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VIRAL HEPATITIS

Liver Stiffness Identifies Two Different Patterns ofFibrosis Progression in Patients with Hepatitis C Virus

Recurrence After Liver TransplantationJose A. Carrion,1 Ferran Torres,2 Gonzalo Crespo,1 Rosa Miquel,3 Juan-Carlos Garcıa-Valdecasas,4

Miquel Navasa,1 and Xavier Forns1

Significant liver fibrosis (F > 2) and portal hypertension (hepatic venous pressure gradient[HVPG] > 6 mmHg) at 1 year after liver transplantation (LT) identify patients with severehepatitis C recurrence. We evaluated whether repeated liver stiffness measurements (LSM)following LT can discriminate between slow and rapid “fibrosers” (fibrosis stage F2-F4 at 1year after LT). Eighty-four patients who had undergone LT and who were infected withhepatitis C virus (HCV) and 19 LT controls who were not infected with HCV underwentLSM at 3, 6, 9, and 12 months after LT. All HCV-infected patients underwent liver biopsy 12months after LT (paired HVPG measurements in 74); 31 (37%) were rapid fibrosers. MedianLSM (in kilopascal) at months 6, 9, and 12 were significantly higher in rapid fibrosers (9.9,9.5, 12.1) than in slow fibrosers (6.9, 7.5, 6.6) (P < 0.01 all time points). The slope of liverstiffness progression (kPa ! month) in rapid fibrosers (0.42) was significantly greater thanin slow fibrosers (0.05) (P < 0.001), suggesting two different speeds of liver fibrosis pro-gression. Figures were almost identical for patients with HVPG > 6 mmHg or HVPG < 6mmHg at 1 year after LT. Multivariate analysis identified donor age, bilirubin level, andLSM as independent predictors of fibrosis progression and portal hypertension in the esti-mation group (n " 50) and were validated in a second group of 34 patients. The areas underthe receiver operating characteristic curve that could identify rapid fibrosers and patientswith portal hypertension as early as 6 months after LT were 0.83 and 0.87, respectively, inthe estimation group and 0.75 and 0.80, respectively, in the validation group. Conclusion:Early and repeated LSM following hepatitis C recurrence in combination with clinicalvariables discriminates between rapid and slow fibrosers after LT. (HEPATOLOGY 2010;51:23-34.)

Hepatitis C virus (HCV) infection recurs univer-sally after liver transplantation (LT)1 and graftcirrhosis develops in a significant proportion of

patients within the first years after LT.2-4 As a result of thisaccelerated course, hepatitis C recurrence is the first cause

of graft loss and reduction in patient survival in most livertransplant programs.5 Thus, identification of patients atrisk of severe recurrence at an early stage, in order to adopttherapeutic decisions,6-8 becomes crucial. It is well knownthat early histological damage after transplantation corre-

Abbreviations: AUROC, area under the receiver operating characteristics; DDLT, deceased donor liver transplantation; F, fibrosis stage; HCV, hepatitis C virus; HVPG,hepatic venous pressure gradient; LDLT, living donor liver transplantation; LR!, likelihood ratio positive; LR", likelihood ratio negative; LSM, liver stiffnessmeasurements; LT, liver transplantation; MMRM, mixed model for repeated measurements; NIA, necroinflammatory activity; NPV, negative predictive value; PPV,positive predictive value; S, sensitivity; Sp, specificity.

From the 1Liver Unit, Institut de Malalties Digestives, Hospital Clınic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de InvestigacionBiomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Barcelona, Spain; 2Laboratory of Biostatistics and Epidemiology (Universitat Autonoma deBarcelona); Statistics and Methodology Support Unit, Hospital Clınic, IDIBAPS, Barcelona, Spain; 3Pathology Unit, Hospital Clınic, IDIBAPS, CIBERehd, Barcelona,Spain; 4Liver Transplantation and Hepatic Surgery Department, Hospital Clınic, IDIBAPS, CIBERehd, Barcelona, Spain.

Received April 17, 2009; accepted August 10, 2009.X.F. received an unrestricted grant support from Schering and Roche, and J.A.C. was given a grant by “Fundacion BBVA”.Address reprint requests to: Miquel Navasa, Senior Consultant, Liver Unit, ICMD, Hospital Clinic, IDIBAPS and CIBERehd, Villarroel 170, 08036 Barcelona,

Spain. E-mail: [email protected]; telephone: 34 03 227 54 99; fax: !34 93 451 55 22.Copyright © 2009 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.23240Potential conflict of interest: Nothing to report.

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lates with severe hepatitis C recurrence and poor long-term outcome.9,10 However, the sampling variability ofliver biopsy may be a problem in individuals with rapiddisease progression.11,12 Interestingly, the hepatic venouspressure gradient (HVPG) has recently demonstrated tobe extremely useful in the transplant setting, being moreaccurate than liver biopsy at identifying patients at risk ofclinical decompensation.13

Nevertheless, liver biopsy and HVPG measurementare invasive and expensive methods, particularly if theyneed to be repeated during follow-up. To date, serologicaltests14,15 and direct fibrosis markers16 have not been fullyvalidated in transplant patients, and diagnostic accuracyof indirect fibrosis markers is significantly lower than inindividuals who have not undergone LT.17-19 The appli-cation of these methods in LT recipients is troublesomebecause some serological markers can be altered by causesnot related to fibrosis progression. In contrast, transientelastography, a new noninvasive and reproduciblemethod to identify cirrhosis in HCV-infected pa-tients,20-22 has been shown to accurately assess liver fibro-sis in the transplant setting.23-25 In a cross-sectionalanalysis performed in HCV-infected LT recipients, therewas a strong relationship between liver stiffness measure-ments (LSM) and fibrosis stage. More importantly, thecorrelation between LSM and HVPG was excellent.23

The latter has recently been confirmed in patients withchronic hepatitis C and cirrhosis.26,27

In this study, we prospectively evaluated whether re-peated LSM during the first year after LT can identifypatients at risk to develop significant fibrosis (F ! 2) orportal hypertension (HVPG ! 6 mmHg) at an earlystage.

