Original Article
Regression of Liver Fibrosis after Biliary Drainage in Patients with Chronic Pancreatitis and Stenosis of the Common Bile Duct
N Engl J Med 2001; 344:418-423February 8, 2001
- Abstract
Background
Chronic obstruction of the common bile duct may cause hepatic fibrosis and secondary biliary cirrhosis.
Methods
We studied liver-biopsy specimens from 11 patients with chronic stenosis of the common bile duct due to chronic pancreatitis; all the patients had undergone liver biopsy before or at the time of surgical biliary decompression and underwent a subsequent liver biopsy for various clinical reasons. The patients were followed as part of a prospective study of 501 patients who had been treated for chronic pancreatitis. Two pathologists, who were unaware of the sequence of specimens, graded fibrosis on a scale of 0 (none) to 3 (cirrhosis).
Results
The 11 patients were all men. Chronic pancreatitis was due to alcohol abuse in 10 of the men; 1 had idiopathic disease. The median age at diagnosis was 38 years. The median interval between the first and second liver biopsies was 2.5 years (range, 0.3 to 9.0). The two patients who had restenosis of the biliary anastomosis were excluded from the analysis of fibrosis. In the group of nine patients without restenosis, the second specimen showed significant improvement in fibrosis (P=0.01). The fibrosis improved by two grades in two patients and by one grade in four patients; in three patients, the grade did not change. The pathologists agreed on the grading of specimens from 10 of the 11 patients.
Conclusions
In patients with chronic pancreatitis and stenosis of the common bile duct, liver fibrosis may regress after biliary drainage.
Media in This Article
Figure 1
Histologic Features of Liver-Biopsy Specimens Obtained during and after Biliary Decompression in Two Patients with Stenosis of the Common Bile Duct Due to Chronic Pancreatitis.Table 1
Characteristics of 11 Patients with Stenosis of the Common Bile Duct Due to Chronic Pancreatitis.Article Activity
- Article
Chronic obstruction of the common bile duct may cause hepatic fibrosis and secondary biliary cirrhosis.1,2 Hepatic fibrosis is usually considered an irreversible process, even when the underlying cause is treated or removed.3 However, the fibrosis can be ameliorated — for example, in patients with primary biliary cirrhosis treated with ursodiol4 or methotrexate.5 Regression of hepatic fibrosis has been observed after treatment with interferon alfa in patients with chronic hepatitis C.6 Studies in rats suggest that liver fibrosis due to chronic obstruction of the common bile duct may regress after the obstruction has been corrected.7 According to a 1963 report describing an infant with cirrhosis due to atresia of the common bile duct, regeneration of the liver occurred after bypass surgery for the biliary atresia.8
Stenosis of the common bile duct is a common complication of chronic pancreatitis, occurring in 8 to 30 percent of patients.1,2,9 It can be treated by surgical biliary drainage1,2,9 or by endoscopic drainage.10,11 We studied liver-biopsy specimens from 11 patients with chronic stenosis of the common bile duct due to chronic pancreatitis; all 11 had undergone an initial biopsy before or at the time of biliary drainage and had undergone a second liver biopsy at a later date.
Methods
Patients
Data from a series of 501 patients with chronic pancreatitis who were followed at Beaujon Hospital, Clichy, France, were collected prospectively from 1975 to 1999. The median follow-up period was 7 years (range, 0 to 35), for a total of 4086 patient-years. Of the 501 patients, 101 (20.2 percent) had stenosis of the common bile duct and cholestasis. Histopathological findings in liver specimens from 48 patients were reported in 1993.1 Seventy-nine of the 101 patients (78.2 percent) underwent surgical biliary drainage. The other 22 patients did not undergo surgery because the associated risks were considered to be too high. A preoperative or perioperative liver biopsy was performed in all 79 patients who underwent surgery, including 11 who underwent a subsequent liver biopsy for various reasons. These 11 patients constituted our study sample. None of them had received concomitant drug therapy known to induce cholestasis, and none had hepatitis B viral markers (hepatitis B surface antigen or antibodies against hepatitis B surface antigen) or were known to be positive for hepatitis C virus antibodies.
The diagnosis of chronic pancreatitis was established on the basis of one or more of the following criteria: the presence of pancreatic calcifications on abdominal plain films, ultrasonograms, computed tomographic (CT) scans, or endosonograms; moderate-to-marked ductal lesions according to the Cambridge classification12; or characteristic histologic findings in an adequate surgical specimen. The duration of follow-up was defined as the interval between the first sign clearly attributable to chronic pancreatitis and the last contact with the patient. Alcohol consumption was considered the cause of chronic pancreatitis if the patient's intake of pure alcohol had exceeded 60 g per day for at least two years in the absence of other causes.13
Stenosis of the common bile duct was suspected on the basis of ultrasonographic, endosonographic, or CT findings. Stenosis was confirmed if endoscopic retrograde or operative cholangiography showed that the diameter of the common bile duct was reduced by 50 percent or more with proximal dilatation. Serum alkaline phosphatase, γ-glutamyltransferase, and aminotransferase levels were recorded in all patients. Cholestasis was defined by an alkaline phosphatase value that was above the upper limit of the normal range.
At the time of liver biopsy, a wedge resection was performed, with a specimen approximately 15 mm deep and 7 mm in diameter obtained from the third segment of the left lobe (rather than from the apex of the left lobe, which might have contained a thickened capsule). Percutaneous core-biopsy specimens were obtained from the right lobe of the liver through an intercostal route.
