cell enlargement acutely and hemosiderosis chronically. The safety of liver biopsies has been questioned, particularly during acute sickling crisis. Treatments include blood transfusions, exchange transfusions, iron-chelating agents, hydroxyurea, and allogeneic stem-cell transplantation.

Thyroid disease is common, and its effects on the gastrointestinal system are protean, affecting most hollow organs. Hashimoto disease, the most common cause of hypothyroidism, may be associated with an esophageal motility disorder presenting as dysphagia or heartburn. Dyspepsia, nausea, or vomiting may be due to delayed gastric emptying. Abdominal discomfort, flatulence, and bloating occur in those with bacterial overgrowth and improve with antibiotics. Reduced acid production may be due to autoimmune gastritis or low gastrin levels. Constipation may result from diminished motility, leading to an ileus, megacolon, or rarely pseudoobstruction. Ascites in myxedema is characterized by a high protein concentration. Graves' disease accounts for 60% to 80% of thyrotoxicosis. Hyperthyroidism is accompanied by normal gastric emptying with low acid production, partly due to an autoimmune gastritis with hypergastrinemia. Transit time from mouth to cecum is accelerated, resulting in diarrhea. Steatorrhea is due to hyperphagia and stimulation of the adrenergic system. Diarrhea in medullary carcinoma of the thyroid (MCT) may be due to elevated calcitonin, prostaglandins, or 5-hydroxyindoleacetic acid. Ileal or colonic function may be abnormal. The esophagus may be compressed by benign processes, but more often by malignancies. MRI and CT scans are the best diagnostic modalities. The gastrointestinal manifestations of thyroid disease are generally due to reduced motility in hypothyroidism, increased motility in hyperthyroidism, autoimmune gastritis, or esophageal compression by a thyroid process. Symptoms usually resolve with treatment of the thyroid disease.

events (i.e.magnifying glass).A 1 year risk of EAC of 0.5 -1% per year was used as the standard risk estimate.Results: A total of 236 patients were recruited.Most participants were male (76%) and Caucasian (94%).Only 43% of participants had perfect numeracy scores (8 out of 8 questions correct).The mean numeracy score for all BE patients was 83%, or 6.6 (SD 1.7) out of 8 questions correct.The mean estimated 1 year risk of EAC was 7% (SD 18%).Overall, 62% overestimated their 1 year risk of EAC.When stratified by high vs. low numeracy skills (score ≥ or < median), there was no difference in the proportion of patients who overestimated their EAC risk (66% vs. 54%, p=0.2).Multivariate logistic regression analysis revealed that age, gender, and employment status were not independently associated with impaired numeracy.Conclusion: A majority of BE patients had measurable deficits in numeracy skills.Poor numeracy was not related to overestimation of cancer risk, indicating that misperception of EAC risk may be an emotional, not cognitive issue.

This review discusses gastrointestinal manifestations of parathyroid diseases. Parathyroid hormone is the primary regulator of calcium physiology. Hypoparathyroidism can be idiopathic, hereditary, or secondary to surgery in the neck. Hyperparathyroidism is usually from adenomas or hyperplasia. Hypoparathyroidism is associated with steatorrhea that may improve with medium-chain triglycerides, correction of the hypoparathyroidism, or administration of vitamin D. Hyperparathyroidism results in constipation because of reduction in neuromuscular excitability by high calcium levels. According to old literature, the incidence of peptic ulcer disease (PUD) in patients with hyperparathyroidism is 9% compared with autopsy rates of 4% to 5%. Any association is difficult to prove today, as hyperparathyroidism is usually mild due to early detection of cases through routine automated measurements of calcium. In addition, PUD is less prevalent now than before the advent of proton pump inhibitors. The presence of ulcers or ulcer symptoms may correct in some patients after parathyroidectomy, suggesting an association. The incidence of pancreatitis in patients with primary hyperparathyroidism ranges from 1.5% to 12% and may be because of the hypercalcemia. Complicating the issue is secondary hyperparathyroidism in response to hypocalcemia from pancreatitis. Pancreatitis may improve in some individuals after parathyroidectomy. Pancreatitis may follow parathyroid surgery because of an acute rise in calcium levels with manipulation of the parathyroid glands or to a blunted response of calcitonin-producing cells from fatigue. Parathyroid diseases have a few distinct effects on the gut: steatorrhea in hypoparathyroidism, and constipation, PUD, and pancreatitis in hyperparathyroidism.

