長坂 光夫

2008年6月にクローン病(CD)の急性出血症例に対しインフリキシマブ(IFX)を投与した15例(男14例、女1例、17〜59歳・平均32.2歳)を対象に、IFXの有効性を検討した。CDの出血症例は罹患期間が平均10.5年、10年以上が8症例(約53%)と、病状が長期にわたる症例が多い傾向にあった。腸管切除例は5例(約33%)で出血時の基本治療はアザチオプリン(AZA)、elemental diet(ED)使用の有無、ED使用量には関連はなかった。IFX治療15例全体では短期的な出血2例(約13%)はあったものの長期的には再出血を認めなかった。過去に出血歴があり、既存の治療では完全に出血を予防することが困難であった再出血の2例を含めて過去に出血の既往のある7例全てがIFX治療でその後出血を予防できた。

潰瘍性大腸炎(UC)、クローン病(CD)に代表される炎症性腸疾患(IBD)は、いまだ原因が不明の難治性の疾患であり、これらは原疾患の悪化による腸管合併症や免疫機序に起因すると考えられる腸管外合併症を併発し、診断、治療に難渋することが多い。潰瘍性大腸炎の腸管合併症には出血、狭窄、穿孔、中毒性巨大結腸症、癌化などがあり、クローン病の腸管合併症は狭窄、閉塞、瘻孔(内瘻・外瘻)、穿孔、膿瘍、出血、肛門病変(痔核、裂肛、痔瘻、肛門潰瘍、肛門皮垂、肛門周囲膿瘍)、癌化がある。また腸管外合併症は皮膚病変(アフタ性口内炎、結節性紅斑、壊疽性膿皮症、乾癬、水疱性天疱瘡、類天疱瘡、苔癬)、関節病変(末梢関節炎、強直性脊椎炎)、肝胆膵系(原発性硬化性胆管炎、胆石症、肝炎、脂肪肝、肝硬変、膵炎)、腎、泌尿器系(尿路結石症、腎炎、ネフローゼ)、眼病変(虹彩炎、角膜潰瘍、ぶどう膜炎)などがある。(著者抄録)

強皮症は全消化管に罹患しうるが,食道,小腸,大腸,胃の順に多く,小腸病変は強皮症患者の約50%に認める.上部消化管X線検査では食道中部〜下部の蠕動低下と下部の拡張を認める.小腸病変には偽性腸閉塞や腸管嚢腫様気腫症などがある.小腸X線検査所見はhide bound appearance,coil spring appearanceが言われている.今回,CREST症候群に小腸病変を伴った症例を経験し,比較的まれな症例であったので報告する.(著者抄録)

Crohn病は近年その症例数は増加の一途を辿り,いまや小腸疾患の代表と言える.近年の様々な検査機器,検査技術の進歩により小腸の詳細な情報を得ることが可能となった.また生物製剤など新たな治療薬の開発で栄養療法中心の治療から欧米型の薬物療法主体の治療へと変化を遂げた.Crohn病の画像上の特徴はまず初期の病変と考えられるアフタ様潰瘍/病変,不整形潰瘍が縦走化し,次いで縦走潰瘍,敷石様外観へと進展しさらに狭窄,瘻孔,膿瘍などの合併症を惹起する.また,手術適応の頻度として最も高い合併症である狭窄に対して,近年のダブルバルーン小腸内視鏡による内視鏡的拡張が可能となり手術を回避できる症例も増加している.(著者抄録)

