Tadashi Kosaka

IL18 polymorphism is associated with an increased risk of Crohn’s disease

Background. The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn’s disease. Methods. To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure. Results. No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/ TCC at codon 35. In patients with Crohn’s disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (χ2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39–4.80). Also, the magnitude of the association was more remarkable in females (χ2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73–24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn’s disease, especially in females. Conclusions.IL18 is probably one of several genes that determine susceptibility to Crohn’s disease.

Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population

Background: Interleukin‐18 (IL‐18) is a pleiotropic cytokine that induces the production of interferon (IFN)‐&ggr; and also to regulate Th2 cytokines. Recently, association studies between IL‐18 gene promoter polymorphisms and several Th1‐ or Th2‐mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohns disease (CD), recent evidence suggests that IL‐18 is involved in the pathogenesis. Methods: Using DNA direct sequencing, we investigated IL‐18 gene promoter polymorphisms at −607C/A and −137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. Results: In UC, the −137C allele frequency was significantly higher in the proctitis‐type patients than in controls (Pc = 0.0068). The −137 genotype frequency was also significantly different in the proctitis‐type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (−607A, −137C), which had a lower promoter activity and IFN‐&ggr; mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis‐type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. Conclusions: IL‐18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC.

Oral Spherical Adsorptive Carbon for the Treatment of Intractable Anal Fistulas in Crohn's Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVES:Anal fistulas are common in individuals with Crohns disease (CD). We sought to evaluate the efficacy of oral spherical adsorptive carbon (AST-120) (Kremezin®; Kureha Corporation, Tokyo, Japan) for the treatment of intractable anal fistulas in patients with CD.METHODS:In this multicenter, randomized, double-blind, placebo-controlled trial, patients with CD and at least one active anal fistula under treatment were assigned to receive either AST-120 or placebo for 8 wk. Improvement was defined as a reduction of 50% or more from baseline in the number of draining fistulas observed at both 4 and 8 wk. Remission was defined by closure of all draining fistulas at both 4 and 8 wk. The Perianal Disease Activity Index (PDAI) and Crohns Disease Activity Index (CDAI) were also assessed.RESULTS:In total, 62 patients were randomized, of whom 57 received AST-120 (N = 27) or placebo (N = 30). The improvement rate in the AST-120 group (37.0%) was significantly greater than that in the placebo group (10.0%) (P= 0.025). The corresponding remission rates were 29.6% and 6.7%, respectively (P= 0.035). PDAI significantly improved at both 4 and 8 wk with AST-120, compared to placebo (P= 0.004 and P= 0.005, respectively). CDAI was also significantly improved at both 4 and 8 wk in the AST-120 group, compared to the placebo group (P= 0.007 and P= 0.001, respectively). AST-120 treatment was well tolerated and no life-threatening adverse events were observed.CONCLUSION:AST-120 is useful for the control of intractable anal fistulas in CD patients.

Effects of Hepatocyte Growth Factor on Rat Inflammatory Bowel Disease Models

Hepatocyte growth factor (HGF) is a hepatotrophic factor and, also, functions as an epithelial growth factor. We examined the therapeutic effects of HGF on rat inflammatory bowel disease models induced by trinitrobenzensulfonic acid or dextran sulfate sodium. Recombinant human HGF was continuously administered at 50 μg/body/day using an intraperitoneally implanted pump for 7 days. Treatment of HGF reduced the ulcerated area, histological damage score, mucosal myeloperoxidase activity, and epithelial apoptotic rate but did not increase epithelial mitotic rate and immunohistochemical labeling indexes of proliferating cell nuclear antigen, Ki-67, and bromodeoxyuridine as indexes of epithelial cell proliferation in either model. We then examined the epithelial localization of the HGF receptor c-met and identified it on the surface epithelia, where apoptosis was observed, but did not find it in the proliferative zone. These results suggest that HGF exhibits therapeutic effects via anti-inflammation including antiapoptosis rather than epithelial cell proliferation in these inflammatory bowel disease models.

Activated platelets as a possible early marker to predict clinical efficacy of leukocytapheresis in severe ulcerative colitis patients

BackgroundLeukocytapheresis (LCAP) is an effective adjunct for patients with active ulcerative colitis (UC). Because LCAP may have the potential to remove and modulate not only leukocytes but also platelets, we evaluated the correlation between activated platelets and the therapeutic response to LCAP.MethodsFourteen patients with severe UC received weekly LCAP for 5 consecutive weeks. Their average clinical activity index (CAI) and endoscopic index (EI) were 9.6 ± 3.4 and 10.9 ± 1.0, respectively. Their peripheral blood was sampled before and after every LCAP and stained with fluorescent antibodies to the activation-dependent surface antigens of platelets (CD63, CD62-P) prior to flow cytometry. Endoscopic evaluations were performed after the last LCAP.ResultsClinical remission (CAI < 4) was induced in 50% of the patients (7/14) after 5 weeks, and there were no significant differences observed in clinical background between the responder group (RG) and the nonresponder group (NG). In the RG, the populations of CD63+ (P < 0.03) and CD62-P+ (P < 0.05) platelets were significantly decreased after the first LCAP, and their reduction ratio decreased gradually with repeated LCAP. A significant improvement of the EI score, especially mucosal damage, was achieved in RG (P < 0.04) but not in NG.ConclusionsThese results indicate that the therapeutic responses to LCAP were reflected in modulations of population and/or platelet functions, especially after the first session. The decrease of such activated platelets immediately after the first LCAP may be an early marker for predicting the response in patients with severe UC.