This review discusses gastrointestinal manifestations of parathyroid diseases. Parathyroid hormone is the primary regulator of calcium physiology. Hypoparathyroidism can be idiopathic, hereditary, or secondary to surgery in the neck. Hyperparathyroidism is usually from adenomas or hyperplasia. Hypoparathyroidism is associated with steatorrhea that may improve with medium-chain triglycerides, correction of the hypoparathyroidism, or administration of vitamin D. Hyperparathyroidism results in constipation because of reduction in neuromuscular excitability by high calcium levels. According to old literature, the incidence of peptic ulcer disease (PUD) in patients with hyperparathyroidism is 9% compared with autopsy rates of 4% to 5%. Any association is difficult to prove today, as hyperparathyroidism is usually mild due to early detection of cases through routine automated measurements of calcium. In addition, PUD is less prevalent now than before the advent of proton pump inhibitors. The presence of ulcers or ulcer symptoms may correct in some patients after parathyroidectomy, suggesting an association. The incidence of pancreatitis in patients with primary hyperparathyroidism ranges from 1.5% to 12% and may be because of the hypercalcemia. Complicating the issue is secondary hyperparathyroidism in response to hypocalcemia from pancreatitis. Pancreatitis may improve in some individuals after parathyroidectomy. Pancreatitis may follow parathyroid surgery because of an acute rise in calcium levels with manipulation of the parathyroid glands or to a blunted response of calcitonin-producing cells from fatigue. Parathyroid diseases have a few distinct effects on the gut: steatorrhea in hypoparathyroidism, and constipation, PUD, and pancreatitis in hyperparathyroidism.

Human intra-epithelial lymphocytes (IELs) are predominantly T-cell receptor-alphabeta(+) (TCR-alphabeta(+)) CD8(+) CD45RO(+) memory T cells located between intestinal epithelial cells. They respond to a greater extent to stimulation with interleukin (IL)-15 than to CD3/TCR triggering, suggesting that they react to the cytokine milieu in their local environment rather than to cognate antigen. A newly described member of the gammac cytokine family, IL-21, has potent antitumor effects. As IELs resemble lymphocytes infiltrating neoplastic lesions, their response to IL-21 may be relevant in vivo. Here, IL-21 was shown to increase perforin-mediated cytotoxicity and serine esterase release by IELs. This IL-21-mediated up-regulation occurred without changes in IEL survival or cell division. Interestingly, the effects of IL-21 occurred without increased phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, STAT4, STAT5, extracellular signal-regulated kinase (ERK), or p38. IL-21 had no effect on Fas ligand (FL)- or tumour necrosis factor-alpha (TNF-alpha)-mediated cytotoxicity, but it down-regulated IL-15-stimulated expression of CD25 and CD94, indicating that it has both positive and negative actions. This functional profile is unique to human IELs, emphasizing that they are a distinct compartment of lymphocytes and that IL-21 may promote their role in tumour immunosurveillance.

