- Email: [email protected]
Efficacy and safety of treatment with pegylated interferon and ribavirin for hepatitis C virus-associated cryoglobulinemia: A multicenter study
A24
Abstracts / Digestive and Liver Disease 40 (2008) A1–A40
apoptosis: the extrinsic, cell surface receptors mediated, and the intrinsic mitochondria dysfunction mediated. Aims. To clarify the role of extrinsic and intrinsic apoptosis pathways in human liver disease, we studied the mRNA expression of Fas/FasL, TNF-␣ and Bcl-2, Bax and Bad in biopsies from patients with different degrees of liver damage and determined whether HCV and HBV infection modulates said expression. Methods. We examined 62 patients: 39 with chronic hepatitis (CH) (31 HCV-related, 8 HBV-related); 7 with cirrhosis (6 HCV-related, 1 HBV-related); 13 with hepatocellular carcinoma (HCC) ((6 HCV-related and 1 HBV-related) and 6 in non viral cirrhosis); 3 controls. mRNAs were quantified by quantitative real-time PCR using -actin as housekeeping gene. Results. Fas mRNA levels were significantly increased in CIRR when compared with HCC (p = 0.026) while FasL mRNAs showed a statistically significant differences between CIRR and cirrhotic tissues surrounding tumours (PHCC) (p = 0.018) or HCC (p = 0.005). Also TNF-␣ mRNAs were higher in CIRR than in PHCC (p = 0.038) and HCC (p = 0.05). Bcl-2 mRNA levels were statistically higher in PHCC than in controls (p = 0.026), in CH (p = 0.004), and in CIRR (p = 0.05). CH coincided with higher Bad levels than in PHCC or HCC tissues (p < 0.00001 and p < 0.0001, respectively). No differences in Bax expression were observed. In CH, only TNF-␣ and Bad mRNAs were significantly different in HBV-related infection versus HCV-related hepatitis. Conclusions. Fas/FasL system expression was upregulated in chronically damaged livers while the onset of cancer was associated with a shut-down of this system in HCC, as a defense mechanisms adopted by HCC against the immune system. Bcl-2 hyperexpression in CIRR seems to play an important role in regulating cell survival in damaged liver cells, contributing to HBV or HCV persistence. The different pattern of TNF-␣ and Bad expression in HCV- and HBVrelated liver disease points to a different modulation of the immune response on the one hand, and, to different apoptotic activation pathways on the other. doi:10.1016/j.dld.2007.12.066 INCIDENCE OF LATE HCC RECURRENCE AFTER RESECTION REMAINS HIGHER THAN FIRST HCC: IMPLICATIONS FOR PATIENTS MANAGEMENT A. Cucchetti a , F. Piscaglia b , L. Benvegn`u c , E. Caturelli d , A. Gianstefani b , G.L. Grazi a , L. Bolondi b , A.D. Pinna a a
Division of Liver Transplant Surgery, Italy
b Division of Internal Medicine, University of Bologna, Hos-
pital S. Orsola-Malpighi, Bologna, Italy c Division of Internal Medicine, University of Padua, Italy d Division of Gastroenterology, Ospedale Belcolle, Viterbo, Italy
Background and aims. Recurrence of hepatocellular carcinoma (HCC) after two years from resection (late recurrence) is considered a de novo HCC. Nonetheless, annual incidence is speculated to remain higher than first HCC in the cirrhotic general population, but never compared in detail. Aims of the present study were to assess incidence and risk factors of HCC recurrence and to compare it with non HCC cirrhotics. Methods. Retrospective analysis of cirrhotic patients with HCC submitted to resection (n = 205) and cirrhotics undergoing surveillance with ultrasonography (n = 150). Results. Resected patients showed higher prevalence of male gender and higher alpha-fetoprotein (AFP) (P < 0.05). Risk factors for early (<2 years) recurrence (incidence = 21.8%/year) were higher AFP, poorly tumour differentiation and presence of microvascular invasion (p < 0.05), all suggesting a metastatic cause for recurrence. Risk factors for both late recurrence (18.4%/year) and first HCC occurrence (3.3%/year) were male gender, older age and higher serum transaminase (suggesting de novo HCC); multiple primary tumours and higher AFP were additional risk factors for respectively late recurrence and first HCC (p < 0.05). Resected patients with ≤1 risk factors for late recurrence showed similar annual incidence of HCC (6.2%/year) to controls with >1 risk factors (6.3%/year; p = 0.919). Conclusion. HCC annual incidence remains higher than in cirrhosis even after two years from resection. However, in low risk resected HCC the incidence is similar to that of cirrhotic controls. The assessment of such characteristics in resected patients could address tailored post-operative follow-up schedules or, in the liver transplantation setting, modify allocation priority in HCC patients (maintaining or preserving priority). doi:10.1016/j.dld.2007.12.067 EFFICACY AND SAFETY OF TREATMENT WITH PEGYLATED INTERFERON AND RIBAVIRIN FOR HEPATITIS C VIRUS-ASSOCIATED CRYOGLOBULINEMIA: A MULTICENTER STUDY C. Mazzaro a , A.M. Baragiotta c , G. Pozzato b , G. Monti d , D. Filippini e , C. Donada f , A. Tellan a , A. Gabrielli g , S. De Vita h , GISC Gruppo Italiano Studio Crioglobulinemia (GISC) a
