今日の臨床サポート

肝内結石症

著者: 本多彰 東京医科大学 茨城医療センター

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2022/07/20
参考ガイドライン:
  1. 日本消化器病学会:胆石症診療ガイドライン2021 改訂第3版
患者向け説明資料

概要・推奨   

  1. 胆道再建術の既往がある患者では、2次性肝内結石発生に対する注意が推奨される(推奨度1)
  1. 肝内結石とともに肝萎縮を認める患者には、内視鏡的な結石除去よりも肝切除を選択することが推奨される(推奨度2)
  1. 無症状で肝萎縮や悪性を示唆する所見、胆道狭窄や拡張がなければ、定期的な経過観察も選択肢の1つとなる(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
本多彰 : 特に申告事項無し[2022年]
監修:金子周一 : 研究費・助成金など(株式会社スギ薬局,株式会社サイトパスファインダー,富士フイルム富山化学株式会社),奨学(奨励)寄付など(EAファーマ株式会社,アッヴィ合同会社,エーザイ株式会社,ゼリア新薬工業株式会社,マイランEPD合同会社,塩野義製薬株式会社,大塚製薬株式会社,大日本住友製薬株式会社,中外製薬株式会社,田辺三菱製薬株式会社)[2022年]

改訂のポイント:
  1. 胆石症診療ガイドラインの改訂に伴い治療選択のフローチャートを変更し、治療に関する解説を中心にアップデートを行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肝内胆管内に結石が形成される疾患であり、成因が不明な「原発性肝内結石症」と胆道再建術後に発生する「2次性肝内結石症」がある。
  1. 原発性肝内結石症は日本を含む東アジアで頻度が高い。2006年度のわが国の調査では全胆石症例に占める肝内結石症例の割合は0.6%で減少傾向にあったが、その後2011年度、2017年度の調査では横ばいになっている。原発性が減少しているのに対して2次性が増えているのが原因である。
  1. 反復する細菌性胆管炎のほか、肝萎縮、肝内胆管癌の原因になると考えられ、適切な診断とガイドラインに沿った治療が推奨される。
  1. 胆嚢結石症、総胆管結石症に比べて結石形成のメカニズムが複雑かつ再発率も高く難治性であり、厚生労働省難治性疾患政策研究事業の調査研究対象疾患である。
 
  1. 胆道再建術の既往がある患者では、2次性肝内結石発生に対する注意が推奨される(推奨度1O)
  1. まとめ:胆道再建後(特に先天性胆道拡張症の術後)の2次性肝内結石は比較的高い頻度で発生し[1][2][3][4]、近年増加傾向にあるため[5][6]、結石の発生に注意した長期的なフォローアップが必要である。
  1. 代表事例:厚生労働省「難治性の肝・胆道疾患に関する調査研究」班(肝内結石症分科会)の報告によると、先天性胆道拡張症の術後には、7~8%の頻度で2次性の肝内結石が発生することが報告されている[1]。わが国の原発性肝内結石症は減少傾向にあるが、先天性胆道拡張症術後の2次性肝内結石症は減少傾向になく、重要な臨床的課題になっている[1][6]。結石発生までの平均期間は小児例で6.8年、成人例で10.3年である[1]。胆管狭窄や吻合部狭窄の存在に加えて、胆管空腸吻合による細菌感染が結石生成の一因と推定されている[3][4]
  1. 結論:このことより、胆道再建術の既往がある患者では、2次性肝内結石の発生に注意することが推奨される。
問診・診察のポイント  
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文献 

K Chijiiwa, M Tanaka
Late complications after excisional operation in patients with choledochal cyst.
J Am Coll Surg. 1994 Aug;179(2):139-44.
Abstract/Text BACKGROUND: The follow-up results of 28 patients with choledochal cysts, 16 type I (solitary extrahepatic cyst) and 12 type IVA (extra and intrahepatic cysts), after excision of extrahepatic dilated bile duct were analyzed to evaluate detailed late complications.
STUDY DESIGN: Hepaticojejunostomy with a wide opening (10 to 30 mm) was created using hepaticoplasty, if necessary, in a Roux-en-Y manner. The mean follow-up period after excisional procedure was 8 +/- 5 (standard error of the mean) years, ranging from one to 18 years.
RESULTS: All patients were alive and carcinoma was not observed. Three patients (two with type I and one with type IVA cysts) had intrahepatic calculi. However, they had no evidence of anastomotic stricture on direct cholangiogram, although all bile cultures infected, mainly with Klebsiella and Escherichia coli. Intrahepatic gallstones were successfully treated with percutaneous transhepatic cholangioscopy and reoperation was not required. Thus, intrahepatic calculi associated with cholangitis, but not with anastomotic stricture, were found in 10.7 percent of the patients after excision of choledochal cyst.
CONCLUSIONS: Long-term follow-up evaluation is necessary, with special attention being given to intrahepatic calculi, even in the absence of an anastomotic stricture.