Patients and Methods

Patients. From August 2004 to January 2008, 132consecutive patients with HCV recurrence after LT out ofa total of 293 patients who underwent transplantation inour institution were considered for the study. Exclusioncriteria were: graft or patient survival shorter than 12months after LT (n # 17); combined kidney and livertransplantation (n # 4); hepatitis B virus or human im-munodeficiency virus coinfection (n # 3); presence ofascites (n # 6), body mass index $ 33 (n # 2), chronicgraft rejection (n # 5), biliary tract complications (n #8), veno-occlusive disease (n # 1), de novo autoimmunehepatitis (n # 1) and recurrence of hepatocellular carci-noma (n # 1) during the first year after LT. Therefore,the final number of HCV-infected LT recipients includedwas 84 (64%). Another 19 patients who underwent LTfor other etiologies were included as the control group.

Patients were managed according to previously pub-lished protocols.28 Induction immunosuppression wascyclosporine A or tacrolimus and prednisone. Mycophe-nolate mofetil was added in patients who required cyclo-sporine or tacrolimus dose reduction or discontinuation.Immunosuppression therapy was recorded throughoutthe study. Acute rejection episodes were documented byliver histologic analysis and treated with steroid boluses ifmoderate or severe.

After discharge, patients were visited at the outpatientclinic, monthly for the first 3 months with complete re-cording of clinical and analytical variables, and every 2 or3 months thereafter. A total of 73 HCV-infected LT re-cipients underwent repeated LSM at 3, 6, 9, and 12months and a liver biopsy 1 year after LT (median # 12.3months). An HVPG measurement was available in 65patients at the same time. The remaining 11 patients hadcholestatic hepatitis.29 In these patients, liver biopsy (n #11) and HVPG (n # 9) were performed when the clinicaldiagnosis was suspected (median # 6.7 months). LSMbefore initiation of antiviral treatment were available at 3and 6 months in eight patients and at months 3, 6, and 9in three. Another five non–HCV-infected patients withelevated alanine aminotransferase (! 40 IU/L) under-went a liver biopsy 1 year after LT (median # 13.4months).

The study was previously approved by the Investiga-tion and Ethics Committee of the Hospital Clinic of Bar-celona following the ethical guidelines of the 1975Declaration of Helsinki. We obtained informed consentfrom all patients included in the study.

Transient Elastography. Patients underwent re-peated LSM using Fibroscan (Echosens, Paris, France).The operator was a nurse (C.B.) who had been previouslytrained by a staff member of the Echosens Company andhad performed more than 100 LSM in patients withchronic liver disease and LT. Liver stiffness was deter-mined as previously described20-23 at months 3, 6, 9, and12 after LT. LSM was determined on the right lobe of theliver. The results were expressed in kilopascals and a me-dian value of 10 acquisitions was considered for analysis,including cases with a success rate lower than 60%.

Liver Biopsies and Paired HVPG Measurements.Percutaneous or transjugular liver biopsies and HVPGmeasurements were performed as previously described.13

Samples were processed at the Pathology Department andstained with hematoxylin and eosin, and Masson’strichrome staining. An expert pathologist (R.M.) who didnot know either the HVPG or transient elastography val-ues scored all the histological samples.

Necroinflammatory activity and fibrosis stage werescored using the Scheuer classification, which classifies

24 CARRION ET AL. HEPATOLOGY, January 2010

liver fibrosis as absent (F0), restricted to the portal tract(F1), periportal or portal-portal septa with intact archi-tecture (F2), bridging fibrosis with architectural distor-tion but no obvious cirrhosis (F3), and cirrhosis (F4).30,31

The minimal acceptable size of liver biopsy was consid-ered 5 mm.

Study Endpoints and Definitions. The main end-point of our study was to evaluate whether repeated LSM,during the first 12 months after LT, was able to discrim-inate patients at risk to develop significant fibrosis (F ! 2)or portal hypertension (HVPG ! 6 mmHg) at an earlystage.

We defined rapid “fibrosers” as patients with liver fi-brosis extending beyond the portal tracts (F2-F4), whileslow “fibrosers” were those showing absent or minimalfibrosis (F0-F1) at 1 year after LT.