Exacerbated autoimmune hepatitis successfully treated with leukocytapheresis and bilirubin adsorption therapy.

A 58-year-old man with subacute fulminant onset of autoimmune hepatitis (AIH) was treated by leukocytapheresis (LCAP) and bilirubin adsorption therapy (BAT), rather than by administration of highdose corticosteroids as he had mild glucose intolerance, and a definitive diagnosis of AIH was not obtained on admission; further, there was a risk of viral infection. After initiation of the therapies, serum transaminases and bilirubin, immunoglobulins, anti-nuclear antibodies, and rheumatoid factor decreased rapidly, as did the initially high levels of activated cells and several pro-inflammatory cytokines. Liver inflammation observed on liver biopsy settled during the course of the therapies, with no adverse side effects. A pause in the therapies was associated with deterioration; however, restoration of apheresis was followed by normalization. Remission was sustained throughout the period monitored, except for a recurrence 14 months after discharge, which was successfully resolved by two additional LCAP sessions. These results suggest that LCAP influences the causal mechanism(s) of exacerbation of AIH.

Hepatocellular carcinoma complicating autoimmune hepatitis without either hepatitis C viral infection or corticosteroid therapy.

She was readmitted to our hospital in June 2000 because of hematemesis. Endoscopic examination demonstrated rupture of esophageal varix, and sclerotherapy was performed. She was also readmitted in June 2001, for the same reason, and blood transfusion was performed. Serum α-fetoprotein was elevated to 62.3ng/ ml, and serum total bilirubin level also gradually became elevated. She died of liver failure in August 2001. Autopsy demonstrated a hepatoma, measuring 7cm in diameter, in the cirrhotic liver. The tumor was recognized as HCC (Fig. 1). Histology of the nontumorous area showed macronodular cirrhosis with interface hepatitis (Fig. 2). There was a small amount of liver cell rosetting (Fig. 3) and plasmacytic infiltration. Neither hepatitis B virus DNA nor HCV RNA was detected in extraction from paraffin-embedded liver tissue by real-time polymerase chain reaction (PCR) or reverse transcriptase-PCR assay.1 Watanabe et al. described the natural course of a patient with HCV-seronegative AIH who had not received corticosteroid therapy, but had developed HCC, and suggested that the development had been related to the cirrhosis itself rather than to corticosteroid therapy.4 The present patient had not received corticosteroid therapy either and also had cirrhosis, but did not demonstrate HCV RNA in either serum or liver tissue. Therefore, our case further suggests that HCC can occur even in patients with serum and tissue HCV-negative AIH without corticosteroid therapy, and screening for HCC should be performed in patients with AIH complicating cirrhosis, regardless of the results of serum HCV detection. The development of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is a rare event.1 Hepatitis C virus (HCV) is a carcinogen, and its detection in liver tissue has been reported in two of four HCV RNA-seronegative patients with HCC complicating AIH.1 Corticosteroid has been used in patients with AIH; however, this therapy is regarded as a risk for the development of HCC.2 Herein, we report a woman with HCC complicating HCV-tissue-negative AIH without corticosteroid therapy. An 89-year-old woman was admitted to our hospital in July 1999 because of tarry stool. Endoscopic examination demonstrated hemorrhagic gastritis and esophageal varices without plug. Computed tomography scans showed a mass measuring 4cm in diameter in a cirrhotic liver, suggesting HCC. Laboratory data are shown in Table 1. There was no evidence of any viral hepatitis infection, and she had no history of either a blood transfusion or of drinking liquor. There was no history of using known or suspected hepatotoxic drugs, and she had no remarkable past medical history, except for mild diabetes beginning 3 years earlier. We scored the AIH as 16 in this patient, using a scoring system for the diagnosis of AIH (definite AIH, 15).3 Her family history was not contributory, except that one of her six children, a daughter, has Behçet’s syndrome. The patient was 140cm in height and weighed 51kg. There was foot and face edema, but no ascites and no struma. Thyroid function suggested autoimmune thyroiditis (Table 1). Corticosteroid therapy was not performed because of her advanced age, hemorrhagic gastritis, diabetes, HCC, and absence of severe hepatitis. She was treated with a proton pump inhibitor for the gastritis, and discharged.

Disappearance of rectal mucosa-associated lymphoid tissue lymphoma following antibiotic therapy.

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal B-cell neoplasm occurring most frequently in the stomach. The majority of gastric MALT lymphomas regress after Helicobacter pylorieradication therapy, and its development is considered to be closely associated with H. pylori infection. A few recent studies have reported on such regression of rectal MALT lymphoma after H. pylori eradication therapy (1–3). We report a case of rectal MALT lymphoma in whichH. pylori eradication therapy had no effect, but lymphoma disappeared under single antibiotic therapy.

Successful eradication of Helicobacter pylori prevents relapse of peptic ulcer disease

The NIH consensus conference in 1994 recommended that all patients with peptic ulcers should be tested and treated for Helicobacter pylori. Recent studies have shown that the eradication of H. pylori is associated with a significant reduction in the relapse rate of peptic ulcers, but there are few reports about long‐term outcome.