PMID 8044381
H Ando, T Ito, K Kaneko, T Seo, F Ito
Intrahepatic bile duct stenosis causing intrahepatic calculi formation following excision of a choledochal cyst.
J Am Coll Surg. 1996 Jul;183(1):56-60.
Abstract/Text BACKGROUND: Formation of intrahepatic calculi is one of the major late complications after excision of a choledochal cyst. There are few studies, however, that have examined this complication. Generally, an anastomotic stricture is believed to be the main cause of intrahepatic calculi. We report our experience with eight patients who had intrahepatic calculi after excision of a choledochal cyst.
STUDY DESIGN: To determine what caused the intrahepatic calculi to form, seven patients underwent cholangioscopy and direct visual inspection during the operation, and one patient underwent percutaneous transhepatic cholangioscopy. Intrahepatic bile was cultured, and calculi were analyzed.
RESULTS: Two types of stenoses (membranous and septal) were demonstrated near the hepatic hilum in all patients. Calculi were always located on the hepatic side of the stenoses. No anastomotic strictures were found in the region of the hepaticojejunostomy. The calculi contained mainly calcium bilirubinate. Escherichia coli and Klebsiella pneumoniae were cultured from the bile in all patients.
CONCLUSIONS: Stenoses of the intrahepatic bile ducts were demonstrated in all eight patients. The stenoses were considered to be the primary cause of intrahepatic calculi formation after excision of the choledochal cysts.

PMID 8673308
Kenitiro Kaneko, Hisami Ando, Takahiko Seo, Yasuyuki Ono, Keiko Ochiai, Yukio Ogura
Bile infection contributes to intrahepatic calculi formation after excision of choledochal cysts.
Pediatr Surg Int. 2005 Jan;21(1):8-11. doi: 10.1007/s00383-004-1253-0.
Abstract/Text Intrahepatic calculi complicate choledochal cysts in 7-8% of patients. Although congenital stenoses and dilatation of the intrahepatic bile ducts are considered responsible for calculi formation, intrahepatic calculi are usually formed after cyst excision. In this study, bile specimens from patients with choledochal cysts were cultured for bacteria. Results were retrospectively analyzed among the following groups: the primary excision group, consisting of 97 patients undergoing cyst excision as a primary treatment (mean age 5.0 years), the internal drainage group, consisting of 13 patients who had previous cyst-enterostomy at cyst excision (mean age 20.2 years); and the hepatolithiasis group, consisting of 12 patients with postoperative hepatolithiasis (mean age 24.2 years). Bacteria were present in the bile of 10 patients (76.9%) in the internal drainage group and in all patients (100%) in the hepatolithiasis group, but present in only 17 patients (17.5%) in the primary excision group (p<0.01). Polymicrobial infection with Gram-negative enterobacteria such as Escherichia coli and Klebsiella species was predominant in the internal drainage and hepatolithiasis groups, while nonenteric bacteria were found in the primary excision group. Bile infection through bilioenterostomy may play an important role in intrahepatic calculus formation after excision of a choledochal cyst.

PMID 15459776
Yutaka Suzuki, Toshiyuki Mori, Masaaki Yokoyama, Tetsuya Nakazato, Nobutsugu Abe, Yasuni Nakanuma, Hirohito Tsubouchi, Masanori Sugiyama
Hepatolithiasis: analysis of Japanese nationwide surveys over a period of 40 years.
J Hepatobiliary Pancreat Sci. 2014 Sep;21(9):617-22. doi: 10.1002/jhbp.116. Epub 2014 May 14.
Abstract/Text The aims of the present study are to clarify the changes in clinicopathologic features, diagnosis and treatment for hepatolithiasis, and propose an appropriate management strategy in Japan. The research group conducted nationwide surveys seven times in the past over a period of 40 years. Furthermore, a cohort was followed up in 2010. We analyzed the clinical features, diagnosis tools, treatment procedures, outcomes, and predictive factors for cholangiocarcinoma. Surgery was the primary method for hepatolithiasis up to 1998, and the frequency of its use has decreased since then. In 2011, 66.7% of hepatolithiasis patients were treated using nonsurgical approaches. In addition, endoscopic retrograde cholangiography (ERC) with stone extraction was the most frequently performed procedure (22.7%). However, the incidences of residual stone and recurrent stone after ERC with stone extraction were higher than those after percutaneous transhepatic cholangioscopic lithotomy and surgery. Bile duct stricture and dilatation during follow up were significant risk factors for stone recurrences. In the cohort study, stone removal only and age >65 years were significant factors for the development of cholangiocarcinoma. In patients without a history of cholangioenterostomy, left-lobe-type stones were a risk factor, and hepatectomy reduced the risk of the development of cholangiocarcinoma significantly. Nonsurgical treatment may be performed as the first-line treatment for hepatolithiasis. Surgery should be performed on patients who were treated incompletely after nonsurgical treatment. However, hepatectomy may be recommended for patients with left-lobe-type stones and without a history of cholangioenterostomy.

© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
PMID 24824191
K H Kim, C K Sung, B G Park, W G Kim, S K Ryu, K S Kim, I S Paik, C H Oh
Clinical significance of intrahepatic biliary stricture in efficacy of hepatic resection for intrahepatic stones.
J Hepatobiliary Pancreat Surg. 1998;5(3):303-8. doi: 10.1007/s005340050050.
Abstract/Text In the Far East, hepatic resection is the definitive treatment for complicated intrahepatic stones (IHS). However, many investigators have reported that the associated intrahepatic biliary stricture is the main cause of treatment failure. A retrospective comparative study was undertaken to clarify the long-term efficacy of hepatic resection for treatment of IHS and to investigate the clinical significance of intrahepatic biliary stricture in treatment failure after hepatic resection performed in 44 patients with symptomatic IHS. The patients were divided into two study groups: group A, with intrahepatic biliary stricture (n = 28) and group B, without stricture (n = 16). Residual or recurrent stones, recurrence of intrahepatic biliary stricture, late cholangitis, and final outcomes were analyzed and compared statistically between the two groups. The patients were followed up for a median duration of 65 months after hepatectomy. The overall incidence of residual or recurrent stones was 36% and 11%, respectively, in groups A and B. The initial treatment failure rate was 50% in group A and 31% in group B. Intrahepatic biliary stricture recurred in 46% of patients in group A, while none of the group B patients had biliary stricture recurrence (P = 0.001). More than two-thirds of the restrictures in group A were identified at the primary site. The incidence of late cholangitis was higher in group A (54%) than in group B (6%) (P = 0. 002). Three-quarters of the patients with cholangitis in group A had severe cholangitis, that was recurrent, and related to stones and strictures (n = 11). They and 2 asymptomatic patients in group B required secondary procedures done at a median of 12 months after hepatectomy. Final outcomes after hepatectomy with or without secondary management were good in 80%, fair in 16%, and poor in 4% of our 44 patients. Most recurrent cholangitis after hepatectomy in patients with IHS was related to recurrent intrahepatic ductal strictures. Therefore, to be effective, hepatic resection should include the strictured duct. However, with hepatectomy alone it is difficult to clear the IHS or relieve the ductal strictures completely, particularly in patients with bilateral IHS, so perioperative team approaches that include both radiologic and cholangioscopic interventions should be combined for the effective management of IHS.