Statistical Analysis. Quantitative variables were ex-pressed as medians (range). Differences between qualita-tive variables were assessed with the Fisher exact test.Differences between quantitative variables were analyzedwith a nonparametric test (Mann-Whitney or Kruskal-Wallis for unpaired samples and Friedman for several re-lated samples). We estimated the linear slope of LSM foreach categorized group of fibrosis (F0-1 versus F2-F4),portal pressure (HVPG % 6 versus HVPG ! 6 mmHg)and control patients using a longitudinal mixed model forrepeated measurements (MMRM). Differences betweenslow and rapid fibrosers (as well as with controls) regard-ing donor age, liver stiffness, and relevant host-relatedvariables were analyzed by univariate analysis during thefirst 6 months after LT. Variables showing a P value %0.05 were included in a multivariate forward stepwiselogistic regression analysis to determine the independentpredictors of significant fibrosis 1 year after LT. The sameprocedure was used to identify independent predictors ofportal hypertension 1 year after LT. Significant fibrosis orportal hypertension were considered as a positive resultand their absence as a negative result. Data from a ran-domly generated split-sample of 50 (60%) patients wereused to estimate the model, and data from the remaining34 (40%) patients were used to validate the model. Apredictive model was constructed by modeling the valuesof the independent variables and their regression coeffi-cients. Each of the variables included in the model wasanalyzed to rule out any significant differences betweenthe estimation and the validation groups. Bootstrappingwas used to perform an additional internal validation bygenerating 10,000 resampling sets with replacement. Theresults of the internal bootstrap validation gave estimatesfor the area under the receiver operator characteristic(AUROC) curve with the median (5th percentile-95thpercentile). The diagnostic accuracy of LSM (at each time

point) and of the predictive model (at 6 months) to iden-tify patients at risk to develop significant fibrosis (F ! 2)and portal hypertension (HVPG! 6 mmHg) at 1 yearafter LT were assessed using the AUROC curve. The op-timal LSM and score cutoff values were selected on thebasis of sensitivity (S), specificity (Sp), positive predictivevalue (PPV), and negative predictive value (NPV) to iden-tify significant fibrosis and portal hypertension. We usedSAS version 9.1.3 software (SAS Institute Inc., Cary, NC)for the MMRM analysis. All other analyses were donewith SPSS 12.0 (SPSS Inc., Chicago, IL).

Results

Patient Characteristics. From August 2004 to Janu-ary 2008, 84 LT recipients with HCV infection and 19with other etiologies were included. The cause of LT innon–HCV-infected patients was: alcoholic cirrhosis (n #10), primary biliary cirrhosis (n # 2), Caroli’s disease(n # 2), familial amyloid polyneuropathy (n # 2), auto-immune hepatitis (n # 1), and cryptogenetic cirrhosis(n # 2). The baseline characteristics (donors and recipi-ents) of all patients (n # 103), including histological andhemodynamic data 1 year after LT, are summarized inTable 1.

Progression of Liver Stiffness and Fibrosis Duringthe First 12 Months After LT. All HCV-infected pa-tients showed histological signs of chronic hepatitis Crecurrence. Acute rejection was carefully investigated andnot detected in any of the liver biopsies performed at 12months. Liver biopsy in the five patients not infected withHCV showed mild steatosis without Mallory hyaline(n # 1), minimal sinusoidal dilatation (n # 1), and un-specific mononuclear infiltration (n # 3). Of the liverbiopsies, 41 (46%) were percutaneous and 48 (54%) weretransjugular. The median of total length was 17 mm(8-23 mm) in percutaneous biopsies and 16 mm (6-36mm) in transjugular biopsies (P # 0.602), with 91% ofspecimens ! 10 mm, 68% ! 15 mm, and 32% ! 20mm. We found a good correlation between significantfibrosis and portal hypertension (kappa # 0.62) includ-ing liver biopsies % 15 mm (kappa # 0.75) and % 10 mm(kappa # 1.0).

A total of 335 valid LSM were available during the first12 months after LT. Seventy-seven (19%) LSM were notdetermined during the study (29 patients underwentthree LSM and 24 patients underwent two) for differentreasons: 19 patients had a high body mass index (rangingfrom 28-33), 11 patients with cholestatic hepatitis re-ceived antiviral therapy, and 9 control and 14 HCV-in-fected patients did not strictly comply with the LSMtimetable. Progression of LSM after LT was different

HEPATOLOGY, Vol. 51, No. 1, 2010 CARRION ET AL. 25

among the control group, and the slow and rapid fibrosers(Fig. 1A). In all control patients (n # 19), LSM did notsignificantly increase during the first year after LT. Me-dian LSM at months 3, 6, 9, and 12 were 5.4, 6.2, 6.4,and 5.6 kPa, respectively (P # 0.334). The median LSMof slow fibrosers (n # 53) at months 3, 6, 9, and 12 was6.9, 6.9, 7.5, and 6.6 kPa, respectively, without a signifi-cant increase during follow-up (P # 0.422). By contrast,rapid fibrosers (n # 31) showed a progressive increaseover time; the median LSM at months 3, 6, 9, and 12 was7.5, 9.9, 9.5, and 12.1 kPa, respectively (P # 0.030).LSM differed significantly between rapid and slow fibros-ers at months 6 (P % 0.001), 9 (P # 0.002), and 12 (P %0.001) after LT (Fig. 1A). The figures were almost iden-tical for patients with and without portal hypertension 1year after LT (Fig. 1B). In patients with cholestatic hep-atitis (n # 11), liver biopsy indicated F0 in one patient,F2 in three patients, F3 in two patients, F4 in one patient,and fibrosing cholestatic hepatitis in four patients. Allpatients with cholestatic hepatitis and HVPG measure-ments (n # 9) showed portal hypertension and seven hadclinically significant portal hypertension (HVPG ! 10).The mean values of LSM at months 3, 6, and 9 in patients

with cholestatic hepatitis were 14.5, 18.2, and 24.5 kPa,respectively (P # 0.050).

