Vitamin D levels in adults with Crohn's disease are responsive to disease activity and treatment.

BACKGROUND: Vitamin D deficiency is common in patients with Crohn's disease (CD), although whether this impairs immune responsiveness, and is related to disease activity per se, remains unclear. We sought to investigate vitamin D pathways in patients with CD according to measures of inflammation and immune response. METHODS: Prospectively collected samples of a well-characterized cohort of patients with CD were used to measure serum 25(OH)-vitamin D levels by enzyme-linked immunoassay. Related gene expression was determined by polymerase chain reaction in T cells. The effect of vitamin D on the proliferation of isolated CD4 cells was determined. RESULTS: Patients with active CD had lower serum vitamin D levels than those in clinical remission; this measurement was independent of season or reported use of vitamin D supplements. Harvey-Bradshaw Index scores, but not C-reactive protein, correlated with serum vitamin D levels. Gene expression of the vitamin D receptor was higher in peripheral blood T cells from patients with active disease than in those in remission. The proportion of CD25hi CD4 cells from patients with CD increased in the presence of vitamin D. After treatment with infliximab, significant increases in serum vitamin D levels were noted in patients. CONCLUSIONS: Low vitamin D levels are associated with disease activity in CD and increase after infliximab treatment.

Lectin-reactive anti-α-gal in patients with Crohn's disease: correlation with clinical phenotypes.

BACKGROUND: Patients with inflammatory bowel disease have higher proportions of immunoglobulin G (IgG) antibodies lacking N-galactose, also called agalactosyl IgG, in their serum. Such agalactosyl IgGs have been associated with disease activity and the immunogenicity of biologics. The aim was to describe the relationship between circulating levels of a subset of agalactosyl IgGs (anti-α-Gal) and Crohn's disease (CD) phenotypes. METHODS: Prospectively collected serum samples of a well-characterized cohort of patients with inflammatory bowel disease and controls were used. Serum anti-α-Gal levels were measured by a high-affinity enzyme-linked immunosorbent assay and referenced to a standard control. RESULTS: Serum samples from 167 subjects were tested; 62 with CD, 76 with ulcerative colitis, and 29 controls. Agalactosyl anti-α-Gal levels were significantly higher in active CD than in active ulcerative colitis (P = 0.0043) or healthy controls (P < 0.0001). Among patients with CD, agalactosyl anti-α-Gal levels were significantly higher in those with a history of arthritis, than those without (P = 0.0002), but lower in those taking immunomodulators (P = 0.03). There was no correlation between agalactosyl anti-α-Gal levels and indices of Crohn's severity, including C-reactive protein levels or Harvey-Bradshaw index. Patients who were primary or secondary nonresponders to infliximab had similar agalactosyl anti-α-Gal levels to clinical responders. CONCLUSIONS: Patients with CD have greater amounts of agalactosylated anti-α-Gal antibodies in their serum, particularly in those with associated joint disease. This increase seems to be independent of indices of disease activity, but is influenced by immunomodulator use.

Mesalamine in the treatment and maintenance of remission of ulcerative colitis.

Ulcerative colitis (UC) is a chronic disease of the GI tract that is characterized by mucosal inflammation in the colon. Mesalamine (mesalazine) is a 5-aminosalicylic acid compound that is the first-line treatment for patients with mild-to-moderate UC. There are multiple formulations of mesalamine available, primarily differentiated by their means of delivering active mesalamine to the colon. Mesalamine has been demonstrated in randomized controlled trials to induce both clinical response and remission, and maintain clinical remission, in these patients. It has few serious adverse effects and is generally well tolerated by patients. The main areas of uncertainty with use of mesalamine in patients with UC center on the optimal dose for induction of response, how to maintain patient adherence and the role of mesalamine in cancer chemoprophylaxis. Generic forms of mesalamine have yet to be approved by regulatory bodies in the USA.

Endogenous luminal surface adenosine signaling regulates duodenal bicarbonate secretion in rats.