Histologic Analysis
All liver-biopsy specimens were evaluated by two pathologists who were unaware of the clinical data and of the sequence of the liver-biopsy specimens. The specimens were fixed in 10 percent formalin solution or in Bouin's fluid and were then embedded in paraffin. The histologic features of sections stained with hematoxylin and eosin, Masson's trichrome, picrosirius, chromotrope aniline blue, and Perls were scored with the use of a scale previously validated in a study of the treatment of primary biliary cirrhosis.14 Fibrosis was scored on a scale from 0 to 3, with 0 denoting no fibrosis, 1 portal and periportal fibrosis, 2 the presence of numerous septa, and 3 cirrhosis. Portal and periportal inflammation was scored on a scale from 0 to 3; 0 denoted no inflammation, 1 mild inflammation (cells in less than one third of portal tracts), 2 moderate inflammation (cells in one third to two thirds of portal tracts), and 3 severe inflammation (dense packing of cells in more than two thirds of portal tracts). Ductular proliferation was scored on a scale from 0 (absent or mild) to 2 (severe). Histologic features of cholestasis were scored on a scale from 0 to 3, with 0 denoting none, 1 bile accumulation in centrolobular hepatocytes, 2 bile accumulation in centrolobular and periportal hepatocytes or in portal tracts, and 3 bile infarcts (bile accumulation and hepatocellular necrosis surrounded by foamy histiocytes). The specimens were carefully examined for histologic features that are consistent with the presence of alcoholic liver disease, including Mallory's bodies, acidophilic necrosis, sinusoidal fibrosis, and polymorphonuclear infiltrates.
Statistical Analysis
Data are reported as medians and ranges. Histologic findings in the first liver-biopsy specimen (obtained at the time of or immediately before biliary drainage) and those in the specimen obtained at a later date were compared with the use of Wilcoxon's signed-rank test for matched pairs.15 A P value of less than 0.05 was considered to indicate statistical significance. The findings in the two patients who had restenosis of the biliary anastomosis (Patients 10 and 11) were excluded from the statistical analysis.
Results
Characteristics of the Patients
The characteristics of the 11 patients, all of whom were men, are shown in Table 1Table 1
Characteristics of 11 Patients with Stenosis of the Common Bile Duct Due to Chronic Pancreatitis.. Chronic pancreatitis was due to alcohol abuse in all but one man (Patient 4), who had idiopathic chronic pancreatitis. The median duration of follow-up was 11 years (range, 4 to 27). The median age at the time of the clinical onset of chronic pancreatitis was 36 years (range, 14 to 50), and the median age at diagnosis was 38 years (range, 33 to 54). Among the nine patients without restenosis of the biliary anastomosis, data on alcohol consumption before the first biopsy were available for all but one (Patient 8). These eight patients had all been abstinent for a median of 4 months (range, 1 to 48) before the first liver biopsy. Three of the eight patients had resumed drinking before the second biopsy (Patients 1, 2, and 8).First Liver Biopsy
The median interval between the clinical onset of chronic pancreatitis and the diagnosis of stenosis of the common bile duct with cholestasis was 3 years (range, 1 to 21) (Table 1). All 11 patients had pancreatic calcifications when the stenosis was diagnosed. The median interval between the diagnosis of bile duct stenosis and the first liver biopsy was 11 weeks (range, 2 to 98). Liver biopsy was performed during surgery for biliary drainage in 10 patients; 1 patient underwent percutaneous biopsy. In all 11 patients, the liver was firm and green at the time of the first biopsy, and no regenerative nodules were observed. Histologic analysis of liver-biopsy specimens from all the patients revealed secondary biliary disease without signs of alcohol-induced liver damage. Six patients had severe fibrosis with numerous septa (grade 2), and one had Child–Pugh class A secondary biliary cirrhosis (grade 3) (Table 2Table 2
Results of Biochemical Tests and Histologic Findings.). At the time of the first biopsy, none of the patients had hepatic insufficiency, including the patient with cirrhosis.Second Liver Biopsy
After biliary drainage, the results of laboratory tests were normal in nine patients. The two patients with biliary anastomotic restenosis (Patients 10 and 11) had persistent cholestasis. The median interval between the first and second liver biopsies was 2.5 years (range, 0.3 to 9.0). In nine patients, the second liver biopsy was performed during surgery for another complication of chronic pancreatitis (pancreaticoduodenectomy was performed in two patients, left-sided pancreatectomy in three, vagotomy in two, and reconstruction of biliary anastomosis in two); a percutaneous biopsy was performed in two patients because of possible acute alcoholic hepatitis. None of the patients had hepatic insufficiency at the time of the second biopsy.
The quantification of fibrosis by the two pathologists was concordant for both series of biopsies in all the patients except one (Patient 4) (Table 2). The second biopsy showed that the fibrosis had worsened in one of the two patients with anastomotic restenosis and remained the same in the other. In the other nine patients, there was a significant reduction of fibrosis (P=0.01) (Figure 1Figure 1
Histologic Features of Liver-Biopsy Specimens Obtained during and after Biliary Decompression in Two Patients with Stenosis of the Common Bile Duct Due to Chronic Pancreatitis.). On the four-grade scale, fibrosis improved by two grades in two patients and by one grade in four; in three patients, the grade did not change. In the patient with secondary biliary cirrhosis at the initial liver biopsy (Patient 3), only mild portal and periportal fibrosis was found at the second biopsy.The second biopsy also showed significant improvement over the first biopsy with regard to ductular proliferation and portal inflammation (P=0.01 for both comparisons, data not shown). In addition, there was a decrease in bile accumulation between the first and second biopsies, but the difference was not significant (data not shown). We detected no signs of alcohol-induced liver damage in any of the specimens from the second liver biopsy. The two patients with suspected acute alcohol hepatitis had steatosis in more than 20 percent of their hepatocytes.