Ulcerative colitis (UC) and Crohn's disease (CD) are considered to be immunologically mediated disorders that share certain features with murine models of colitis. Whether any of these models are physiologically relevant to the human condition remains controversial. The hypothesis is that increased amounts of antibodies neutralizing transforming growth factor (TGF)-beta, interleukin (IL)-2 or IL-10 create a relative immunodeficient state in inflammatory bowel disease (IBD) that predisposes to disease. To evaluate this, serum samples from patients with UC or CD and from normal healthy individuals were studied by enzyme-linked immunosorbent assays. Antibodies recognizing TGF-beta were most prevalent in UC (P<0.01); anti-IL-10 antibodies were elevated in CD (P<0.05), while anti-IL-2 antibodies were the same for all three groups. Importantly, the percentage of IBD patients with at least one of the antibody levels greater than any control value was 30% for UC and 33% for CD. To verify the presence of these antibodies, immobilized TGF-beta was exposed to UC sera and the attached proteins identified by Western blot assay. The proteins proved to be exclusively immunoglobulin (Ig) G. To evaluate the neutralizing activity of these antibodies, cytokine-specific IgG from subjects in each group of patients was incubated with TGF-beta, IL-2 or IL-10 before addition to a bioassay with changes in viability determined by a colorimetric analysis. Antibodies from most individuals in all three groups neutralized the action of each cytokine. This study shows that about one-third of IBD patients may have a relative deficiency of TGF-beta, IL-2 or IL-10 due to an increase in neutralizing antibodies in their sera.

OBJECTIVES: Tropomyosins (TMs) are cytoskeletal microfilament proteins present in all eukaryotic cells. Human TM isoform 5 (hTM5) is the predominant isoform in colonic epithelial cells. Antibodies against hTM5 are found both in the sera and in the mucosa of patients with ulcerative colitis (UC) but not Crohn's disease (CD). We investigated whether anti-hTM5 autoantibodies are pathogenic.METHODS: Normal-appearing colonic mucosal biopsy specimens were incubated with autologous serum. After 45 min, deposition of the complement component C3b was identified by indirect immunofluorescence assay (IFA). Additional specimens were incubated with autologous serum fixed in formalin, and their architecture was examined by hematoxylin and eosin (H&E) staining.RESULTS: For 79% of UC patients, autologous serum caused C3b staining along the colonic epithelium. Recombinant hTM5 or anti-hTM5 monoclonal antibody blocked serum-induced C3b deposition. Immunoglobulin G (IgG) antibody and affinity-purified anti-hTM5 IgG antibody from UC sera with complement caused C3b deposition, indicating specificity of hTM5 as an autoantigen. When analyzed by H&E staining, sera obtained from 71% of UC patients caused a significant loss of epithelium. This process was inhibited by Fc fragments, indicating that it is complement mediated. With medium, normal, or CD serum, there was no C3b deposition or morphological changes of the colonic epithelium, indicating disease specificity. The ileal mucosa was not affected by UC sera, suggesting specificity for the colon. In UC mucosa, expression of hTM5 increased.CONCLUSIONS: hTM5 acts as an autoantigen in UC. hTM5-specific IgG autoantibody in sera from UC patients induces C3b deposition and destruction of colonic epithelial cells, suggesting a direct pathogenic effect. If used as a diagnostic test to distinguish UC from CD, IFA would have 79% sensitivity and 100% specificity. Development of blocking antibodies may lead to novel therapies.

Behçet’s disease is a rare vasculitis diagnosed by the presence of recurrent oral ulcers and two of the following: genital ulcers, typical eye lesions, typical skin lesions, and positive pathergy test. It is most commonly seen in countries along the ancient silk road from Eastern Asia to the Mediterranean Basin. Young adults between the second and fourth decades of life are mainly affected, with abdominal pain being the most common symptom. The ileocecal region is most commonly affected, with ulcerations that may penetrate or perforate. Rarely, the esophagus and stomach may have ulcerations. Bowel wall thickening is the most common finding on computed tomography (CT) scan. Pathology shows a vasculitis mainly involving the small veins or, alternatively, nonspecific inflammation. Corticosteroids, with or without other immunosuppressive drugs, are used for severe eye disease. Their use in intestinal disease is largely empirical. Surgery may be required for perforation. Behçet’s disease runs a chronic, unpredictable course with exacerbations and remissions which decrease in frequency and severity over time. Death is mainly due to major vessel disease and neurological involvement.