Luminal ATP increases duodenal bicarbonate secretion (DBS) via brush border P2Y receptors. Because ATP is sequentially dephosphorylated to adenosine (ADO) and the brush border highly expresses adenosine deaminase (ADA), we hypothesized that luminal [ADO] regulators and sensors, including P1 receptors, ADA, and nucleoside transporters (NTs) regulate DBS. We measured DBS with pH and CO(2) electrodes, perfusing ADO ± adenosine receptor agonists or antagonists or the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR(inh)-172 on DBS. Furthermore, we examined the effect of inhibitors of ADA or NT on DBS. Perfusion of AMP or ADO (0.1 mM) uniformly increased DBS, whereas inosine had no effect. The A(1/2) receptor agonist 5'-(N-ethylcarboxamido)-adenosine (0.1 mM) increased DBS, whereas ADO-augmented DBS was inhibited by the potent A(2B) receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide (MRS1754) (10 µM). Other selective adenosine receptor agonists or antagonists had no effect. The A(2B) receptor was immunolocalized to the brush border membrane of duodenal villi, whereas the A(2A) receptor was immunolocalized primarily to the vascular endothelium. Furthermore, ADO-induced DBS was enhanced by 2'-deoxycoformycin (1 µM) and formycin B (0.1 mM), but not by S-(4-nitrobenzyl)-6-thioinosine (0.1 mM), and it was abolished by CFTR(inh)-172 pretreatment (1 mg/kg i.p). Moreover, ATP (0.1 mM)-induced DBS was partially reduced by (1R,2S,4S,5S)-4-2-iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (MRS2500) or 8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine (PSB603) and abolished by both, suggesting that ATP is sequentially degraded to ADO. Luminal ADO stimulates DBS via A(2B) receptors and CFTR. ATP release, ecto-phosphohydrolases, ADA, and concentrative NT may coordinately regulate luminal surface ADO concentration to modulate ADO-P1 receptor signaling in rat duodenum.

Intestinal alkaline phosphatase regulates protective surface microclimate pH in rat duodenum.

Regulation of localized extracellular pH (pH(o)) maintains normal organ function. An alkaline microclimate overlying the duodenal enterocyte brush border protects the mucosa from luminal acid. We hypothesized that intestinal alkaline phosphatase (IAP) regulates pH(o) due to pH-sensitive ATP hydrolysis as part of an ecto-purinergic pH regulatory system, comprised of cell-surface P2Y receptors and ATP-stimulated duodenal bicarbonate secretion (DBS). To test this hypothesis, we measured DBS in a perfused rat duodenal loop, examining the effect of the competitive alkaline phosphatase inhibitor glycerol phosphate (GP), the ecto-nucleoside triphosphate diphosphohydrolase inhibitor ARL67156, and exogenous nucleotides or P2 receptor agonists on DBS. Furthermore, we measured perfusate ATP concentration with a luciferin-luciferase bioassay. IAP inhibition increased DBS and luminal ATP output. Increased luminal ATP output was partially CFTR dependent, but was not due to cellular injury. Immunofluorescence localized the P2Y(1) receptor to the brush border membrane of duodenal villi. The P2Y(1) agonist 2-methylthio-ADP increased DBS, whereas the P2Y(1) antagonist MRS2179 reduced ATP- or GP-induced DBS. Acid perfusion augmented DBS and ATP release, further enhanced by the IAP inhibitor l-cysteine, and reduced by the exogenous ATPase apyrase. Furthermore, MRS2179 or the highly selective P2Y(1) antagonist MRS2500 co-perfused with acid induced epithelial injury, suggesting that IAP/ATP/P2Y signalling protects the mucosa from acid injury. Increased DBS augments IAP activity presumably by raising pH(o), increasing the rate of ATP degradation, decreasing ATP-mediated DBS, forming a negative feedback loop. The duodenal epithelial brush border IAP-P2Y-HCO(3-) surface microclimate pH regulatory system effectively protects the mucosa from acid injury.

Decision analysis model for hepatitis B prophylaxis one year after liver transplantation.