Discussion
Animal models have provided much information about the structure and function of the liver in chronic obstruction of the common bile duct.7,16,17 In a study of rats with bile-duct obstruction for four weeks, biliary cirrhosis was found in all surviving animals.16 Several surgical methods of biliary decompression have been described in such models.7,18,19 In one study, relief of obstruction after 14 days led to normalization of portal pressure and hepatic venous wedge pressure.19 If biliary obstruction persisted for a longer period, relief of the obstruction failed to lower portal pressure, although biochemical signs of cholestasis resolved. In another study, secondary biliary fibrosis was reversed in rats after four weeks of bile-duct obstruction.7 Improvements in histologic findings (ductular proliferation, fibrosis, and portal hypertension) were correlated with improvements in liver-enzyme values, and these changes were accompanied by improved hepatic function and the reversal of portal hypertension.
There are few data on the effect of surgery on histologic findings after biliary decompression. In a study reported in 1968, biliary decompression appeared to alleviate portal hypertension.20 When stenosis of the common bile duct is due to chronic pancreatitis, the stenosis is usually incomplete. It is largely due to pancreatic fibrosis rather than pancreatic pseudocysts and may be associated with duodenal stenosis.21 In 6 to 29 percent of patients, stenosis of the common bile duct may cause severe liver disease, including cirrhosis.1,2,9 In one study, secondary biliary cirrhosis led to portal hypertension with esophageal or gastric varices in 23 percent of patients,22 and patients with biliary cirrhosis may die from hepatocellular failure or sepsis.23 The condition may develop in a relatively short period (3 to 12 months in one third of the patients studied by Scobie and Summerskill22).
Stenosis of the common bile duct due to biliary compression in patients with chronic pancreatitis provides a unique opportunity to study the course of liver disease after the obstruction has been relieved. Other causes of chronic stenosis of the common bile duct (e.g., ampullary tumors) are rare or are associated with a poor prognosis (e.g., pancreatic adenocarcinoma), with death occurring shortly after decompression. Our data confirm the potential severity of liver disease in a selected group of patients with severe stenosis of the common bile duct due to chronic pancreatitis. The damage appears to occur rapidly; the median time between the detection of stenosis and the first liver biopsy was 11 weeks.1
Our study provides evidence of the reversibility of secondary biliary fibrosis after surgical treatment of chronic obstruction of the common bile duct. Since in the absence of clinical reasons it would be unethical to perform a second liver biopsy, in our study the second biopsy was performed for identifiable clinical reasons or during surgery. There was selection bias in the study, because only 11 patients in a series of 501 met the criterion of a second biopsy. Thus, our patients may not be representative of patients with stenosis of the common bile duct due to chronic pancreatitis.
In our patients the stenosis was severe; 10 of the patients (91 percent) had jaundice at the time of the first liver biopsy, a higher proportion than that in our earlier study (40 percent).1 However, each patient was his own control, and selection was not based on the severity of the disease. We also cannot exclude the possibility that the variation in histologic findings was due to a sampling error. However, only 3 of the 22 specimens were from core biopsies of the right lobe. The other 19 were wedge-biopsy specimens obtained in the same way from the same hepatic segment in all cases. In addition, there is no documented evidence that biliary changes due to distal obstruction of the common bile duct are not widely distributed in the liver.1,2,7 Despite the retrospective design of our study, we minimized bias by ensuring that the two pathologists were unaware of both the clinical data and the sequence of the biopsy specimens and by using a scoring system that has been validated for cholestatic disease.12 Comparison of our patients with a control group consisting of patients with bile-duct obstruction in whom bypass procedures were not performed would have been valuable. However, it is not possible to perform such a comparison because the detection of an obstruction of the common bile duct is usually followed rapidly by surgical decompression.
None of the patients in our study had both biliary and alcoholic changes on liver biopsy. This finding is probably due to the severity of biliary lesions, which may mask minor changes related to the consumption of alcohol. We cannot rule out a synergistic effect of biliary decompression and abstinence from alcohol. However, the pathological findings in the three patients who continued to abuse alcohol were similar to those in the patients who remained abstinent. Regression of fibrosis due to alcohol consumption has not been clearly demonstrated.24 Thus, the major benefits we observed were probably due to relief of biliary obstruction. With the exception of the two patients with restenosis of the biliary anastomosis, all the patients had significant improvement in liver damage, even those with severe damage initially.
Source Information
From Fédération Médico-Chirurgicale d'Hépato-Gastroentérologie, Service de Gastroentérologie (P.H., D.O.T., A.R., P.B., P.R., P.L.), Service d'Anatomie Pathologique (A.C., J.F.F., C.D.), Service de Chirurgie Digestive (A.S., J.B.), and Service d'Hépatologie (D.V.), Hôpital Beaujon, Clichy, France.
Address reprint requests to Dr. Ruszniewski at Fédération Médico-Chirurgicale d'Hépato-Gastroentérologie, Hôpital Beaujon, AP-HP, 92118 Clichy CEDEX, France, or at philippe.ruszniewski@bjn.ap-hop-paris.fr.