PMID 9880779
Min-Ho Huang, Chien-Hua Chen, Jee-Chun Yang, Chi-Chieh Yang, Yung-Hsiang Yeh, Der-Aur Chou, Lien-Ray Mo, Sen-Kou Yueh, Chiu-Kuei Nien
Long-term outcome of percutaneous transhepatic cholangioscopic lithotomy for hepatolithiasis.
Am J Gastroenterol. 2003 Dec;98(12):2655-62. doi: 10.1111/j.1572-0241.2003.08770.x.
Abstract/Text OBJECTIVES: Percutaneous transhepatic cholangioscopic lithotomy (PTCSL) for the treatment of hepatolithiasis is particularly suited for those patients who are poor surgical risks or who refuse surgery and those with previous biliary surgery or stones distributed in multiple segments. However, hepatolithiasis is characterized by high rates of treatment failure and recurrence. We examined the long-term results of 245 patients with hepatolithiasis treated by PTCSL.
METHODS: This was a retrospective study of 245 patients who underwent PTCSL for hepatolithiasis; the patients were followed for 1-22 yr to evaluate the immediate and long-term results. Sonography was used to search for stone recurrence every year or whenever the patients presented symptoms suggestive of cholangitis. Cholangiography and/or CT were performed to verify recurrence.
RESULTS: PTCSL achieved complete clearance of hepatolithiasis in 209 patients (85.3%); the rate of incomplete clearance was higher in patients with intrahepatic duct stricture (29/118, 24.6% vs 7/127, 5.5%; p = 0.002). The rate of major complications was 1.6% (4/245) and included liver laceration (n = 2), intra-abdominal abscess (n = 1), and disruption of the percutaneous transhepatic biliary drainage fistula (n = 1). The overall recurrence rate of hepatolithiasis and/or cholangitis was 63.2%. The absolute rate of stone recurrence was not significantly related to the presence of intrahepatic duct stricture (51/89, 56.2% vs 53/120, 44.4%; p = 0.08), although the median time to recurrence was less in those with stricture (11 vs 18 yr; p = 0.007). In the patients without intrahepatic duct stricture, the rate of complete stone clearance was not related to the presence of dilation (34/38, 89.5% vs 86/89, 96.6%; p = 0.196), but the recurrence rate was higher in those with dilation (20/34, 58.8% vs 33/86, 38.4%; p = 0.042). Among the 209 patients with a successful initial PTCSL, the incidence of recurrent cholangitis or cholangiocarcinoma was significantly higher in those with incompletely removed recurrent hepatolithiasis than in those without coexisting hepatolithiasis (44.3%, 27/61 vs 16.2%, 24/148; p < 0.001 and 6.6%, 4/61 vs 0.7%, 1/148; p = 0.026).
CONCLUSIONS: PTCSL is a relatively safe and effective procedure for treating hepatolithiasis. Long-term follow-up is required because the overall recurrence rate of hepatolithiasis and/or cholangitis is high. The rate of complete stone clearance and the median time to stone recurrence are less in the presence of stricture, but the absolute rate of stone recurrence is not significantly related to stricture. In the absence of stricture, the rate of stone recurrence is higher in patients with dilated intrahepatic duct. Complete stone clearance is necessary, because the incidence of recurrent cholangitis or cholangiocarcinoma is higher in patients with incomplete clearance of recurrent hepatolithiasis.

PMID 14687812
M Shimatani, M Matsushita, M Takaoka, M Koyabu, T Ikeura, K Kato, T Fukui, K Uchida, K Okazaki
Effective "short" double-balloon enteroscope for diagnostic and therapeutic ERCP in patients with altered gastrointestinal anatomy: a large case series.
Endoscopy. 2009 Oct;41(10):849-54. doi: 10.1055/s-0029-1215108. Epub 2009 Sep 11.
Abstract/Text BACKGROUND AND STUDY AIMS: Although endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging in patients with altered gastrointestinal anatomy, a double-balloon enteroscope (DBE) permits examinations of a much longer segment of the small bowel than does a standard endoscope, and may be used to perform ERCP in such patients. Since only limited accessories are available for a conventional DBE, we performed ERCP with a "short" DBE, which has a 2.8-mm working channel and a 152-cm working length and for which conventional accessories are available, in patients with altered gastrointestinal anatomy, and evaluated this alternative technique.
PATIENTS AND METHODS: In 68 patients with a Roux-en-Y total gastrectomy (n = 36), Billroth II gastrectomy (n = 17), or pancreatoduodenectomy (n = 15), ERCP (103 procedures) was performed with a "short" DBE.
RESULTS: Deep insertion was successful in 100/103 procedures (97 %). Cholangiogram was successfully obtained in 98/100 procedures (98 %). Treatment was accomplished in all 98 procedures in which a cholangiogram was obtained (100 %). Therapeutic interventions including stone extraction (n = 47), nasobiliary drainage (n = 38), stent placement (n = 36), sphincterotomy (n = 31), choledochojejunostomy dilation (n = 29), tumor biopsy (n = 10), and naso-pancreatic duct drainage (n = 1) were performed successfully. Complications occurred in 5/103 procedures (5 %), all in patients with Roux-en-Y reconstruction.
CONCLUSIONS: Despite the relatively high rate of complications seen in patients with Roux-en-Y reconstruction, ERCP with a "short" DBE is effective in patients who have undergone bowel reconstruction.

