Thierry Bizollon

Small nodule detection in cirrhotic livers : Evaluation with US, spiral CT, and MRI and correlation with Pathologic examination of explanted liver

Purpose The purpose of this work was to evaluate the detection and characterization of nodules ≥8 mm and small hepatocellular carcinomas (HCCs) in liver cirrhosis. Method Pathologic examination and results of US, helical CT, and dynamic MRI with gadolinium were compared after orthotopic liver transplantation (OLT) of 43 cirrhotic patients. Nodules were classified as macroregenerative nodules (MRNs), borderline nodules (BNs), and HCC. Results Pathologic examination classified 69 nodules: 50 MRNs, 6 BNs, and 13 HCCs. Sensitivities of MRN, BN, and HCC detection were, respectively, for US imaging 2% (1/50), 33.3% (2/6), and 46.2% (6/13); for helical CT 2% (1/50), 50% (3/6), and 53.8% (7/13); and for MRI 42% (21/50), 50% (3/6), and 76.9% (10/13). MRI detected 21 MRNs. They presented on T1/T2-weighted images as hyperintense/hypointense (n = 8), hyperintense/isointense (n = 7), hypointense/hypointense (n = 4), hypointense/isointense (n = 1), and hypointense depicted only on echo planar imaging (n = 1). The three detected BNs were hyperintense/hypointense nodules. The 10 detected HCCs appeared hyperintense/isointense (n = 7), hyperintense/hypointense (n = 2), and hypointense/isointense (n = 1). None of the MRNs but eight HCCs and one BN were enhanced after gadolinium injection. Conclusion Contrast-enhanced MRI is the most sensitive technique for detecting liver nodules. No MR signal intensity pattern characteristic of small HCCs enables differentiation from benign nodules, however. Gadolinium enhancement is the most sensitive and specific characteristic of HCC.

Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.

Background and objective: A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy. Patients and methods: Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples. Results: At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1–8) versus 8.3 (range 5–12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested. Conclusion: In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.

Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C.

Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis and graft loss after liver transplantation. Treatment for post‐transplant recurrence results in sustained virological response (SVR) in up to 30% of cases. The aim of this study was to evaluate the impact of SVR on patients and graft survival. Thirty‐four patients with an SVR to IFN‐ribavirin were included. Forty‐six nonresponders to the combination formed the control group. Follow‐up data were recorded every 6 months and included HCV RNA, and the occurrence of clinical problems (cirrhosis, decompensation, hepatocellular carcinoma, death). A graft biopsy was performed every year. The mean follow‐up duration was 52 months in responders and 57 months in nonresponders. Two patients died in each group of patients. Two patients with SVR developed late virological relapse. Fibrosis decreased in 38% of patients with SVR, remained stable in 44% and worsened in 18%. In contrast, fibrosis increased in the majority of nonresponder patients (74%, p < 0.001). At the end of follow‐up, no patient without cirrhosis at inclusion developed cirrhosis of the graft versus 9 among nonresponder patients (p = 0.009). No difference in patient survival was observed in the two groups. In conclusion, this study shows that HCV eradication has a positive impact on graft survival.

Hepatic outflow study after piggyback liver transplantation

BACKGROUND Hepatic vein outflow is discussed in liver transplantation after preservation of recipient retrohepatic vena cava. The aim of this study was to compare two methods of suparahepatic caval anastomosis. METHODS From January 1993 to January 1995, 81 patients received 88 liver transplants because of liver cirrhosis (n = 70), acute liver failure (n = 7), elective retransplantation after hepatic artery thrombosis (n = 2), giant hemangioma (n = 1), and combined liver-small bowel transplantation (n = 1). Seven patients underwent urgent retransplantation, 12 had preoperative transjugular intrahepatic portocaval stent, and 11 had portal vein thrombosis. Five patients required extracorporeal venous shunt. A total of 82 liver transplantations had preservation of RHVC, and 70 patients received temporary end-to-side portacaval shunt. Suprahepatic caval anastomosis was carried out in 52 patients (group 1) between the graft suprahepatic vena cava and the ostia of recipient left and median hepatic veins. Thirty patients (group 2) had associated 3 cm vertical cavotomy with partial clamping of RHVC. In the fourth postoperative month 20 patients from each group had pressure and gradient measurement made among the hepatic veins, right atria, and the RHVC. RESULTS Mean pressure gradient between hepatic veins and right atria was 0.75 +/- 0.49 mm Hg in group 1 and 2.06 +/- 0.85 mm Hg in group 2. Between the RHVC and the right atria it was 0.63 +/- 0.5 mm Hg in group 1 and 2.22 +/- 1.29 mm Hg in group 2. A pressure gradient higher than 3 mm Hg was considered hemodynamically significant. This pressure gradient was found between the hepatic veins and right atria in 10% of patients in group 1 and 40% of patients in group 2 (p = 0.03) and between the RHVC and right atria in 15% of patients in group 1 and 30% of patients in group 2 (p = 0.3). CONCLUSIONS Preservation of the recipient RHVC with recipient caval anastomosis at the ostia of the median and left hepatic veins is a reliable technique without any hepatic venous outflow alteration. Associated cavotomy is not necessary.