- References
References
1
Lesur G ,Levy P ,Flejou JF ,Belghiti J ,Fekete F ,Bernades P . Factors predictive of liver histopathological appearance in chronic alcoholic pancreatitis with common bile duct stenosis and increased serum alkaline phosphatase. Hepatology 1993;18:1078-1081
CrossRef | Web of Science | Medline2
Afroudakis A ,Kaplowitz N . Liver histopathology in chronic common bile duct stenosis due to chronic alcoholic pancreatitis. Hepatology 1981;1:65-72
CrossRef | Web of Science | Medline3
Friedman SL . The cellular basis of hepatic fibrosis: mechanisms and treatment strategies. N Engl J Med 1993;328:1828-1835
Full Text | Web of Science | Medline4
Poupon RE, Balkau B, Eschwege E, Poupon R, UDCA-PBC Study Group
Full Text | Web of Science | Medline5
Kaplan MM ,DeLellis RA ,Wolfe HJ . Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997;126:682-688
Web of Science | Medline6
Sobesky R ,Mathurin P ,Charlotte F , et al. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. Gastroenterology 1999;116:378-386
CrossRef | Web of Science | Medline7
Zimmerman H ,Reichen J ,Zimmerman A ,Sagesser H ,Thenisch B ,Hoflin F . Reversibility of secondary biliary fibrosis by biliodigestive anastomosis in the rat. Gastroenterology 1992;103:579-589
Web of Science | Medline8
Bunton GL ,Cameron R . Regeneration of liver after biliary cirrhosis. Ann N Y Acad Sci 1963;111:412-421
CrossRef | Web of Science | Medline9
Bernades P ,Belghiti J ,Athouel M ,Mallardo N ,Breil P ,Fekete F . Histoire naturelle de la pancréatite chronique: étude de 120 cas. Gastroenterol Clin Biol 1983;7:8-13
Web of Science | Medline10
Deviere J ,Cremer M ,Baize M ,Love J ,Sugai B ,Vandermeeren A . Management of common bile duct stricture caused by chronic pancreatitis with metal mesh self expandable stents. Gut 1994;35:122-126
CrossRef | Web of Science | Medline11
Barthet M ,Bernard JP ,Duval JL ,Affriat C ,Sahel J . Biliary stenting in benign biliary stenosis complicating chronic calcifying pancreatitis. Endoscopy 1994;26:569-572
CrossRef | Web of Science | Medline12
Axon ATR ,Classen M ,Cotton PB ,Cremer M ,Freeny PC ,Lees WR . Pancreatography in chronic pancreatitis: international definitions. Gut 1984;25:1107-1112
CrossRef | Web of Science | Medline13
Levy P ,Milan C ,Pignon JP ,Baetz A ,Bernades P . Mortality factors associated with chronic pancreatitis: unidimensional and multidimensional analysis of a medical-surgical series of 240 patients. Gastroenterology 1989;96:1165-1172
Web of Science | Medline14
Degott C ,Zafrani ES ,Callard P ,Balkau B ,Poupon RE ,Poupon R . Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 1999;29:1007-1012
CrossRef | Web of Science | Medline15
Hollander M, Wolfe DA. Nonparametric statistical methods. New York: John Wiley, 1973.
16
Kontouras J ,Billing BH ,Scheuer PJ . Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 1984;65:305-311
Web of Science | Medline17
Gross JB ,Reichen J ,Zeltner T ,Zimmerman A . The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass. Hepatology 1987;7:457-463
CrossRef | Web of Science | Medline18
Posner MC ,Burt ME ,Stone MD , et al. A model of reversible obstructive jaundice in the rat. J Surg Res 1990;48:204-210
CrossRef | Web of Science | Medline19
Franco D ,Gigou M ,Szekely AM ,Bismuth H . Portal hypertension after bile duct obstruction: effect of bile diversion on portal pressure in the rat. Arch Surg 1979;114:1064-1067
Web of Science | Medline20
Adson MA ,Wychulis AR . Portal hypertension in secondary biliary cirrhosis. Arch Surg 1968;96:604-612
Web of Science | Medline21
Levy P ,Lesur G ,Belghiti J ,Fekete F ,Bernades P . Symptomatic duodenal stenosis in chronic pancreatitis: a study of 17 cases in a medical-surgical series of 306 patients. Pancreas 1993;8:563-567
CrossRef | Web of Science | Medline22
Scobie BA ,Summerskill WHJ . Hepatic cirrhosis secondary to obstruction of the biliary system. Am J Dig Dis 1965;10:135-146
CrossRef | Medline23
Way LW ,Bernhoft RA ,Thomas MJ . Biliary stricture. Surg Clin North Am 1981;61:963-972
Web of Science | Medline24
Lieber CS . Prevention and treatment of liver fibrosis based on pathogenesis. Alcohol Clin Exp Res 1999;23:944-949
CrossRef | Web of Science | Medline
- Citing Articles (97)
Citing Articles
1
P.J. Trivedi, R.W. Chapman. (2012) PSC, AIH and overlap syndrome in inflammatory bowel disease. Clinics and Research in Hepatology and Gastroenterology
CrossRef2
Detlef Schuppan, Massimo Pinzani. (2012) Anti-fibrotic therapy: Lost in translation?. Journal of Hepatology 56, S66-S74
CrossRef3
Yasuni Nakanuma, Yoh Zen, Bernard C. Portmann. 2012. Diseases of the bile ducts. , 491-562.
CrossRef4
Don C. Rockey, Scott L. Friedman. 2012. Hepatic Fibrosis and Cirrhosis. , 64-85.