59歳男。14年前に潰瘍性大腸炎を指摘され、メサラジン内服を開始した。その後の内視鏡でS状結腸に深い縦走潰瘍、注腸でS状結腸から下行結腸にかけてのcobblestone appearance、下行結腸中部での管腔狭小化を認め、クローン病を疑われた。プレドニゾロン投与や経腸成分栄養剤(ED)で症状は落ち着いていたが、腹痛が増強し、ガストロ注腸で脾彎曲部の狭窄と胃・結腸瘻を認めた。手術予定で入院したが、突然腹痛を訴え、緊急CTで穿孔性腹膜炎と診断し緊急手術となった。脾彎曲部より5cm口側に径1cmの穿孔部を確認し、結腸左半切除術を施行した。切除標本では狭窄前後で色調が異なり、穿孔側結腸で菲薄化がみられ、壁内瘻孔の形成も認めた。病理所見で粘膜側は浮腫性で腺管が萎縮し、漿膜側にも炎症性細胞浸潤を認めた。またpaneth cell metaplasiaやgoblet cell depressionがあり、潰瘍性大腸炎に近いと考えられた。術後経過は順調で、ED導入後退院した。

患者は27歳,女性.関節リウマチ(RA)と診断されてから約6年間,Loxoninなどを内服していた.下血を契機に消化管の検査を行った.初診時には,診断が困難であったが,約3年間の経過を追うことによって非ステロイド系消炎鎮痛剤(NSAID)起因性小腸病変と診断しえたRAの1例を経験した.小腸X線検査では回腸終末に地図状潰瘍とアフタ様病変が散在しており,ダブルバルーン小腸内視鏡検査では下掘れ潰瘍と露出血管を認めた.NSAIDの中止とsulfapyridine内服によって治療開始後約1年に小腸X線検査で治癒を確認した.(著者抄録)

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify associations of the functional polymorphisms of the MIF gene promoter with the development of chronic gastritis. The study was performed with 290 stocked DNAs from subjects with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Both the 7/7-CATT repeat at position -794 and the -173 C/C genotypes were significantly associated with a risk of developing severe gastric mucosal atrophy (OR, 9.69; 95% CI, 1.29-72.5; and OR, 4.60; 95% CI, 1.05-20.2, respectively). In subjects younger than 60 years old, the number of 7-CATT alleles was significantly correlated with both the activity and inflammation scores (p=0.0079 and 0.0080, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene might be associated with the severity of gastric mucosal inflammation in younger subjects and with the subsequent development of mucosal atrophy.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify associations of the functional polymorphisms of the MIF gene promoter with the development of chronic gastritis. The study was performed with 290 stocked DNAs from subjects with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Both the 7/7-CATT repeat at position -794 and the -173 C/C genotypes were significantly associated with a risk of developing severe gastric mucosal atrophy (OR, 9.69; 95% CI, 1.29-72.5; and OR, 4.60; 95% CI, 1.05-20.2, respectively). In subjects younger than 60 years old, the number of 7-CATT alleles was significantly correlated with both the activity and inflammation scores (p=0.0079 and 0.0080, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene might be associated with the severity of gastric mucosal inflammation in younger subjects and with the subsequent development of mucosal atrophy.

Cyclooxygenase-1 (COX-1) has been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. We attempted to clarify the association between potentially functional polymorphisms (T-1676C and A-842G/C50T) in the COX-1 gene promoter and gastroduodenal disorders in a Japanese population. The study was performed with 480 stocked DNAs from subjects (gastric ulcers in 93 subjects and duodenal ulcers in 44) with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. The T1676C polymorphism was not associated with either gastric mucosal atrophy or infiltration of inflammatory cells into gastric mucosa. In non-NSAID (non-steroidal antiinflammatory drug) users, male gender and Helicobacter pylori (HP) infection were significantly associated with both gastric and duodenal ulcers, whereas the -1676T allele carrier was significantly associated with only gastric ulcers (OR, 2.86; 95% Cl 1.29-6.34). In NSAID users, the number of -1676T alleles was significantly associated with developing gastroduodenal ulcers (OR, 5.80; 95% Cl, 1.59-21.1), whereas male gender and HP infection were not. The -842T/ C50T polymorphism was not detected in any of the 480 Japanese subjects. In conclusion, a carrier of the -1676T allele in the COX-1 gene promoter, as well as HP infection and male gender, seem to be significant risk factors for developing gastric ulcers, and the number of -1676T alleles was also a significant risk factor for the NSAID-induced ulcer, whereas the frequency of the A-842G polymorphism was thought to be very rare in the Japanese population.