The diagnostic accuracy of liver stiffness to identifyrapid fibrosers improved over time after LT. The AU-ROC curve for diagnosis of rapid fibrosers at months 3, 6,9 and 12 after LT was 0.67, 0.79, 0.77, and 0.92 in theestimation group and 0.47, 0.66, 0.74, and 0.80 in thevalidation group, respectively (Fig. 2). The sensitivity,specificity, predictive values, and the likelihood ratio ofthe optimal cutoffs values of liver stiffness at 6 months forpredicting significant fibrosis (F ! 2) are summarized inTable 2.

Patients with Discrepancies Between Liver Biopsyand HVPG Values. Among 74 patients with liver bi-opsy and HVPG determination, 13 (18%) patients haddiscrepancies between liver fibrosis and portal pressure.The median length of “discrepant” biopsies was 17 mm(11-25 mm). There were five patients with F ! 2 andHVPG % 6. These patients (n # 5) had periportal fibrosis(F # 2) and the median LSM was 10.8 kPa (5.9-18 kPa).However, the median HVPG was 4 (3.5-5) mmHg. Incontrast, there were 8 patients with F % 2 and HVPG !6. The median HVPG was 7 mmHg (6-10 mmHg) and

Table 1. Baseline Characteristics of the Patients Who Underwent LT, Including HCV-Infected Patients (Validation Group,n " 50 and Estimation Group, n " 34) and Patients Not Infected with HCV (n " 19)

VariablesEstimation Group

(n " 50)Validation Group

(n " 34) PNon-HCV Group

(n " 19)

Receptor age (years) 58 (39–70) 57 (20–69) 0.367 54 (25–66)Sex, males (%) 32 (64) 23 (68) 0.803 13 (68)MELD before LT 15 (7–34) 15 (7–34) 0.900 18 (6–24)Body mass index 25 (17–33) 25 (17–33) 0.856 25 (20–30)HCV viral load (Log10 IU/mL) before LT 4.8 (0.7–6.8) 5.0 (0.7–6.3) 0.874 —HCV genotypes 1b/1a/4 (%) 41 (82)/4 (8)/0 (0) 21 (62)/7 (23)/1 (3) 0.283 —

2/3 (%) 0 (0)/2 (4) 1 (3)/1 (3) —Non-typable (%) 3 (6) 2 (6) —

Donor age (years) 48 (16–79) 55 (11–79) 0.106 53 (17–79)Ischemia time (minutes) 430 (150–730) 435 (115–735) 0.638 462 (280–663)Type of LT (DDLT/LDLT) (%) 48 (96)/2 (4) 30 (88)/4 (12) 0.209 19 (100)/0 (0)Cyclosporine/Tacrolimus/Rapamycin (%) 20 (40)/28 (56)/2 (4) 11 (32)/22 (65)/1 (3) 0.785 3 (16)/16 (84)/0(0)Acute rejection (moderate-severe) (%) 4 (8) 4 (12) 0.707 1 (5)Fibrosis 1 year after LT (Scheuer) (n) (n # 50) (n # 34) (n # 5)

F % 2 (%) 30 (60) 23 (68) 0.539 5 (100)(1)

F ! 2 (%) 20 (40) 11 (32) 0 (0)NIA 1 year after LT (Scheuer) (n) (n # 50) (n # 34) (n # 5)

NIA % 4 (%) 24 (48) 20 (59) 0.313 5 (100)(1)

NIA ! 4 (%) 26 (52) 14 (41) 0 (0)Cholestatic hepatitis (%) 7 (14) 4 (12) 1.000 —

FCH (%) 3 (6) 1 (3) 1.000HVPG 1 year after LT (n) (n # 43) (n # 31) —

HVPG (mmHg) 5.0 (1.5–27) 5.0 (1.5–21) 0.510 —HVPG % 6 (%) 25 (58) 20 (64) 0.804 —HVPG ! 6 (%) 18 (42) 11 (36) —

Qualitative variables are shown in n (%) and quantitative variables are expressed as medians (range).DDLT: deceased-donor liver transplantation, LDLT: living-donor liver transplantation, F: fibrosis stage. NIA: necroinflammatory activity, HVPG: hepatic venous pressure

gradient. FCH: Fibrosing cholestatic hepatitis.(1) Five non-HCV infected patients with elevated Alanine aminotransferase (ALT! 40 IU/L) underwent percutaneous liver biopsy.


Fig. 1. (A) Progression of LSM after LT in non–HCV-infected patients (n # 19), slow (F % 2, n # 53) and rapid (F ! 2, n # 31) fibrosers. MedianLSM were significantly higher in rapid fibrosers compared to slow fibrosers at months 6 (P % 0.001), 9 (P # 0.002) and 12 (P % 0.001) after LT.LSM were similar in slow fibrosers and non–HCV-infected patients at 3, 6, and 9 months. (B) Progression of liver stiffness values after LT innon–HCV-infected patients and patients with normal portal pressure (HVPG % 6 mmHg, n # 46) or portal hypertension (HVPG ! 6 mmHg, n #28) at 1 year after LT. Median liver stiffness values were significantly higher in patients who developed portal hypertension compared to patients withnormal portal pressure at months 3 (P # 0.023); 6 (P % 0.001), 9 (P % 0.001), and 12 (P % 0.001) after LT. LSM were similar in slow fibrosersand patients not infected with HCV at 3, 6, and 9 months.


median LSM was 10 kPa (8.4-28 kPa). Liver biopsyshowed steatosis ! 60% in one patient, hepatocyte bal-looning in three patients, necroinflammatory activity ! 4in three patients, and sinusoidal fibrosis in four patients.