CrossRef5
Yu-Ting Lo, Ya-Hui Tsai, Shu-Ju Wu, Jiun-Rong Chen, Jane C.-J. Chao. (2011) Ginsenoside Rb1 Inhibits Cell Activation and Liver Fibrosis in Rat Hepatic Stellate Cells. Journal of Medicinal Food 14:10, 1135-1143
CrossRef6
Rafael Kemp, Whemberton Martins de Araújo, Adelson Antonio de Castro, José Celso Ardengh, Luciano Neder, José Sebastião dos Santos. (2011) Influence of Biliary Drainage on the Repair of Hepatic Lesions in Biliary Fibrosis. Journal of Surgical Research 169:2, e127-e136
CrossRef7
Kyung-Ah Cho, Goh-Woon Lim, Sun-Young Joo, So-Youn Woo, Ju-Young Seoh, Su Jin Cho, Ho-Seong Han, Kyung-Ha Ryu. (2011) Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Liver International 31:7, 932-939
CrossRef8
Vincenzo Perri, Pietro Familiari, Andrea Tringali, Ivo Boskoski, Guido Costamagna. (2011) Plastic Biliary Stents for Benign Biliary Diseases. Gastrointestinal Endoscopy Clinics of North America 21:3, 405-433
CrossRef9
Mihir R. Bakhru, Michel Kahaleh. (2011) Expandable Metal Stents for Benign Biliary Disease. Gastrointestinal Endoscopy Clinics of North America 21:3, 447-462
CrossRef10
D. A. Klibansky, S. H. Mehta, M. Curry, I. Nasser, T. Challies, N. H. Afdhal. (2011) Transient elastography for predicting clinical outcomes in patients with chronic liver disease. Journal of Viral Hepatitisno-no
CrossRef11
Fred M. Wu, Chinweike Ukomadu, Robert D. Odze, Anne Marie Valente, John E. Mayer Jr., Michael G. Earing. (2011) Liver Disease in the Patient with Fontan Circulation. Congenital Heart Disease 6:3, 190-201
CrossRef12
Rodrigo T. Calado, Jennifer Brudno, Paulomi Mehta, Joseph J. Kovacs, Colin Wu, Marco A. Zago, Stephen J. Chanock, Thomas D. Boyer, Neal S. Young. (2011) Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53:5, 1600-1607
CrossRef13
Victoria K. Snowdon, Jonathan A. Fallowfield. (2011) Models and Mechanisms of Fibrosis Resolution. Alcoholism: Clinical and Experimental Research 35:5, 794-799
CrossRef14
James S. Dooley. 2011. Gallstones and Benign Biliary Diseases. , 257-293.
CrossRef15
P. Aiden McCormick. 2011. Hepatic Cirrhosis. , 103-120.
CrossRef16
Tatiana Kisseleva, David A. Brenner. (2011) Anti-fibrogenic strategies and the regression of fibrosis. Best Practice & Research Clinical Gastroenterology 25:2, 305-317
CrossRef17
Tom Luedde, Robert F. Schwabe. (2011) NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology 8:2, 108-118
CrossRef18
Yoko Yashima, Takeshi Tsujino, Ryota Masuzaki, Yousuke Nakai, Kenji Hirano, Ryosuke Tateishi, Naoki Sasahira, Hiroyuki Isayama, Minoru Tada, Haruhiko Yoshida, Takao Kawabe, Masao Omata. (2011) Increased liver elasticity in patients with biliary obstruction. Journal of Gastroenterology 46:1, 86-91
CrossRef19
José Miguel Valera, Gladys Smok, Sylvia Márquez, Jaime Poniachik, Javier Brahm. (2011) Regresión histológica de la fibrosis hepática con tratamiento inmunosupresor en hepatitis autoinmune. Gastroenterología y Hepatología 34:1, 10-15
CrossRef20
Damien Meng Yew Tan, Stuart Sherman. (2011) Endoscopic Therapy in Chronic Pancreatitis. The Korean Journal of Internal Medicine 26:4, 384
CrossRef21
Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Eun Hee Choi, Jae Yeon Seok, Jung Min Lee, Young Nyun Park, Chae Yoon Chon, Kwang-Hyub Han. (2010) Non-invasive assessment of changes in liver fibrosis via liver stiffness measurement in patients with chronic hepatitis B: impact of antiviral treatment on fibrosis regression. Hepatology International 4:4, 673-680
CrossRef22
Christelle Guyot, Sébastien Lepreux, Chantal Combe, Vincent Sarrazy, Fabrice Billet, Charles Balabaud, Paulette Bioulac-Sage, Alexis Desmoulière. (2010) Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. Liver International 30:10, 1529-1540
CrossRef23
Hau D. Le, Kathleen M. Gura, Danielle A. Arsenault, Erica M. Fallon, Alexis K. Potemkin, Mark Puder. (2010) Assessing portal fibrosis in parenteral nutrition-dependent patients treated with omega-3 fatty acid lipid emulsion. The Journal of Pediatrics 157:3, 517
CrossRef24
Ting-Tsung Chang, Yun-Fan Liaw, Shun-Sheng Wu, Eugene Schiff, Kwang-Hyub Han, Ching-Lung Lai, Rifaat Safadi, Samuel S. Lee, Waldemar Halota, Zachary Goodman, Yun-Chan Chi, Hui Zhang, Robert Hindes, Uchenna Iloeje, Suzanne Beebe, Bruce Kreter. (2010) Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52:3, 886-893
CrossRef25
Emmanouil Sinakos, Keith Lindor. (2010) Treatment options for primary sclerosing cholangitis. Expert Review of Gastroenterology & Hepatology 4:4, 473-488
CrossRef26
Thai Nguyen-Tang, Jean-Marc Dumonceau. (2010) Endoscopic treatment in chronic pancreatitis, timing, duration and type of intervention. Best Practice & Research Clinical Gastroenterology 24:3, 281-298
CrossRef27