Diagnostic value and tolerance of Lipiodol-computed tomography for the detection of small hepatocellular carcinoma : correlation with pathologic examination of explanted livers

BACKGROUND/AIMS This study aimed to assess the tolerance and the real sensitivity of Lipiodol-computed tomography in the detection of small hepatocellular carcinoma by comparison with pathological examination of the explanted livers. METHODS Seventy-two patients with cirrhosis (Child A=8, B=36, C=28) awaiting orthotopic liver transplantation underwent Lipiodol-computed tomography to determine the presence, number and location of possible hepatocellular carcinoma nodules. Before liver transplantation six patients had a presumed single hepatocellular carcinoma diagnosed by biopsy. Liver transplantation was performed a mean of 6 months after Lipiodol-computed tomography. Explanted livers were sectioned at 0.8- to 1-cm intervals. Lipiodol-computed tomography staging and pathologic findings were compared. RESULTS Pathologic studies showed 24 hepatocellular carcinoma nodules (diameter, 2-42 mm) not diagnosed before liver transplantation in 14 of the 72 livers. Lipiodol-computed tomography detected 6 of these 24 nodules, but none of the daughter lesions (n=9) in the six patients with a presumed single hepatocellular carcinoma. Lesion-by-lesion analysis revealed a sensitivity of 37%. Lipiodol-computed tomography falsely detected three additional nodules not confirmed by pathologic examination (1 haemangioma, 2 nondysplastic regenerating nodules). One Child C patient developed variceal bleeding within 2 days after injection of Lipiodol. CONCLUSIONS Tolerance of this procedure was satisfactory, even in Child C patients. Lipiodol-computed tomography has a low sensitivity in the detection of small hapatocellular carcinoma. These results must be considered when liver resection or liver transplantation is proposed for the treatment of hepatocellular carcinoma.

Hemodynamic profiles during piggyback liver grafts using arterial or portal revascularization

BACKGROUND The order of revascularization in human liver grafts is still discussed. This study tries to answer this question in terms of hemodynamic data. STUDY DESIGN Fifty-nine patients were randomized in this study to compare hemodynamic data just before and 15 minutes after revascularization of liver grafts in relation to first hepatic artery (n = 29) or first portal vein (n = 30) revascularization procedure. RESULTS Hemodynamic variations were significantly greater in the portal vein group than in the hepatic artery group in terms of mean arterial pressure, cardiac index, central venous pressure, pulmonary capillary pressure, and systemic vascular resistance. The latter decreased from 741.8 +/- 390.3 to 659.9 +/- 411.1 dynes/ cm5 (NS) in the hepatic artery group versus 807.7 +/-336.7 to 439.7 +/- 215 dynes/cm5 (p < 0.05) in the portal vein group. Clinical results and postoperative complications, graft characteristics, patient survival, and graft survival were not significantly different between the groups. CONCLUSIONS Initial arterial revascularization of the liver graft leads to a more stable hemodynamic profile during revascularization of the liver graft after vascular unclamping. This technique is always feasible and has become our reference procedure.

Transjugular intra-hepatic portosystemic shunt for refractory variceal bleeding.

Background The most dramatic complication of portal hypertension in cirrhotic patients is oesophageal variceal bleeding. Moreover, patients with bleeding unresponsive to medical and endoscopic treatment have a poor prognosis. Objective The aim of this study was to evaluate the efficacy of early transjugular intra-hepatic portosystemic shunt (TIPS) in patients with refractory variceal bleeding. Patients and methods TIPS was performed for 28 patients (17 were stage Child C), successfully in 26. Variceal bleeding was controlled in all but one successfully stented patient. Results There was no mortality associated with the procedure. The two patients with a failure of TIPS insertion died of persistent bleeding in the first 48 h after failed TIPS. The 40-day mortality rate was 25%. Five patients died (one from persistent bleeding from gastric varices and four from multi-organ failure). Using multivariate analysis, the only independent factor associated with early mortality was the total bilirubin value. Fifteen surviving patients were listed for liver transplantation: four deaths occurred, eight patients were transplanted in the 6 months after TIPS and three are still waiting. Among the six patients who survived but were ineligible for transplantation, two died and four are still alive. Two episodes of early rebleeding and eight of late rebleeding occurred. Actuarial survival was 75% at one year and 52% at two years. Conclusions Early TIPS is an effective rescue therapy for controlling refractory variceal bleeding.