Georg Thieme Verlag KG Stuttgart. New York.
PMID 19750447
Takeshi Tsujino, Atsuo Yamada, Hiroyuki Isayama, Hirofumi Kogure, Naoki Sasahira, Kenji Hirano, Minoru Tada, Takao Kawabe, Masao Omata
Experiences of biliary interventions using short double-balloon enteroscopy in patients with Roux-en-Y anastomosis or hepaticojejunostomy.
Dig Endosc. 2010 Jul;22(3):211-6. doi: 10.1111/j.1443-1661.2010.00985.x.
Abstract/Text BACKGROUND: The efficacy of double-balloon enteroscopy (DBE) for biliary interventions has been shown in patients with surgical anatomy. However, the use of available endoscopic retrograde cholangiography accessories during this procedure is limited because of the length of the conventional instrument (200 cm). The aim of this study was to evaluate the feasibility of short DBE for managing biliary disorders in patients with a Roux-en-Y gastrectomy or hepaticojejunostomy (HJ).
PATIENTS AND METHODS: Using a short enteroscope (152 cm) and commercially available endoscopic retrograde cholangiography accessories, biliary interventions were performed in six patients with Roux-en-Y reconstruction or HJ anastomosis.
RESULTS: A total of 12 biliary interventions were performed; balloon dilations of the HJ anastomosis or intrahepatic ducts (four patients), nasobiliary drainages (three patients), bile duct stone removal after endoscopic papillary large balloon dilation with or without small sphincterotomy (two patients), and a biliary stent placement (one patient). One patient showed retroperitoneal air following endoscopic papillary large balloon dilation, but recovered conservatively.
CONCLUSIONS: Biliary interventions via DBE using a short enteroscope are feasible in patients with surgical anatomy.

PMID 20642611
Young Koog Cheon, Young Deok Cho, Jong Ho Moon, Joon Seong Lee, Chan Sup Shim
Evaluation of long-term results and recurrent factors after operative and nonoperative treatment for hepatolithiasis.
Surgery. 2009 Nov;146(5):843-53. doi: 10.1016/j.surg.2009.04.009. Epub 2009 Jun 28.
Abstract/Text BACKGROUND: Hepatolithiasis is a common disease in East Asia. Operative and nonoperative procedures for the management of hepatolithiasis have been discussed, but long-term follow-up results of such treatments are only reported rarely. We evaluated the long-term results of operative and nonoperative treatments and examined risk factors for the recurrence of stones or cholangitis.
METHODS: We conducted a retrospective study of case records of patients with hepatolithiasis who underwent treatment by operative therapy or nonoperative percutaneous transhepatic cholangioscopy (PTCS), or peroral cholangioscopy. Of 311 patients with hepatolithiasis, 236 underwent follow-up after operative (n = 90), PTCS (n = 97), or peroral cholangioscopy (n = 49) treatment.
RESULTS: Complete stone clearance was achieved in 83.3% of hepatectomy, 63.9% of PTCSL, and 57.1% of peroral cholangioscopy patients. After a median follow-up period of 8.0 years (up to 37 years), we observed stone recurrence in 30.9% (73/236) of patients, secondary biliary cirrhosis in 8.5% (19/224), late development of cholangiocarcinoma in 4.8% (11/227), and a mortality rate of 8.1% (19/236). Stricture, stones in both lobes, and nonoperative treatments were significant risk factors for incomplete stone clearance on multivariate analysis. In addition, recurrent stones and/or cholangitis were associated with nonoperative therapy (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.10-3.65), biliary cirrhosis (HR, 2.22; 95% CI, 1.24-3.98), residual stones (HR, 1.98; 95% CI, 1.24-3.17), and stricture (HR, 1.86; 95% CI, 1.01-3.43).
CONCLUSION: In this long-term follow-up study, nonoperative therapy, biliary cirrhosis, residual stones, and biliary stricture were associated with recurrent stones and/or cholangitis after treatment.