Tetsuya Ishimaru, Yoshihiro Kitano, Hiroo Uchida, Hiroshi Kawashima, Chikashi Gotoh, Kaori Satoh, Mariko Yoshida, Hiroshi Kishimoto, Tadashi Iwanaka. (2010) Histopathologic improvement in biliary cirrhosis after definitive surgery for choledochal cyst. Journal of Pediatric Surgery 45:5, e11-e14
CrossRef28
Daniel Gotthardt, Adolf Stiehl. (2010) Endoscopic Retrograde Cholangiopancreatography in Diagnosis and Treatment of Primary Sclerosing Cholangitis. Clinics in Liver Disease 14:2, 349-358
CrossRef29
S. C. Schmidt, P. Fikatas, T. Denecke, G. Schumacher, F. Aurich, U. Neumann, D. Seehofer. (2010) Hepatic resection for patients with cholecystectomy related complex bile duct injury. European Surgery 42:2, 77-82
CrossRef30
Matthew L. Cowan, Tony M. Rahman, Sanjeev Krishna. (2010) Proteomic approaches in the search for biomarkers of liver fibrosis. Trends in Molecular Medicine 16:4, 171-183
CrossRef31
Jing-Hua Wang, Jang-Woo Shin, Jin-Young Son, Jung-Hyo Cho, Chang-Gue Son. (2010) Antifibrotic effects of CGX, a traditional herbal formula, and its mechanisms in rats. Journal of Ethnopharmacology 127:2, 534-542
CrossRef32
H.E. Wasmuth, C. Trautwein. (2010) Leberfibrose. Der Internist 51:1, 14-20
CrossRef33
Marlene Domínguez, Jordi Colmenero, Ramón Bataller. (2009) Tratamiento de la fibrosis hepática. Gastroenterología y Hepatología 32:9, 627-632
CrossRef34
M. Isabel Fiel, Hai-Shan Wu, Kishore Iyer, Gonzalo Rodriguez-Laiz, Thomas D. Schiano. (2009) Rapid Reversal of Parenteral-Nutrition-Associated Cirrhosis Following Isolated Intestinal Transplantation. Journal of Gastrointestinal Surgery 13:9, 1717-1723
CrossRef35
Massimo Pinzani. (2009) Unraveling the Spider Web of Hepatic Stellate Cell Apoptosis. Gastroenterology 136:7, 2061-2063
CrossRef36
E. C. Verna, E. De Martin, P. Burra, D. Neri, P. J. Gaglio, J. C. Emond, R. S. Brown, Jr.. (2009) The Impact of Hepatitis C and Biliary Complications on Patient and Graft Survival Following Liver Transplantation. American Journal of Transplantation 9:6, 1398-1405
CrossRef37
Frank M Strutz. (2009) EMT and proteinuria as progression factors. Kidney International 75:5, 475-481
CrossRef38
Byung Moo Yoo, Glen A. Lehman. (2009) Update on Endoscopic Treatment of Chronic Pancreatitis. The Korean Journal of Internal Medicine 24:3, 169
CrossRef39
Sadiq S Sikora, Gadiyaram Srikanth, Vinita Agrawal, Ramesh K Gupta, Ashok Kumar, Rajan Saxena, Vinay K Kapoor. (2008) Liver histology in benign biliary stricture: Fibrosis to cirrhosis . . . and reversal?. Journal of Gastroenterology and Hepatology 23:12, 1879-1884
CrossRef40
Don C. Rockey. (2008) Current and Future Anti-Fibrotic Therapies for Chronic Liver Disease. Clinics in Liver Disease 12:4, 939-962
CrossRef41
C. D. ZOIS, G. H. BALTAYIANNIS, P. KARAYIANNIS, E. V. TSIANOS. (2008) Systematic review: hepatic fibrosis - regression with therapy. Alimentary Pharmacology & Therapeutics 28:10, 1175-1187
CrossRef42
Gonca Ustundag, Zarife Kuloglu, Ceyda Tuna Kırsaçlıoğlu, Aydan Kansu, Esra Erden, Nurten Girgin. (2008) Complete regression of cirrhosis after immunosuppressive treatment in autoimmune hepatitis. Pediatrics International 50:5, 711-713
CrossRef43
Patrick Asbach, Dieter Klatt, Uwe Hamhaber, Jürgen Braun, Rajan Somasundaram, Bernd Hamm, Ingolf Sack. (2008) Assessment of liver viscoelasticity using multifrequency MR elastography. Magnetic Resonance in Medicine 60:2, 373-379
CrossRef44
J. H. Tsai, J. Y. Liu, T. T. Wu, P. C. Ho, C. Y. Huang, J. C. Shyu, Y. S. Hsieh, C. C. Tsai, Y. C. Liu. (2008) Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. Journal of Viral Hepatitis 15:7, 508-514
CrossRef45
Alexis Laurent, Alain Sauvanet, Olivier Farges, Thierry Watrin, Emmanuel Rivkine, Jacques Belghiti. (2008) Major Hepatectomy for the Treatment of Complex Bile Duct Injury. Annals of Surgery 248:1, 77-83
CrossRef46
Jason P. Etzel, Sue C. Eng, Cynthia W. Ko, Scott D. Lee, Michael D. Saunders, Bruce Y. Tung, Michael B. Kimmey, Kris V. Kowdley. (2008) Complications after ERCP in patients with primary sclerosing cholangitis. Gastrointestinal Endoscopy 67:4, 643-648
CrossRef47
Yury Popov, Eleonora Patsenker, Felix Stickel, Jessica Zaks, K. Ramakrishnan Bhaskar, Gerald Niedobitek, Armin Kolb, Helmut Friess, Detlef Schuppan. (2008) Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. Journal of Hepatology 48:3, 453-464
CrossRef48
Mark Topazian, Thomas E. Witzig, Thomas C. Smyrk, Jose S. Pulido, Michael J. Levy, Patrick S. Kamath, Suresh T. Chari. (2008) Rituximab Therapy for Refractory Biliary Strictures in Immunoglobulin G4–Associated Cholangitis. Clinical Gastroenterology and Hepatology 6:3, 364-366
CrossRef49
Yuji Iimuro, David A. Brenner. (2008) Matrix Metalloproteinase Gene Delivery for Liver Fibrosis. Pharmaceutical Research 25:2, 249-258
CrossRef50
Maurizio Parola, Fabio Marra, Massimo Pinzani. (2008) Myofibroblast – like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Molecular Aspects of Medicine 29:1-2, 58-66