Results of orthotopic liver transplantation for liver cirrhosis in the presence of incidental and/or undetected hepatocellular carcinoma and tumour characteristics

Abstract Orthotopic liver transplantation (OLT) for liver cirrhosis in the presence of hepatocellular carcinoma (HCC) is based on tumour number and size. The high incidence of undetected HCC before OLT has been reported previously. The object of this work to report the results of OLT for liver cirrhosis in the presence of incidental and/or undetected HCC and tumour characteristics. From 1985 to 1996, 334 patients received OLT. Two groups of patients were studied; group 1 (G1) where HCC was diagnosed on radiological examination before OLT (n= 13, mean age 53.8 ± 8.1 years), and group 2 (G2), where HCC was diagnosed on pathological review (n= 13, mean age 53.3 ± 6.1 years). Indications for OLT were (G1/G2) hepatitis C = 6/8, hepatitis B = 5/2, alcoholic = 2/3. There was no statistically significant difference in α‐foetoprotein levels between both groups. Pathological review showed 26 and 30 HCC with a mean size of 1.6 ± 0.8 and 1.6 ± 1.2 cm (P > 0.05) in G1 and G2, respectively. Tumour stagings were (G1/G2) stage I = 6/2, stage II = 4/6, stage III = 2/3, stage IVa = 1/2. We had two (G2) hospital and three (G1) later mortalities; none had HCC recurrence. The other patients are alive and recurrence free. Reinforced immunosuppression related to acute or chronic rejection treatment was not associated with HCC recurrence. The 5‐year actuarial survival rates were 76% for G1 and 85% for G2 (P > 0.05). Our study revealed that long‐term survival can be achieved with liver transplantation in the presence of HCC in carefully selected patients.

Anti-hepatitis C virus core IgM antibodies correlate with hepatitis C recurrence and its severity in liver transplant patients

BACKGROUND The significance of immunoglobulin (Ig) M antibody to hepatitis C virus (HCV) core antigen was studied in 60 patients with HCV infection after orthotopic liver transplantation (OLT) diagnosed by polymerase chain reaction. METHODS Patients were followed up for a mean of 28 months after transplantation. Sera collected three months before transplantation, and one and 12 months after transplantation were analysed for anti-HCV core IgM (HCV-IgM EIA 2.0 assay). After OLT protocol biopsies, procedures were performed routinely every six months. Semiquantitative histopathological assessment of allograft hepatitis was performed using Knodells score. The results were correlated with clinical features, liver histology findings, and virological features, such as genotype and viraemic levels assessed by a branched DNA assay. RESULTS One year after liver transplantation, 29/60 (48%) patients had chronic hepatitis on graft biopsy. The presence of anti-HCV core IgM one month (p=0.004) and 12 months (p=0.003) after OLT was positively correlated with recurrence of chronic hepatitis. The positive predictive value of anti-HCV core IgM detected one month after transplantation was 0.88. A significant relationship was observed between severity of graft disease and presence of anti-HCV core IgM 12 months after transplantation. The mean Knodell score was 8.9 in anti-HCV core IgM positive patients compared with 3.6 in those who were anti-HCV core IgM negative (p=0.001). The presence of IgM anti-HCV did not correlate with serum HCV RNA level or HCV genotype. CONCLUSION We confirm that the presence of anti-HCV core IgM after OLT is a marker of HCV induced graft damage. The recurrence and severity of HCV hepatitis in patients undergoing OLT for HCV cirrhosis is related to the presence of anti-HCV core IgM after liver transplantation. These findings have diagnostic relevance and confirm that measurement of IgM anti-HCV core may help to better monitor the treatment of HCV recurrence after transplantation.

Influence of systematic echodoppler arterial survey on hepatic artery thrombosis after liver transplantation in adults

Abstract Hepatic artery thrombosis after liver transplantation remains a major problem which may lead to graft loss and retransplantation. Hepatic artery diseases were compared in two matched groups of liver grafted patients. In Group I (67 patients), echodoppler examinations of the graft hepatic artery were carried out after clinical or biological abnormalities became evident. In Group II (85 patients), echodoppler examinations were systematically made during the follow‐up at 2 weeks, 1, 3, 6, and 12 months after liver transplantation. In cases of an abnormal echodoppler examination, arteriography was carried out in order to confirm hepatic artery stenosis and to perform endoluminal angioplasty. In Group I, echodoppler examinations revealed no arterial blood flow in three cases and reduction of hepatic blood flow in two cases. Hepatic artery thromboses were always confirmed by angiography, in the latter two cases, a collateral arterial revascularization of the graft was developed. In this group, two retransplantations, one choledocojejunostomy, and four percutaneous radiological biliary drainages were necessary. In Group II, echodoppler results showing a resistive index below 0.5 and a systolic acceleration time above 0.08 s involved 13 arteriographies. Ten stenoses were diagnosed without any biological abnormalities. Nine endoluminal angioplasties were made without any complication. There was no recurrence of stenosis. One pseudoaneurysm of the femoral artery was cured by compression. The early and non‐aggressive detection of hepatic artery stenoses after liver transplantation by echodoppler allows treatment by angioplasty in order to prevent hepatic artery thrombosis and reduce retransplantation.