PMID 19744434
Toshio Tsuyuguchi, Kaoru Miyakawa, Harutoshi Sugiyama, Yuji Sakai, Takao Nishikawa, Dai Sakamoto, Masato Nakamura, Shin Yasui, Rintaro Mikata, Osamu Yokosuka
Ten-year long-term results after non-surgical management of hepatolithiasis, including cases with choledochoenterostomy.
J Hepatobiliary Pancreat Sci. 2014 Nov;21(11):795-800. doi: 10.1002/jhbp.134. Epub 2014 Jul 29.
Abstract/Text BACKGROUND: Long-term follow-up of non-surgical procedures for the management of hepatolithiasis has been reported, but risk factors for mortality have not been properly evaluated.
METHODS: We conducted a retrospective study of the case records of 121 patients with hepatolithiasis who underwent endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy (POCS), percutaneous transhepatic cholangioscopy (PTCS), or conservative treatment at the Department of Gastroenterology of Chiba University Hospital between January 1980 and July 2011. The primary outcome measure was mortality, defined as death due to hepatolithiasis (concomitant liver failure with cholangitis and cholangiocarcinoma).
RESULTS: Complete clearance of intrahepatic stones was achieved in 22 (57.8%) of 38 patients by POCS, in 12 (66.7%) of 18 patients by ERCP, and in 10 (52.6%) of 18 patients by PTCS. The remaining 46 patients were treated conservatively. The mean follow-up period was 11.4 ± 7.1 years (range, 0.6-32.8). There were 14 hepatolithiasis-related deaths (11 with cholangiocarcinoma and three from liver failure with cholangitis) during the follow-up periods. Multivariate Cox proportional hazards analysis revealed liver atrophy (P = 0.015; HR = 3.98; 95% CI, 1.30-12.20) and congenital biliary dilatation after biliary-enteric anastomosis (P = 0.036; HR = 4.57; 95% CI, 1.11-18.87) as significant risk factors for mortality.
CONCLUSIONS: Analysis of the 10-year long-term results after non-surgical management of hepatolithiasis identified liver atrophy and congenital biliary dilatation as risk factors for mortality. Patients with hepatic lobe atrophy should undergo a hepatectomy, if operable.

© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
PMID 25070702
Yutaka Suzuki, Toshiyuki Mori, Nobutsugu Abe, Masanori Sugiyama, Yutaka Atomi
Predictive factors for cholangiocarcinoma associated with hepatolithiasis determined on the basis of Japanese Multicenter study.
Hepatol Res. 2012 Feb;42(2):166-70. doi: 10.1111/j.1872-034X.2011.00908.x. Epub 2011 Dec 13.
Abstract/Text AIM:   The aim of this study was to delineate predictive factors for cholangiocarcinoma in patients with hepatolithiasis, and to establish optimal management for hepatolithiasis from the viewpoint of carcinogenesis on the basis of a Japanese nationwide survey for hepatolithiasis.
METHODS:   The Hepatolithiasis Research Group was organized in 2006 by the Ministry of Health, Labour and Welfare of Japan, and conducted a nationwide survey. The research group collected data on 336 cases of hepatolithiasis in 2006, in a cross-sectional survey involving 2592 institutions in Japan. Predictive factors for cholangiocarcinoma associated with hepatolithiasis were analyzed by univariate and multivariate analyses of clinicopathological and therapeutic factors.
RESULTS:   Twenty-three patients had cholangiocarcinoma. Histories of choledocoenterostomy and liver atrophy were found to be significantly predictive factors by multivariate analysis. In 87.5% of cases of cholangiocarcinoma with liver atrophy, cholangiocarcinoma was located in the atrophic lobes. The method of reconstruction did not affect the incidence of cholangiocarcinoma (choledochojejunostomy vs. choledochoduodenostomy; side-to-end vs. side-to-side anastomosis).
CONCLUSIONS:   Choledocoenterostomy and liver atrophy may increase the risk of developing cholangiocarcinoma. Choledocoenterostomy is thus contraindicated in patients with hepatolithiasis. An aggressive resection strategy is recommended for an atrophic segment.

© 2011 The Japan Society of Hepatology.
PMID 22151748
E Ros, S Navarro, C Bru, R Gilabert, L Bianchi, M Bruguera
Ursodeoxycholic acid treatment of primary hepatolithiasis in Caroli's syndrome.
Lancet. 1993 Aug 14;342(8868):404-6.
Abstract/Text Congenital cystic dilation of the intrahepatic bile ducts (Caroli's syndrome) is a rare cause of chronic cholestasis and hepatolithiasis in young adults. Long-term prognosis is poor even with surgical drainage. We treated twelve patients who had Caroli's syndrome and intrahepatic stones with ursodeoxycholic acid (UDCA), 10-20 mg/kg daily. The duodenal bile of these patients contained cholesterol crystals, which suggests that the stones were cholesterol rich. UDCA led to sustained clinical remission, return to normal liver function, and dissolution of intrahepatic stones on ultrasound in all patients (nine partial, three complete) after 48 (range 12-114) months' follow-up. Litholytic therapy is indicated for intrahepatic stones in Caroli's syndrome.