CrossRef51
Andrea Tringali, Ivo Boskoski, Guido Costamagna. (2008) The role of endoscopy in the therapy of chronic pancreatitis. Best Practice & Research Clinical Gastroenterology 22:1, 145-165
CrossRef52
Doh Kyung-Oh. (2008) Effects of TGF-β1 Ribbon Antisense on CCl4-induced Liver Fibrosis. The Korean Journal of Physiology and Pharmacology 12:1, 1
CrossRef53
Mark Pines. (2008) Targeting TGFβ signaling to inhibit fibroblast activation as a therapy for fibrosis and cancer: effect of halofuginone. Expert Opinion on Drug Discovery 3:1, 11-20
CrossRef54
Alexandre Rodrigues Ferreira, Mariza Leitão Valadares Roquete, Nivaldo H Toppa, Lúcia Porto Fonseca de Castro, Eleonora Druve Tavares Fagundes, Francisco José Penna. (2008) Effect of Treatment of Hepatic Histopathology in Children and Adolescents With Autoimmune Hepatitis. Journal of Pediatric Gastroenterology and Nutrition 46:1, 65-70
CrossRef55
Rafael Bruck, Sigal Weiss, Alexandra Traister, Isabel Zvibel, Hussein Aeed, Zamir Halpern, Ran Oren. (2007) Induced hypothyroidism accelerates the regression of liver fibrosis in rats. Journal of Gastroenterology and Hepatology 22:12, 2189-2194
CrossRef56
Yasukane Asano, Yuji Iimuro, Gakuhei Son, Tadamichi Hirano, Jiro Fujimoto. (2007) Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver. Hepatology Research 37:12, 1080-1094
CrossRef57
Zhaoyang Ye, Houssam S. Hajj Houssein, Ram I. Mahato. (2007) Bioconjugation of Oligonucleotides for Treating Liver Fibrosis. Oligonucleotides 17:4, 349-404
CrossRef58
Sami Arslanlar, Rajeev Jain. (2007) Benign biliary strictures related to chronic pancreatitis: Balloons, stents, or surgery. Current Treatment Options in Gastroenterology 10:5, 369-375
CrossRef59
Qin Pan, Zhong-Bing Zhang, Xin Zhang, Jian Shi, Yue-Xiang Chen, Ze-Guang Han, Wei-Fen Xie. (2007) Gene Expression Profile Analysis of the Spontaneous Reversal of Rat Hepatic Fibrosis by cDNA Microarray. Digestive Diseases and Sciences 52:10, 2591-2600
CrossRef60
Gabriela Gutierrez-Reyes, Maria Concepcion Gutierrez-Ruiz, David Kershenobich. (2007) Liver Fibrosis and Chronic Viral Hepatitis. Archives of Medical Research 38:6, 644-651
CrossRef61
B. Saile, G. Ramadori. (2007) Fibrogenese – Zirrhose. Der Gastroenterologe 2:4, 228-237
CrossRef62
Flavia Bortolotti, Maria Guido. (2007) Reversal of Liver Cirrhosis: A Desirable Clinical Outcome and Its Pathogenic Background. Journal of Pediatric Gastroenterology and Nutrition 44:4, 401-406
CrossRef63
John P. Iredale. (2007) Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. Journal of Clinical Investigation 117:3, 539-548
CrossRef64
Reiichi Higashiyama, Yutaka Inagaki, Yun Yu Hong, Miwa Kushida, Sachie Nakao, Maki Niioka, Tetsu Watanabe, Hideyuki Okano, Yumi Matsuzaki, Goshi Shiota, Isao Okazaki. (2007) Bone marrow–derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology 45:1, 213-222
CrossRef65
Tadashi Ikegami, Yining Zhang, Yasushi Matsuzaki. (2007) Liver Fibrosis: Possible Involvement of EMT. Cells Tissues Organs 185:1-3, 213-221
CrossRef66
Ajay K. Muddu, Indra Neil Guha, Ahmed M. Elsharkawy, Derek A. Mann. (2007) Resolving fibrosis in the diseased liver: Translating the scientific promise to the clinic. The International Journal of Biochemistry & Cell Biology 39:4, 695-714
CrossRef67
Jeanne Serpaggi, Françoise Carnot, Bertrand Nalpas, Danièle Canioni, Jérôme Guéchot, Pascal Lebray, Anaïs Vallet-Pichard, Hélène Fontaine, Pierre Bedossa, Stanislas Pol. (2006) Direct and indirect evidence for the reversibility of cirrhosis. Human Pathology 37:12, 1519-1526
CrossRef68
Ludivine Falize, Anne Guillygomarc'h, Michele Perrin, Fabrice Lainé, Dominique Guyader, Pierre Brissot, Bruno Turlin, Yves Deugnier. (2006) Reversibility of hepatic fibrosis in treated genetic hemochromatosis: A study of 36 cases. Hepatology 44:2, 472-477
CrossRef69
C. Mel Wilcox, Shyam Varadarajulu. (2006) Endoscopic therapy for chronic pancreatitis: An evidence-based review. Current Gastroenterology Reports 8:2, 104-110
CrossRef70
Scott L. Friedman, Meena B. Bansal. (2006) Reversal of hepatic fibrosis — Fact or fantasy?. Hepatology 43:S1, S82-S88
CrossRef71
Dinesh Singhal, Steve de Castro, Neerav Goyal, Dirk J. Gouma, A. Chaudhary, Thomas M. van Gulik. (2006) Current Role of Portosystemic Shunt Surgery in the Management of Hepatic Venous Outflow Obstruction. Digestive Surgery 23:5-6, 358-369
CrossRef72
A. M. Gressner, R. Weiskirchen. (2006) Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-? as major players and therapeutic targets. Journal of Cellular and Molecular Medicine 10:1, 76-99
CrossRef73
SANJAY SINGH NEGI, ADARSH CHAUDHARY. (2005) Analysis of abnormal recovery pattern of liver function tests after surgical repair of bile duct strictures. Journal of Gastroenterology and Hepatology 20:10, 1533-1537