In patients receiving orthotopic liver transplantation, hepatitis B recurrence rates have decreased significantly with the use of various methods for prophylaxis. At present, a combination of hepatitis B immunoglobulin (HBIG) and lamivudine is the standard of care, resulting in recurrence rates of 0% to 11%. Recent data suggest that the addition of adefovir to lamivudine is successful in treating patients with recurrent hepatitis B infection. A Markov model was used to compare costs and outcomes of 2 strategies for hepatitis B prophylaxis 1 year after transplantation. The first consisted of prophylaxis with lamivudine and adefovir (strategy 1), whereas the second consisted of intramuscular HBIG and lamivudine (strategy 2) with the addition of adefovir in patients who subsequently developed hepatitis B recurrence. Patients who failed with adefovir and lamivudine were then treated with tenofovir and entecavir. 16.8% of liver transplant recipients had hepatitis B recurrence after 10 years of treatment with lamivudine and HBIG. The medical costs for strategy 1 and strategy 2 after 10 years of therapy were $151,819 and $166,246, respectively, and this resulted in cost savings of $14,427. The decision analysis model began 1 year after liver transplantation. A 1-way sensitivity analysis demonstrated that the model was most sensitive to cost changes of adefovir and HBIG injections as well as variations in the hepatitis B virus recurrence rate. The model was robust to costs of lamivudine, laboratory costs, administrative fees, and office visit fees. Our decision analysis model resulted in marked savings in costs with strategy 1 (lamivudine and adefovir), providing pharmacoeconomic support for the use of this strategy as first-line therapy in hepatitis B prophylaxis in liver transplant recipients 1 year after liver transplantation.

Gastroduodenal mucosal defense.

PURPOSE OF REVIEW: The gastrointestinal tract has developed multiple mechanisms of protection from intrinsic and extrinsic sources of injury, including but not limited to drugs, ischemic/reperfusion injuries, and infections such as Helicobacter pylori. We review recent developments in host defense against Helicobacter pylori, duodenal bicarbonate secretion, protection from nonsteroidal anti-inflammatory drug induced gastrointestinal injury, and apoptosis, as well as newer therapies. RECENT FINDINGS: Leptin and survivin confer protection against ethanol and indomethacin induced injury. Mucin-1, a cell surface mucin, is an important barrier to gastrointestinal infection. Prostaglandin E(2), Escherichia coli heat-stable enterotoxin, orexins, and carbonated beverages stimulate duodenal bicarbonate secretion. SUMMARY: Gastroduodenal mucosal defense is a dynamic process, and further insights into these defense mechanisms have and will lead to safer and more effective treatments.

Fistuloclysis: case report and literature review.

Enterocutaneous fistulae are a common postoperative entity, causing serious complications such as sepsis, malnutrition, and electrolyte and fluid abnormalities. Because sepsis coupled with malnutrition is the leading cause of death in these patients, it is especially important to provide nutrition support. Although parenteral nutrition (PN) is widely used in these patients, it is not without risks, because PN is known to cause liver dysfunction, among other problems. We report a case in which a male patient with an enterocutaneous fistula, having experienced increased liver enzymes receiving PN, began receiving enteral nutrition (EN) via a feeding tube placed in the fistula. Known as fistuloclysis, this method provided adequate nutrition and improved his serum albumin and prealbumin levels, body weight, and liver function tests. Upon stabilization of his nutrition status, he was able to undergo successful surgical repair of the enterocutaneous fistula. According to our experience and that of others, we recommend that patients with high-output enterocutaneous fistulae be considered for EN via fistuloclysis after nutrition stabilization with PN; then the fistulae can be surgically repaired if not spontaneously healed. Use of EN via fistuloclysis, if used appropriately, avoids the complications of long-term PN and may promote faster fistula healing.

Gastroduodenal defense.

PURPOSE OF REVIEW: The gastroduodenum resists mucosal injury despite continuous exposure to concentrated gastric acid. The mucosal barrier consists of a preepithelial mucus HCO3- layer, intercellular tight junctions connecting the epithelial cells, and submucosal acid sensors, prostaglandins, cytokines, enteric nerves and blood flow. In the past year, study of these defensive mechanisms has revealed new insight into the observed sex differences in ulcer prevalence, the protective role of transforming growth factor, the role of serotonin in regulating HCO3- secretion, the role of mechanisms in ulcer healing, the interaction of trefoil factors with the mucus gel, the interaction of glucocorticoids with cyclooxygenase and the characterization of novel, mucosal sparing antiinflammatory agents. RECENT FINDINGS: Transforming growth factor, melatonin, serotonin, trefoil factors and H2S all enhance mucosal barrier function or accelerate ulcer healing. Newer coxibs may have safety and advantages over existing compounds. Existing nonsteroidal antiinflammatory drugs may be safer than originally thought. SUMMARY: The continued elucidation of basic defense mechanisms has led to the development of several new compounds designed to enhance barrier function and repair mechanisms.