PMID 8101905
O Rosmorduc, B Hermelin, R Poupon
MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.
Gastroenterology. 2001 May;120(6):1459-67.
Abstract/Text BACKGROUND & AIMS: Many studies indicate that gallstone susceptibility has genetic components. MDR3 is the phosphatidylcholine translocator across the hepatocyte canalicular membrane. Because phospholipids are a carrier and a solvent of cholesterol in hepatic bile, we hypothesized that a defect in the MDR3 gene could be the genetic basis for peculiar forms of cholesterol gallstone disease, in particular those associated with symptoms and cholestasis without evident common bile duct stone.
METHODS: We studied 6 adult patients with a peculiar form of cholelithiasis. MDR3 gene sequence was determined by reverse-transcription polymerase chain reaction amplification of mononuclear cell RNAs followed by direct sequencing. Hepatic bile was analyzed in 2 patients.
RESULTS: All patients shared the following features: at least 1 episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestasis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid therapy. Hepatic bile composition showed a high cholesterol/phospholipid ratio and cholesterol crystals. In all patients, we found MDR3 gene mutations involving a conserved amino acid region.
CONCLUSIONS: These preliminary observations suggest that MDR3 gene mutations represent a genetic factor involved in this peculiar form of cholesterol gallstone disease in adults. They require further studies to assess the prevalence of MDR3 gene defects in symptomatic and silent cholesterol gallstone disease.

PMID 11313316
T Ohta, T Nagakawa, N Ueda, T Nakamura, T Akiyama, K Ueno, I Miyazaki
Mucosal dysplasia of the liver and the intraductal variant of peripheral cholangiocarcinoma in hepatolithiasis.
Cancer. 1991 Nov 15;68(10):2217-23.
Abstract/Text Four cases are reported of the intraductal variant of peripheral cholangiocarcinoma among surgical specimens from 32 cases of hepatolithiasis. The cancers arose from the periphery of the stone-containing bile duct and spread chiefly along the luminal surface. Microscopically, these tumors showed papillary proliferation and therefore were diagnosed as the intraductal spreading type of peripheral cholangiocarcinoma. Mucosal dysplasia also was noticed in the vicinity of the tumors. In six other cases, mucosal dysplasia was observed in the periphery of the stone. Immunohistochemically, anti-CA 19-9 staining was observed diffusely in the cytoplasm of dysplastic lesions and carcinomas. Anti-carcinoembryonic antigen staining was restricted to the luminal surface and/or the supranuclear region of the cytoplasm in carcinomas. It was not identified in dysplastic cells. These results suggest that the mucosal dysplasia occasionally observed near stones is a precursor of the intraductal spreading type of peripheral cholangiocarcinoma in the presence of hepatolithiasis. The authors hypothesize that the lining epithelium of the large bile duct, when persistently exposed to biochemically altered bile, may undergo a carcinomatous transformation through a stage of mucosal dysplasia.

PMID 1655206
K Chijiiwa, H Ichimiya, S Kuroki, A Koga, F Nakayama
Late development of cholangiocarcinoma after the treatment of hepatolithiasis.
Surg Gynecol Obstet. 1993 Sep;177(3):279-82.
Abstract/Text Although the association of cholangiocarcinoma with intrahepatic calculi (hepatolithiasis) is well recognized, the late development of cholangiocarcinoma after the treatment of hepatolithiasis has not been reported in detail. Of 109 consecutive patients with hepatolithiasis treated during 19 years, eight patients had cholangiocarcinoma, seven of whom had cholangiocarcinoma two to 14 years, with a mean of eight years, after the treatment of hepatolithiasis. Absence of cholangiocarcinoma was confirmed when stones were removed at the time of the initial treatment. The mean age was 56 years, with a female to male ratio of 2:5. At the time of detecting cholangiocarcinoma, three patients had no gallstones and four had gallstones at the corresponding site to the carcinoma. Cystic dilatation of the intrahepatic bile duct was often observed on the direct cholangiogram. The biles were all infected mainly with Escherichia coli and Klebsiella species. Thus, bile stasis and bacteria infection seems to be the important causative factor, causing cholangiocarcinoma rather than the calculi itself. Because the symptoms only mimic those of cholangitis, the possible presence of cholangiocarcinoma should be considered even after the treatment of hepatolithiasis for early detection and curative resection.