Human intestinal CD3+TCRalphabeta+CD8+ intraepithelial lymphocytes (IELs) are intimately associated with epithelial cells (ECs) through binding of CD103 to E-cadherin. How these two cell types functionally interact is largely unknown. IEL-EC cross talk was determined using HT-29 cells as the model EC and IL-8 as the readout. IL-8 was derived from both cell types and synergistically increased when the cells were combined. This synergistic effect required active transcription by both IELs and HT-29 cells. Cell contact was required as shown by the loss of the synergistic increase in IL-8 when the two cell types were separated by Transwells. Specifically, IL-8 release required the binding of CD2 on the IELs to CD58 on the HT-29 cells. The association of the CD3/TCR complex with major histocompatibility antigen class I antigens was not involved. Antibody neutralization of tumor necrosis factor-alpha (TNF-alpha), but not interferon-gamma (IFN-gamma), resulted in increased IL-8 production by the coculture. Although both TNF-alpha and IFN-gamma increased IL-8 synthesis and CD58 expression by the HT-29 cells, only IFN-gamma reduced IL-8 production by IELs. IL-8 production by either cell type involved phosphorylation of p38 and JNK. In summary, the synergistic synthesis of IL-8 occurs when IELs are stimulated through the CD2 pathway by CD58 on HT-29 cells, resulting in TNF-alpha release that, in turn, augments IL-8 synthesis and CD58 expression by the HT-29 cells.

Infliximab, a chimeric monoclonal antibody against TNF-alpha, is efficacious in Crohn's disease (CD) and rheumatoid arthritis (RA). Its main mechanism of action is thought to be the induction of apoptosis. The present study evaluates in detail the effects of infliximab on the TNF-alpha system using peripheral blood monocytes and T cells as well as lamina propria lymphocytes from normal individuals and patients with CD, ulcerative colitis, and RA. Lymphocytes were studied in the resting state in the absence of strong stimuli that may obscure subtle findings. Infliximab did not change the numbers of viable cells. Rather, it caused monocytes to increase their release of soluble TNFR2, which serves to neutralize TNF-alpha, potentiating the action of infliximab. It reduced TNFR2 expression, thereby decreasing TNF-alpha responsiveness. These changes were due to upregulated production of TNFR2 rather than increased shedding. Infliximab did not cause rebound production of TNF-alpha transcripts that would counteract its effects. It specifically enhanced production of IL-10 but not proinflammatory cytokines secreted by leukocytes, thereby promoting an anti-inflammatory microenvironment. In addition, infliximab caused a rise in c-Jun amino-terminal kinase phosphorylation by monocytes. Thus infliximab manipulates the TNF-alpha system to promote its anti-TNF-alpha effects.

Aliment Pharmacol Ther 31, 359–365

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets.

Polyarteritis nodosa (PAN) is a necrotizing, focal segmental vasculitis that affects predominantly medium-sized arteries in many different organ systems. It is associated with hepatitis B virus (HBV) in about 7% of cases, a decline from about 30% before the mandatory testing of blood products and the widespread vaccination programs. HBV PAN is an early postinfectious process. The hepatitis is silent in most cases, with mild transaminase level increases in 50% of patients. Gastrointestinal involvement occurs in 14% to 65% of patients with PAN. Postprandial abdominal pain from ischemia is the most common symptom. When transmural ischemia develops, there may be necrosis of the bowel wall with perforation, associated with a poor prognosis. Liver involvement occurs in 16% to 56% of patients, although clinical manifestations related to liver disease are quite rare. Acalculous gangrenous cholecystitis may develop owing to arteritis involving the wall of the gallbladder. Microaneurysms on arteriography or computed tomography angiography are characteristic of PAN, but are seen in other conditions. Tissue biopsy may confirm the diagnosis, although involvement is segmental. Corticosteroids are used for non-HBV PAN with cyclophosphamide added for severe disease. For PAN related to HBV, a 2-week course of corticosteroids is begun, with plasma exchanges and an antiviral agent. Corticosteroids and cyclophosphamide have improved patient outcome so that the 1-year survival rate is now about 85%.