Correlation Between Liver Stiffness and HVPGValues. A paired HVPG determination 12 months afterLT was available in 74 (88%) HCV-infected patients.The correlation between liver stiffness and HVPG valuesincreased during the first year after LT, being significant

after the first 6 months. Differences in LSM betweenpatients who developed portal hypertension (HVPG ! 6mmHg) (n # 29) and patients with normal portal pres-sure (HVPG % 6 mmHg) (n # 45) at 1 year after LT weresignificant at months 6, 9, and 12 (P % 0.001 at all timepoints; Fig. 1B). The diagnostic accuracy of liver stiffnessto identify patients with portal hypertension (HVPG ! 6mmHg) at 1 year after LT improved over time. The AU-ROC curves at 3, 6, 9, and 12 months after LT to identify

Fig. 2. Diagnostic accuracy (AUROC) of liver stiffness to predict significant fibrosis (F ! 2) and portal hypertension (HVPG ! 6 mmHg) in theestimation (n # 50) and validation (n # 34) groups at 3, 6, 9, and 12 months.

Table 2. Predictive Values of LSM for Predicting Significant Fibrosis (F> 2) and Portal Hypertension (HVPG> 6) at 6Months After LT in the Estimation and Validation Group of LT Patients who had HCV

LSM (kPa) Cutoff at6 Months After LT F<2 n (%) F> 2 n (%) S (%) Sp (%) PPV (%) NPV (%) LR#/LR$

Correctly Classified,n (%)

Estimation group (n # 50) n # 30 n #20 34 (68)%7.7 20 (67) 4 (20) 80 67 62 83 2.4/0.3 20 (40)! 9.0 6 (20) 14 (70) 70 80 70 80 3.5/0.4 14 (28)

Validation group (n # 34) (n # 23) (n # 11) 19 (56)%7.7 14 (61) 2 (18) 82 61 50 87 2.1/0.3 14 (41)! 9.0 6 (55) 5 (45) 45 74 45 74 1.7/0.7 5 (15)

HVPG< 6 n (%) HVPG> 6 n (%) S (%) Sp (%) PPV (%) NPV (%) LR#/LR–Correctly Classified,

n (%)

Estimation group (n # 43) (n # 25) (n # 18) 30 (70)%7.7 18 (69) 4 (23) 76 69 62 82 2.5/0.3 18 (42)! 9.0 5 (20) 12 (67) 67 80 71 77 3.3/0.4 12 (28)

Validation group (n # 31) (n#20) (n#11) 20 (65)%7.7 13 (65) 2 (18) 82 65 56 87 2.3/0.3 13 (42)! 9.0 2 (10) 7 (64) 64 90 78 82 6.4/0.4 7 (23)

F, fibrosis stage; HVPG, hepatic venous pressure gradient; LR!, likelihood ratio positive; LR–, likelihood ratio negative; LSM, liver stiffness measurement; NPV,negative predictive value; PPV, positive predictive value; S, sensitivity; Sp, specificity.


patients with portal hypertension were 0.72, 0.77, 0.80,and 0.92 in the estimation group and 0.58, 0.79, 0.84,and 0.93 in the validation group, respectively (Fig. 2).The comparative performance of liver stiffness cut-off val-ues at 6 months for predicting portal hypertension(HVPG ! 6) is summarized in Table 2.

Regression Model Using Liver Stiffness Changes/Progression to Recognize Rapid and Slow Fibrosers inthe Total Cohort. In order to demonstrate the existence ofdifferent rates of liver fibrosis progression we used theMMRM of liver stiffness determinations. In patients withabsent or mild fibrosis (F0-F1) and those with normal portalpressure (HVPG % 6 mmHg) at 1 year after transplantation,liver stiffness did not progress during the first 12 months(P # 0.5). The slope of liver stiffness progression (kPa &month) in these slow fibrosers (0.05) and in patients withnormal portal pressure (0.00), was similar to that of controls("0.02). On the contrary, the slope of liver stiffness progres-sion in patients with significant fibrosis (0.42) or portal hy-pertension (0.46) at 1 year after LT was significantly higherthan that found in controls and slow fibrosers (P % 0.0001)(Fig. 3A). In patients with cholestatic hepatitis the slope(1.54) of liver stiffness progression was significantly higherthan that found in rapid fibrosers without cholestatic hepa-titis (P % 0.0001) (Fig. 3B).

Predictors of Rapid Fibrosis Progression and/orPortal Hypertension and Estimation of the Model.Univariate and multivariate analyses were performed inthe estimation group (n # 50) to identify the variablesassociated with the presence of significant fibrosis (F ! 2)at 1 year after LT (Table 3). The univariate analysis iden-tified six variables associated with rapid fibrosis progres-sion: cytomegalovirus infection, alanine aminotransferaselevel, bilirubin level and HCV viral load (at 3 months),and bilirubin level and LSM (at 6 months). The multi-variate analysis showed that only two variables at 6months were independent predictors of fibrosis: LSM(P # 0.032) and bilirubin level (P # 0.034). We usedthese variables and their coefficients of regression to con-struct a predictive model to identify rapid fibrosers("4.347 ! 0.264 & LSM [kPa] 6m ! 0.442 & bilirubin[mg/dL] 6m). The diagnostic value of this fibrosis scorewas assessed in the estimation (area under the curve #0.83) and validation group (area under the curve # 0.75)(Fig. 4). The results of the internal bootstrap validationgave good estimates for the AUROC curve of 0.840(0.667-0.960) for fibrosis score. A fibrosis score cutoff of"1.99 identified 63% of slow fibrosers with high cer-tainty (NPV # 86%) in the estimation group. The samecutoff identified 59% of slow fibrosers with 94% of cer-tainty in the validation group (Table 4). Using a highercutoff of "1.27 we identified 70% of rapid fibrosers in

the estimation group (PPV # 70%) and 64% in the val-idation group (PPV # 58%) (Table 4). This cutoff alsoidentified the 11 patients with cholestatic hepatitis.