Department of Medicine, Pordenone General Hospital, Italy of Medicine University, Trieste, Italy c Gastroenterology, Pordenone General Hospital, Italy d Department of Medicine, Saronno General Hospital, Italy e Rheumatology, Milano General Hospital, Italy f Department of Medicine, Gorizia General Hospital, Italy g Rheumatology, University, Ancona, Italy h Rheumatology, University Udine, Italy b Department
Abstracts / Digestive and Liver Disease 40 (2008) A1–A40
Background. Limited data are available regarding the treatment of patients with HCV-related mixed cryoglobulinemia. Aim. The objective of this study was to evaluate the efficacy and safety of therapy with peginterferon alfa-2b plus ribavirin (RBV) in patients with chronic hepatitis C related MC. Methods. 66 consecutive pts with MC were recruited in this study (34 F and 32 M, median age 55). A liver biopsy was performed before therapy (83%). A chronic liver disease of variable severity (from A1F0 to A3F4) was found in 94% of these patients. In four (6%) patients liver cirrhosis was observed. Fourteen patients (21%) presented with peripheral neuropathy s-m; five patients (8%) were affected by nephropathy and five (8%) had B cell lymphoma. All cases were HCV–RNA positive, genotype 1 (52%), or non-1 genotypes (48%). All patients were treated with Peginterferon alfa2b 1.5 mcg/kg/week for 48 week plus RBV 1000–1200 mg/daily for 48 weeks in genotype 1 and for 24 weeks in Genotype 2 or 3 associated with Prednisone: 0.2–0.5 mg/kg/daily for 4 weeks. All patients were followed for at least 24 weeks after the end of the therapy. The response to treatment was analysed by comparing clinical, immunologic, virologic and biochemical parameters at the initial evaluation with those observed during follow-up. Results. Relevant variables at enrolment, end of treatment (EOT) and the end follow-up (EFU)
A25
OLDER DONOR AGE IS ASSOCIATED WITH INCREASED DONOR OXIDATIVE STRESS AND FAILURE TO RESTORE BASAL TOTAL PROTEIN GRAFT CONTENT AFTER ISCHEMIA REPERFUSION INJURY IN HUMAN LIVER TRANSPLANTATION S. Ginanni Corradini a , A. Molinaro a , M. Siciliano a , E. Costi c , R. Monticolo c , C. Pirazzi a , M.A. Burza a , M. Merli a , A.F. Attili a , G.L. Mennini b , P. Berloco b , M. Rossi b , L. Iuliano c a
Div. Gastro Dip Med Clinica, Italy Chir. Generale “Paride Stefanini”, Italy c Dip. Med. Int., Universita’ “La Sapienza” Roma, Italy b Dip.
In summary, at the end of the follow-up, 40 (61%) had a clinical and biochemical response and 31 patients (46%) had a virological response, but among them 23 (35%) had also a sustained immunological response. Conclusions. This study shows that this treatment is safe and well tolerated and adverse events are comparable to standard interferon plus RBV.
Background and aim. Although advanced donor age is considered one of the characteristics of the expanded criteria donor for liver transplantation, it is not clear the mechanism by which older donor age predisposes to inferior liver transplant outcomes. Proteolysis occurs in the graft during ischemia, and post-reperfusion protein synthesis restores hepatic protein content. However, hepatic ischemia reperfusion injury is characterized by oxidative stress and endoplasmic reticulum stress which lead to reduced graft protein synthesis eventually associated with impaired survival. We investigated the degree of liver donor systemic oxidative stress and early changes of liver graft total protein and ATP content during liver transplantation according to donor age. Methods. Blood and liver graft (BxT1 ) samples were obtained from heartbeating donors before the aorta was clamped. A second liver graft sample was obtained 2 h after reperfusion in the recipient (BxT2 ) during 49 consecutive primary non urgent whole organ liver transplantations. Plasma oxysterols (7 OH-cholesterol and 7 keto-cholesterol) were measured by mass spectrometry. Total hepatic protein (Bio-Rad protein assay method) and ATP content (chemiluminescence) were measured in liver homogenates. The differences between BxT1 and BxT2 of total protein (P) and of ATP (ATP) hepatic contents were considered expression of the degree of post-reperfusion graft protein and ATP recovery impairment. Hepatic steatosis was evaluated semiquantitatively. The data were evaluated by comparing donors older (OD; n = 14; mean age 71.1 ± 5.7 years) and younger (YD; n = 35 mean age 37.5 ± 13.7 years) than 65 years. Results. OD had a significantly (P < 0.05) higher P than YD (82.3 ± 77.0 vs. 7.4 ± 118.6 g/mg dry liver, respectively), while no intergroup difference in ATP and in BxT1 graft steatosis was found. Plasma oxysterol concentration was significantly (p < 0.005) higher in OD than in YD (168.6 ± 65.6 vs. 64.2 ± 41.5 ng/ml, respectively). Conclusions. Older donor age is associated with increased donor systemic oxidative stress and reduced graft postreperfusion protein recovery after ischemia reperfusion injury in human liver transplantation.