Noncoding microRNAs regulate the expression of various mRNAs. We attempted to clarify the relationship between miR-27a genome polymorphism and chronic gastritis. The study was performed in 179 patients with no evidence of gastric malignancy. The severity of histologic chronic gastritis was classified according to the updated Sydney system. The frequency of miR-27a G allele was 34.6%. Although the frequencies of miR-27a G allele were increased in subjects with peptic ulcer or severe mucosal atrophy, no significant differences were seen. The miR-27a polymorphism showed an interaction with gender in relation to gastric mucosal atrophy (P =.090). In only male subjects, the miR-27a polymorphism was associated with the gastric mucosal atrophy (P =.039) and both atrophy and metaplasia scores in G/G group were significantly higher than those in the other groups. The miR-27a genome region polymorphism may be an important definitive factor to develop the gastric mucosal atrophy in Japanese male subjects.

症例は44歳女性。29歳の時、潰瘍性大腸炎全大腸炎型と診断。経過観察の内視鏡検査にてS状結腸に結節集簇様病変を認め、生検にてUC-IIIと診断され当院紹介となる。注腸X線検査ではS状結腸に粗大結節集簇様病変を認め、側面像では陰影欠損像も見られた。内視鏡検査では、活動性炎症の中に粗大な結節集簇様の隆起を認め、有茎性の部分も存在した。拡大内視鏡では粗大結節部でV型のピットが観察された。また、超音波内視鏡検査では筋層までの腫瘍浸潤が疑われ、腹腔鏡補助下大腸全摘術を施行。病理組織は隆起部分は径70×35mmの大きさで、中分化型腺癌、ss,ly(+),v0,n(-)でdysplasiaを伴っていた。病変肛門側では、異型が弱く、炎症性ポリープに近い所見を呈する部分と、不規則な形態の腺管が浸潤性に増殖し、漿膜下まで達している部分が混在していた。癌部の遺伝子検索では、K-ras codon12の変異が陽性、p-53(exon5-9)変異陰性、MSI陽性であった。(著者抄録)

Background and aim: Ulcerative colitis (UC) is a multifactorial disease resulting from a complex interaction of genetic and environmental factors. Identifying genetic variants that alter the innate immune response is highly relevant to understanding the pathogenesis of UC. The aim of this study was to investigate the association between CD14 and Toll-like receptor-2 (TLR2) genetic polymorphisms and chronic UC in Japanese patients. Methods: The study population consisted of 102 chronic UC patients and 146 healthy control subjects. Polymorphisms in the promoter at C-260T of CD14 gene were investigated by PCR restriction fragment length polymorphism, and -196 to -174 del of TLR2 was investigated by allele-specific PCR. Results: The frequencies of CD14 TT and T carrier were significantly higher in UC patients than in controls (TT: OR = 3.98, 95% CI 1.82-8.71, P = 0.0005; T carrier: OR = 2.98, 95% CI 1.47-6.01, P = 0.002). In addition, TT and T carrier were more closely associated with distal colitis phenotype (TT: OR = 7.78, 95% CI 2.14-28.28, P = 0.0007; T carrier: OR = 6.30, 95% CI 2.71-14.58, P = 0.005), onset after 20 years of age (TT: OR = 5.28, 95% CI 2.18-12.79; T carrier: OR = 3.79, 95% CI 1.67-8.59), chronic continuous type (TT: OR = 4.26, 95% CI 1.56-11.64; T carrier: OR = 3.09, 95% CI 1.33-7.82), and fewer than two hospitalizations (TT: OR = 4.44, 95% CI 1.81-10.89; T carrier: OR = 3.26, 95% CI 1.43-7.27). There was no significant difference in TLR2 -196 to -174 del/del and del/ins carrier frequencies between UC patients and healthy controls. However, these frequencies were significantly higher in steroid-dependant patients than in controls (del/del: OR = 6.08, 95% CI 1.41-26.21; del carrier: OR = 3.00, 95% CI 1.13-7.98). Conclusion: The results suggest that existence of a mutation in the CD14 gene is associated with an increased susceptibility to developing UC, especially chronic continuous distal colitis phenotypes that develop after 20 years of age. Furthermore, polymorphism of TLR2 may be related to an increased risk of intensive types such as steroid-dependent patients.