Univariate and multivariate analyses were performedin the estimation group (n # 43) to identify the variablesassociated with the presence of portal hypertension(HVPG ! 6) at 1 year after LT (Table 5). Donor age,cytomegalovirus infection, HCV viral load at 3 months,and LSM at 3 and 6 months were associated with portalhypertension in the univariate analysis. Only two vari-ables were identified as independent predictors ofHVPG ! 6 by multivariate analysis: donor age (P #0.004) and LSM at 6 months (P # 0.003). We used thesevariables and their coefficients of regression to construct apredictive model to identify patients at risk to developportal hypertension 6 months after LT (HVPG-score #0.05 & donor age [years] ! 0.26 & LSM [kPa] at 6months). The diagnostic value of HVPG-score was as-sessed in the estimation group (area under the curve #0.87) and in the validation group (0.80) (Fig. 4). Theresults of the internal bootstrap validation gave good es-timates for the AUROC curve of 0.881 (0.708-0.987) forHVPG score. A HVPG score cutoff of "0.3 identified89% of patients with normal portal pressure with 89% ofcertainty in the estimation group. The same cutoff iden-tified 85% of patients with HVPG % 6 mmHg (NPV #85% in the validation group). A cutoff of 0.15 identified61% of patients with portal hypertension with 92% ofcertainty in the estimation group and 73% of patients inthe validation group (PPV # 90%) (Table 4).

DiscussionThis longitudinal study evaluates whether repeated

LSM during the first year after LT are useful to identifypatients with severe hepatitis C recurrence at an earlystage. The results show that repeated LSM are able todiscriminate between rapid and slow fibrosers during thefirst year after LT.

Our study clearly shows two different speeds of liverfibrosis progression during the first year after LT: slowfibrosers, with fibrosis progression similar to patientswithout HCV, and rapid fibrosers, with early develop-ment of significant fibrosis and portal hypertension. Infact, the mathematical mixed model for repeated LSMand the slope of liver stiffness progression in rapid andslow fibrosers, clearly confirmed the different speed ofliver stiffness progression in patients with mild andsevere recurrence. In a subgroup of patients with cho-lestatic hepatitis, liver stiffness progression was ex-tremely fast, but the small number of patients does notallow firm conclusions to be drawn. It seems that theevents leading to different speeds of fibrosis progres-


sion in HCV-infected LT recipients take place veryearly following transplantation.

Liver fibrosis progression is extremely accelerated afterLT, and graft cirrhosis develops in a significant propor-

tion of patients within the first years.2-4 Early histologicaldamage and increased HVPG values, only 1 year aftertransplantation, correlate with long-term outcome andidentify patients with severe hepatitis C recurrence.10,13

Fig. 3. (A) Liver stiffness progression in each group of patients using a mathematical mixed model for repeated measurements (MMRM). The slopeof linear function in slow fibrosers (0.05) and patients with normal portal pressure (0.00) was similar to that of patients not infected with HCV ("0.02)(P # 0.55). The slope of linear function in patients with rapid fibrosis (0.42) and portal hypertension (0.46) was significantly higher than the slopeof non-HCV and slow fibrosers (P % 0.0001). (B) Liver stiffness progression using MMRM in patients with cholestatic hepatitis compared with rapidfibrosers without cholestasis. The slope of linear function in patients with cholestatic hepatitis (1.54) was significantly higher than the slope of rapidfibrosers without cholestasis (0.71) (P % 0.0001).


Table 3. Univariate and Multivariate Analysis Were Performed in the Estimation Group (n " 50) to Identify the VariablesAssociated with the Presence of Significant Fibrosis (F > 2) at 1 Year After LT

Characteristic

No SignificantFibrosis (F < 2)

(n " 30)

SignificantFibrosis (F > 2)

(n " 20)P

(Univariate)Odds Ratio (95% CI)

P (Multivariate)

Receptor age (years) 58 (42–64) 60 (39–70) 0.45Sex, males (%) 21 (70) 11 (55) 0.28Body mass index 25 (18–33) 24 (17–32) 0.59MELD before LT 15 (7–30) 15 (7–34) 0.92HCV viral load before LT (log10 IU) 5.0 (1.5–6.8) 4.7 (0.7–6.7) 0.36HCV genotype 1 (%) 27 (90) 18 (90) 1.00Donor age (years) 46 (20–69) 54 (16–79) 0.09

Ischemia time (minutes) 430 (150–730) 383 (195–570) 0.34Type of LT (DDLT) (%) 28 (93) 20 (100) 0.24Tacrolimus (%)/Cyclosporine (%) 18 (60)/10 (33) 10 (50)/10 (50) 0.32Cytomegalovirus infection (%) 1 (3) 6 (30) 0.012 —Diabetes (%) 13 (43) 12 (60) 0.25Acute rejection (moderate-severe) (%) 3 (10) 1 (5) 0.64

At 3 months:LSM (kPa) 5.7 (3.5–13) 8.3 (4.2–30) 0.07ALT (IU/L) 52 (14–479) 145 (31–708) 0.007 1.00 (0.99–1.01), P # 0.077Bilirubin (mg/dL) 0.7 (0.3–6.3) 1.3 (0.5–11) 0.011 —HCV viral load (log10 IU) 6.1 (4.7–7.7) 7.2 (4.7–7.9) <0.001 —