CrossRef74
A. M. Elsharkawy, F. Oakley, D. A. Mann. (2005) The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10:5, 927-939
CrossRef75
Bo Jin, Harvey J Alter, Zhi-Cheng Zhang, J Wai-Kuo Shih, Juan M Esteban, Tao Sun, Yun-Sheng Yang, Qi Qiu, Xiao-Lin Liu, Lin Yao, Hai-Dong Wang, Liu-Fang Cheng. (2005) Reversibility of experimental rabbit liver cirrhosis by portal collagenase administration. Laboratory Investigation 85:8, 992-1002
CrossRef76
Mark W. Harty, Hannah M. Huddleston, Elaine F. Papa, Tauquir Puthawala, Aaron P. Tracy, Grant A. Ramm, Stephan Gehring, Stephen H. Gregory, Thomas F. Tracy. (2005) Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity. Surgery 138:2, 313-320
CrossRef77
Brygida Beck, Marian Ciszek, Renata Polaniak, Zbigniew Beyga, Wojciech Król, Marek Drozdz, Jashovam Shani. (2005) The Activity of Ornithine Transcarbamoylase and Arginase During Mechanical Jaundice in the Rat Model. Journal of Surgical Research 126:1, 19-26
CrossRef78
Mehdi Mohamadnejad, Reza Malekzadeh, Siavosh Nasseri-Moghaddam, Sepideh Hagh-Azali, Nasser Rakhshani, Seyed Mohamad Tavangar, Mojtaba Sedaghat, Seyed Meysam Alimohamadi. (2005) Impact of Immunosuppressive Treatment on Liver Fibrosis in Autoimmune Hepatitis. Digestive Diseases and Sciences 50:3, 547-551
CrossRef79
Ramón Bataller, David A. Brenner. (2005) Liver fibrosis. Journal of Clinical Investigation 115:2, 209-218
CrossRef80
Don C. Rockey. (2005) Antifibrotic therapy in chronic liver disease. Clinical Gastroenterology and Hepatology 3:2, 95-107
CrossRef81
Sophie Lotersztajn, Boris Julien, Fatima Teixeira-Clerc, Pascale Grenard, Ariane Mallat. (2005) HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets. Annual Review of Pharmacology and Toxicology 45:1, 605-628
CrossRef82
Tomoaki Kato, Andreas G. Tzakis. 2005. Transplantation of the Liver with Digestive Organs. , 787-802.
CrossRef83
Jin Kang, Keiichirou Morimura, Elsayed Salim, Hideki Wanibuchi, Shuji Yamaguchi, Shoji Fukushima. (2005) Persistence of Liver Cirrhosis in Association with Proliferation of Nonparenchymal Cells and Altered Location of α-Smooth Muscle Actin-Positive Cells. Toxicologic Pathology 33:3, 329-335
CrossRef84
Jonathan A Fallowfield, John P Iredale. (2004) Targeted treatments for cirrhosis. Expert Opinion on Therapeutic Targets 8:5, 423-435
CrossRef85
S. Massarrat, V. Fallahazad, N. Kamalian. (2004) Clinical, biochemical and imaging-verified regression of hepatitis B-induced cirrhosis. Liver International 24:2, 105-109
CrossRef86
Reza Malekzadeh, Mehdi Mohamadnejad, Nasser Rakhshani, Siavosh Nasseri-Moghaddam, Shahin Merat, Seyed Mohamad Tavangar, Amir Ali Sohrabpour. (2004) Reversibility of cirrhosis in chronic hepatitis B. Clinical Gastroenterology and Hepatology 2:4, 344-347
CrossRef87
József Pozsár, Péter Sahin, Ferenc László, Györgyi Forró, Lajos Topa. (2004) Medium-term Results of Endoscopic Treatment of Common Bile Duct Strictures in Chronic Calcifying Pancreatitis With Increasing Numbers of Stents. Journal of Clinical Gastroenterology 38:2, 118-123
CrossRef88
John G Kral, Swan N Thung, Simon Biron, Frederic-Simon Hould, Stefane Lebel, Simon Marceau, Serge Simard, Picard Marceau. (2004) Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 135:1, 48-58
CrossRef89
Stanislas Pol, Françoise Carnot, Bertrand Nalpas, Jean-Luc Lagneau, Héléne Fontaine, Jeanne Serpaggi, Lawrence Serfaty, Pierre Bedossa, Christian Bréchot. (2004) Reversibility of hepatitis C virus-related cirrhosis. Human Pathology 35:1, 107-112
CrossRef90
Thierry Poynard, John McHutchison, Michael Manns, Christian Trepo, Karen Lindsay, Zachary Goodman, Janice Albrecht. (2003) Reply. Gastroenterology 125:2, 630-631
CrossRef91
Pierre Bedossa, Valérie Paradis. (2003) Liver extracellular matrix in health and disease. The Journal of Pathology 200:4, 504-515
CrossRef92
Barbara L Bass. (2002) What’s new in general surgery: gastrointestinal conditions. Journal of the American College of Surgeons 195:6, 835-854
CrossRef93
Frank Murphy, Michael Arthur, John Iredale. (2002) Developing strategies for liver fibrosis treatment. Expert Opinion on Investigational Drugs 11:11, 1575-1585
CrossRef94
L.A Köpke-Aguiar, J.R.M Martins, C.C Passerotti, C.F Toledo, H.B Nader, Durval R Borges. (2002) Serum hyaluronic acid as a comprehensive marker to assess severity of liver disease in schistosomiasis. Acta Tropica 84:2, 117-126
CrossRef95
Jay H. Lefkowitch. (2002) Hepatobiliary pathology. Current Opinion in Gastroenterology 18:3, 290-298
CrossRef96
Michael Trauner, James L. Boyer. (2002) Cholestatic syndromes. Current Opinion in Gastroenterology 18:3, 314-329
CrossRef97
Bonis, Peter A.L., , Friedman, Scott L., , Kaplan, Marshall M., . (2001) Is Liver Fibrosis Reversible?. New England Journal of Medicine 344:6, 452-454
Full Text