PMID 8395085
K Chijiiwa, H Yamashita, J Yoshida, S Kuroki, M Tanaka
Current management and long-term prognosis of hepatolithiasis.
Arch Surg. 1995 Feb;130(2):194-7.
Abstract/Text OBJECTIVE: To assess the surgical and endoscopic treatment results and long-term prognosis of hepatolithiasis.
DESIGN: Retrospective case series.
SETTING: University hospital.
PATIENTS: Eighty-five consecutive patients with hepatolithiasis treated between 1980 and 1993.
MAIN OUTCOME MEASURES: Location of calculi, associated diseases, treatment procedures, and long-term prognosis were analyzed.
RESULTS: Thirty-eight percent of the 85 patients had stones only in intrahepatic ducts, while others had intrahepatic and extrahepatic calculi. Seventy-two percent of the patients had repeated biliary surgery, and 14% were associated with liver cirrhosis. After surgery combined with cholangioscopy and electrohydraulic lithotripsy, the complete stone clearance rate was 71%. The treatment-related mortality rate was 3.8%; the stone recurrence rate after complete stone removal was 11%. However, it was notable that 17 patients (20%) died of related diseases during a mean follow-up of 6 years. The reasons for death were liver failure, bleeding from esophageal varices, hepatocellular carcinoma, and cholangiocarcinoma.
CONCLUSION: Improvement of stone clearance rate is evident by a systematic approach. Complete relief from calculi, bile stasis, and cholangitis at an early stage of the disease is mandatory to prevent progressive liver damage, because repeated recurrence of intrahepatic calculi and cholangitis ultimately lead to irreversible liver damage and hepatobiliary carcinomas with a high mortality.

PMID 7848091
S Kubo, H Kinoshita, K Hirohashi, H Hamba
Hepatolithiasis associated with cholangiocarcinoma.
World J Surg. 1995 Jul-Aug;19(4):637-41.
Abstract/Text Hepatolithiasis is a risk factor for cholangiocarcinoma. It is difficult to make an accurate diagnosis before treatment. In a retrospective study, we identified characteristic clinical features of 103 patients with hepatolithiasis (group H) and 10 patients with hepatolithiasis associated with cholangiocarcinoma (group HC), and examined the methods for diagnosis and treatment. The main symptoms were abdominal pain, fever, and jaundice, although few patients in group HC had jaundice. The incidence of abnormal serum levels of carcinoembryonic antigen (CEA) in group HC was higher than in group H. The incidence of cholangiocarcinoma in cases in which most of the stones were present in the intrahepatic ducts of the left lobe (type I-L) was higher than the incidence in the other patients. Of the patients who underwent portography in group HC, portal veins in the portion of the liver containing the cholangiocarcinoma were not seen, and this region was atrophic in the operative specimens. The incidence of portal obstruction in portograms in group HC was higher than that in group H. The possibility of carcinoma should be kept in mind if there are high levels of CEA, if the location of the stones is classified as type I-L, or if portal veins cannot be seen on portograms. In such patients, liver resection should be considered because there may be undiagnosed cholangiocarcinoma.

PMID 7676713
Kazuo Chijiiwa, Kazuhiro Ohtani, Hirokazu Noshiro, Toru Yamasaki, Shuji Shimizu, Koji Yamaguchi, Masao Tanaka
Cholangiocellular carcinoma depending on the kind of intrahepatic calculi in patients with hepatolithiasis.
Hepatogastroenterology. 2002 Jan-Feb;49(43):96-9.
Abstract/Text BACKGROUND/AIMS: Association of cholangiocellular carcinoma in patients with hepatolithiasis has been reported. However, its incidence depending on the kind of stones is obscure. The aim was to examine the association rate of cholangiocellular carcinoma in patients with hepatolithiasis with a special reference to the kind of intrahepatic stones.
METHODOLOGY: One hundred and thirty-nine patients with hepatolithiasis who have been treated from 1973 to 1997 were retrospectively reviewed to examine the characteristics of cholangiocellular carcinoma. The type and location of intrahepatic calculi were analyzed.
RESULTS: Cholangiocellular carcinoma was found in 8 of 139 patients, the incidence being 5.8%. The incidence of carcinoma was more than twice in patients whose stones were located in intrahepatic bile duct only (9.3%; 5/54) than in those located in both intrahepatic and extrahepatic bile duct (3.5%; 3/85). Of 121 patients excluding 18 whose calculi were not available for classification, the kind of intrahepatic calculi was brown pigment in 106 patients (87.6%), cholesterol in 10 (8.3%), black pigment in 4, and fatty acid calcium in one. Cholangiocellular carcinoma was associated in 3 (2.8%) of 106 patients with brown pigment stones, 3 (30%) of 10 with cholesterol stones, in one with fatty acid calcium stones, and one patient whose stone was not available for analysis. The association rate of cancer was significantly (P < 0.01) higher in patients with cholesterol stones than those with brown pigment stones. One patient survived for 24 months after left lobectomy but the others died within six months.
CONCLUSIONS: An early and attentive evaluation for the possible presence of cholangiocellular carcinoma is mandatory not only in patients with brown pigment stones but also in those with intrahepatic cholesterol stones.

PMID 11941992

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