At 6 months:LSM (kPa) 6.9 (3.4–13) 10.1 (5.1–33) <0.001 1.30 (1.02–1.66), P # 0.032ALT (IU/L) 78 (17–458) 140 (26–400) 0.34Bilirubin (mg/dL) 0.8 (0.4–6.0) 1.3 (0.5–10.9) 0.015 1.55 (1.03–2.34), P # 0.034HCV viral load (log10 IU) 6.4 (4.4–7.7) 6.7 (4.4–7.4) 0.09

Qualitative variables are shown in n (%) and quantitative variables are expressed as medians (range).ALT, alanine aminotransferase; LSM, liver stiffness measurement.Fibrosis score at 6 months after LT # ["4.347 ! 0.264 & LSM (kPa) 6m ! 0.442 & bilirubin (mg/dL) 6m].

Table 4. Univariate and Multivariate Analysis Were Performed in the Estimation Group (n " 43) to Identify the VariablesAssociated with the Presence of Portal Hypertension (HVPG > 6) at 1 Year After LT

Characteristic

Normal PortalPressure (HVPG < 6)

(n " 25)

Portal Hypertension(HVPG > 6)

(n " 18)P

(Univariate)Odds Ratio (95% CI),

P (Multivariate)

Receptor age (years) 58 (42–70) 59 (39–65) 0.88Sex, males (%) 17 (68) 11 (61) 0.64Body mass index 26 (18–33) 23 (17–32) 0.09MELD before LT 16 (8–30) 15 (7–28) 0.54HCV viral load before LT (log10 IU) 5.0 (1.7–6.8) 4.7 (3.2–6.7) 0.84HCV genotype 1 (%) 22 (88) 16 (94) 0.51Donor age (years) 38 (20–70) 58 (16–79) 0.004 1.06 (1.01–1.12), P # 0.034Ischemia time (minutes) 430 (150–730) 386 (218–570) 0.63Type of LT (DDLT) (%) 24 (86) 18 (100) 1.00Tacrolimus (%)/Cyclosporine (%) 14 (56)/9 (36) 8 (44)/10 (56) 0.27Cytomegalovirus infection (%) 1 (4) 6 (33) 0.015 —Diabetes (%) 13 (52) 9 (50) 1.00Acute rejection (moderate-severe) (%) 2 (8) 2 (11) 1.00At 3 months:

LSM (kPa) 5.5 (3.5–10) 7.3 (4.2–30) 0.029 —ALT (IU/L) 78 (14–708) 65 (21–678) 0.57Bilirubin (mg/dL) 0.9 (0.4–6.3) 1.1 (0.5–11) 0.10HCV viral load (log10 IU) 6.0 (4.7–7.6) 7.1 (4.7–7.9) 0.005 —

At 6 months:LSM (kPa) 6.9 (4.6–13) 11.5 (5.1–33) 0.003 1.24 (1.01–1.52), P # 0.034ALT (IU/L) 82 (17–458) 98 (26–400) 0.57Bilirubin (mg/dL) 0.9 (0.5–7.0) 1.2 (0.5–10.9) 0.18HCV viral load (log10 IU) 6.3 (4.4–7.7) 6.7 (4.4–7.4) 0.14

Qualitative variables are shown in n (%) and quantitative variables are expressed as medians (range).ALT, alanine aminotransferase; LSM, liver stiffness measurement.HVPG score at 6 months after LT # ["5.628 ! 0.061 & donor age (y) ! 0.212 & LSM (kPa) 6m ]


Patients with significant fibrosis and particularly withportal hypertension 1 year after LT have a high probabil-ity of clinical decompensation and graft loss. For thisreason, in the current study, patients were classified usingboth liver biopsy and HVPG, to identify patients withslow or rapid disease progression. In addition, liver stiff-ness determination has recently been shown to be an ex-cellent noninvasive method to identify patients withsignificant fibrosis and is even more accurate to diagnosepatients with portal hypertension.23

In the present study, the diagnostic accuracy of liverstiffness increased with time. The accuracy to identifyrapid fibrosers was poor at 3 months, good at 6 and 9months, and excellent at 12 months after LT, especially inpatients with portal hypertension. Actually, we have pre-viously shown that LSM at 1 year after LT is very accurateto identify significant fibrosis and has an excellent corre-lation with HVPG values to diagnose portal hyperten-sion.23 On the other hand, the current study shows thatLSM at 3 months after LT is not useful in the prediction

Fig. 4. Diagnostic accuracy of fibrosisscore and HVPG score at 6 months to iden-tify rapid fibrosers and patients with risk ofdeveloping portal hypertension in the esti-mation (n # 50) and validation group (n #34). (A) The diagnostic accuracy of thefibrosis score to identify rapid fibrosers was0.83 in the estimation group and 0.75 inthe validation group. (B) The diagnosticaccuracy of the HVPG score to identify por-tal hypertension was 0.87 in the estimationgroup and 0.80 in the validation group.