Backgound: Trypsin acting at protease-activated receptor 2 (PAR2) contributes to a progression of malignant tumors. An abnormal DNA methylation has been recognized as an important molecular mechanism for the genesis of various types of cancers. We attempted to clarify the relationship between the promoter methylation of PAR2 and gastric cancer. Method: We estimated the methylation of the PAR2 promoter in both antral non-cancerous mucosa and cancer lesions in 94 patients with gastric cancer. We employed a methylation-specific PCR method. Results: Regarding the methylation ratio (MR) of antral-non-cancerous mucosa, no significant difference was despite among gender, age and Helicobacter pylori infection status, whereas MR increased rising inflammation scores. The MR of cancer lesions was significantly lower than that of antral non-cancerous mucosa. This finding was not dependent on tumor staging, but also histological classification. In venous invasion, lymph node metastasis, or peritoneal dissemination negative cases, this significant lower MR was also seen. Conclusion: The promoter methylation of PAR2 seems to be increased with a progression of chronic inflammation and has an inhibitory effect on carcinogenesis of the stomach.

大阪医科大学、藤田保健衛生大学の2施設のCrohn病患者を対象に上部消化管病変に関する臨床的検討を行った。対象は男42名、女17名、平均年齢36.8歳で、上部消化管内視鏡検査の有所見率は78%(46例)であった。胃では竹の節状外観、たこいぼ型びらんを含むびらん性病変が多く、十二指腸ではアフタおよびびらん、不整形潰瘍が多かった。幽門・十二指腸狭窄は約9%とわずかであったが、閉塞症状を来たした例が認められた。内視鏡の重症度とCrohn病活動度との間に相関はなかった。上部消化管病変に対する治療としてはH2-blocker、proton pump inhibitor、mesalazine粉末等が行われていたが、いずれも病変の進行を阻止できなかった。病理組織学的検討では、granulomaは12.5%に検出され、H. pylori陽性率は13.3%であった。上部消化管病変を把握し、適切な生検やH. pylori感染の検索を行うことで、早期診断が可能となり、重篤な合併症を予防できると考えられた。

36歳女。下血、腹痛を主訴とした。23歳頃より1ヵ月程度続く軽度の下痢、軟便を認め、整腸剤などを投与され軽快していた。同様の経過を10年間に3〜4回繰り返しており、今回、下痢が出現した後、約1ヵ月の経過で次第に下血を認める様になり、近医で全大腸炎型潰瘍性大腸炎の診断で加療されたが、頻回の下痢、下血多量となった。精査・加療目的で当院入院となり、入院翌日より38℃台の発熱、後頸部痛が出現し、下血に変化なく、抗菌薬投与を開始するも発熱は持続し、炎症反応高値となった。入院5日目に施行した全大腸内視鏡検査では全大腸にびまん性に小発赤と小びらんを認め、血管透見は消失し、易出血性の粘膜を認め、活動性中等度の全大腸型潰瘍性大腸炎と診断された。入院7日目に潰瘍性大腸炎の増悪を認めたため顆粒球除去療法(G-CAP)を開始し、次第に発熱、炎症反応、下痢・下血は軽快改善し、入院40日目の全大腸内視鏡検査では浮腫状の炎症粘膜は軽快し、一部血管透見が回復し回復期の像となった。7回目のG-CAP施行後の入院47日目に退院となり、退院後は外来にてG-CAPを継続し経過良好であった。しかし、退院後3ヵ月頃より上腹部不快感〜上腹部痛が出現するようになり、famotidine内服にて経過を診ていたが軽快せず、退院113日目に上部消化管内視鏡検査を施行したところ、体上部に竹の節状外観を認めた。