Table 5. Predictive Values of the Fibrosis-Score and HVPG-Score Obtained from the Estimation and Validation Groups toIdentify Patients with F < 2, HVPG < 6 or F > 2, HVPG > 6 at 6 Months After LT

Fibrosis-score (1)

F < 2n (%)

F > 2n (%) S (%) Sp (%) PPV (%) NPV (%) LR#/LR$

Correctly classified,n (%)

Estimation group (n " 50) (n # 30) (n # 20) 43 (66)% "1.99 19 (63) 3 (15) 85 63 61 86 2.3/0.2 19 (38)! "1.27 6 (20) 14 (70) 70 80 70 80 3.5/0.4 14 (28)

Validation group (n " 34) (n # 22) (n # 11) 20 (60)% "1.99 13 (59) 1 (9) 90 65 53 94 2.2/0.1 13 (39)! "1.27 5 (23) 7 (64) 64 77 58 81 2.8/0.5 7 (21)

HVPG-score (2)

HVPG < 6n (%)

HVPG > 6n (%) S (%) Sp (%) PPV (%) NPV (%) LR#/LR$

Correctly classified,n (%)

Estimation group (n " 43) (n # 25) (n # 18) 34 (79)% "0.30 23 (89) 3 (18) 82 89 82 89 7.1/0.2 23 (53)! 0.15 1 (4) 11 (61) 61 96 92 77 15.3/0.4 11 (26)

Validation group (n " 31) (n # 20) (n # 11) 25 (81)% "0.30 17 (85) 3 (27) 73 85 73 85 4.8/0.3 17 (55)! 0.15 1 (5) 8 (73) 73 95 90 86 14.6/0.3 8 (26)

HVPG, hepatic venous pressure gradient; LR!, likelihood ratio positive; LR–, likelihood ratio negative; NPV, negative predictive value; PPV, positive predictive value;S, sensitivity; Sp, specificity.

(1) Fibrosis-score at 6 months after LT " [$4.347 # 0.264 ! LSM (kPa) 6m # 0.442 ! bilirubin (mg/dL) 6m].(2) HVPG-score at 6 months after LT " [$5.628 # 0.061 ! donor age (y) # 0.212 ! LSM (kPa) 6m].


of the different patterns of HCV recurrence. At this earlytime, fibrosis deposition is probably too low to affect liverstiffness determination. Moreover, other complicationswhich are frequent during the first months following LT(acute hepatitis, acute rejection, or vascular or biliaryproblems) might influence liver stiffness independently ofthe degree of liver fibrosis.32-35

Six months appears to be an important time point forLSM for two reasons: first, the accuracy is high enough todiscriminate patients with severe recurrence from thosewith mild recurrence; second, antiviral treatment at thistime could probably decrease or even interrupt fibrosisprogression in patients with severe hepatitis C recurrence.Therefore, we sought to increase the diagnostic accuracyof liver stiffness by developing fibrosis—and HVPG—scores at this time point. The variables selected in theestimation group by the multivariate regression modelwere donor age, LSM, and bilirubin at 6 months. Donorage appeared as an important factor influencing HCVrecurrence. Several studies have pointed out the impor-tance of this variable in the severity of HCV recur-rence.36,37 In addition, recipients who develop severeHCV-induced graft damage have significantly higheraminotransferases and bilirubin levels than patients withmilder forms.4 The fibrosis score cutoff of "1.99 identi-fied 63% of slow fibrosers with a high NPV of 86%.Interestingly, values higher than "1.27 identified 64%-70% of patients with severe recurrence and 100% of pa-tients with cholestatic hepatitis.

As we have previously shown, LSM are very accurate atidentifying patients who underwent liver transplantationwho have portal hypertension.23 This probably also ex-plains the high accuracy of the HVPG score in the currentstudy in which a cutoff of "0.3 identified 89% of patientswith normal portal pressure (89% of certainty). In con-trast, values higher than 0.15 identified 61% of patientswith a risk of developing portal hypertension (92% ofcertainty). These results reinforce the concept of HVPGdetermination as a good “gold standard” for the evalua-tion of new noninvasive methods.13,23,38

These results support the use of noninvasive methodsto monitor HCV recurrence in the transplant setting. Thefibrosis and/or HVPG score at 6 months may be useful todecide the best therapeutic strategy in these patients. Inpatients with a HVPG score below "0.3 at 6 months afterLT, follow-up with repeated LSM may be appropriate,because 80% (41 of 51) of these patients remain withoutsignificant fibrosis at 1 year. In contrast, in patients with aHVPG score higher than 0.15, antiviral treatment shouldbe considered, because 90% (19 of 21) of these patientsdevelop portal hypertension 1 year after LT. Nevertheless,if HCV treatment is indicated, a liver biopsy before treat-

ment initiation is still necessary to exclude other causes ofliver dysfunction.39

Despite the importance of these results, the main lim-itation of our study is the number of patients included,especially in the validation group. Nevertheless, it is im-portant to note that our data were obtained using the twocurrent gold standards to assess disease severity: liver bi-opsy and HVPG measurements.13,23,38 In addition, aninternal validation using a bootstrapping system was per-formed.

In summary, repeated measurements of liver stiffnessin HCV patients after LT allow discrimination betweenrapid and slow fibrosers. Simple scores including bilirubinand LSM, or donor age and LSM at 6 months can accu-rately predict the risk to develop significant fibrosis orportal hypertension in these patients. This could be rele-vant to adopt therapeutic decisions at an early stage ofHCV recurrence. Although our results need to be vali-dated by other centers, we believe that these models mightbe widely used in clinical practice.

Acknowledgment: We thank Concepcio Bartres forperforming all liver stiffness measurements during thestudy. M.N. received support in part by a grant from“Instituto de Salud Carlos III” (PI050230) and X.F. re-ceived support in part by a grant from “Instituto de SaludCarlos III” (PI080239).

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liver stiffness identifies two different patterns of ...cirrhosis develops in a signiﬁcant...

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