doi:10.1016/j.dld.2007.12.068
doi:10.1016/j.dld.2007.12.069
Variable
Enrolment
EOT
EFU
HCV-RNA positivity ALT (>53 IU/l) Cryocrit (%) Rheumatoid Factor (>25 IU/ml) Purpura
66 (100%) 55 (83%) 66 (100%) 60 (91%) 59 (89%)
19 (29%) 16 (24%) 42 (64%) 60 (91%) 10 (15%)
35 (54%) 23 (33%) 43 (65%) 59 (89%) 26 (39%)
Efficacy of antiviral treatment in the 66 patients wit HCVrelated MC. Response
EOT
EFU
Virological Clinical Immunological Biochemical
47 (71%) 55 (85%) 24 (36%) 39 (71%)
31 (46%) 40 (61%) 23 (35%) 33 (60%)
Side effects. Neutropenia Thrombocitopenia Ribavirin dose reduction because anaemia* Interrupted therapy because depression Interrupted therapy because thrombocitopenia with neutropenia * Two
4 (6%) 4 (6%) 8 (12%) 2 (3%) 1 (2%)
patients EPO.
Abstracts / Digestive and Liver Disease 40 (2008) A1–A40
apoptosis: the extrinsic, cell surface receptors mediated, and the intrinsic mitochondria dysfunction mediated. Aims. To clarify the role of extrinsic and intrinsic apoptosis pathways in human liver disease, we studied the mRNA expression of Fas/FasL, TNF-␣ and Bcl-2, Bax and Bad in biopsies from patients with different degrees of liver damage and determined whether HCV and HBV infection modulates said expression. Methods. We examined 62 patients: 39 with chronic hepatitis (CH) (31 HCV-related, 8 HBV-related); 7 with cirrhosis (6 HCV-related, 1 HBV-related); 13 with hepatocellular carcinoma (HCC) ((6 HCV-related and 1 HBV-related) and 6 in non viral cirrhosis); 3 controls. mRNAs were quantified by quantitative real-time PCR using -actin as housekeeping gene. Results. Fas mRNA levels were significantly increased in CIRR when compared with HCC (p = 0.026) while FasL mRNAs showed a statistically significant differences between CIRR and cirrhotic tissues surrounding tumours (PHCC) (p = 0.018) or HCC (p = 0.005). Also TNF-␣ mRNAs were higher in CIRR than in PHCC (p = 0.038) and HCC (p = 0.05). Bcl-2 mRNA levels were statistically higher in PHCC than in controls (p = 0.026), in CH (p = 0.004), and in CIRR (p = 0.05). CH coincided with higher Bad levels than in PHCC or HCC tissues (p < 0.00001 and p < 0.0001, respectively). No differences in Bax expression were observed. In CH, only TNF-␣ and Bad mRNAs were significantly different in HBV-related infection versus HCV-related hepatitis. Conclusions. Fas/FasL system expression was upregulated in chronically damaged livers while the onset of cancer was associated with a shut-down of this system in HCC, as a defense mechanisms adopted by HCC against the immune system. Bcl-2 hyperexpression in CIRR seems to play an important role in regulating cell survival in damaged liver cells, contributing to HBV or HCV persistence. The different pattern of TNF-␣ and Bad expression in HCV- and HBVrelated liver disease points to a different modulation of the immune response on the one hand, and, to different apoptotic activation pathways on the other. doi:10.1016/j.dld.2007.12.066 INCIDENCE OF LATE HCC RECURRENCE AFTER RESECTION REMAINS HIGHER THAN FIRST HCC: IMPLICATIONS FOR PATIENTS MANAGEMENT A. Cucchetti a , F. Piscaglia b , L. Benvegn`u c , E. Caturelli d , A. Gianstefani b , G.L. Grazi a , L. Bolondi b , A.D. Pinna a a
Division of Liver Transplant Surgery, Italy
b Division of Internal Medicine, University of Bologna, Hos-
pital S. Orsola-Malpighi, Bologna, Italy c Division of Internal Medicine, University of Padua, Italy d Division of Gastroenterology, Ospedale Belcolle, Viterbo, Italy
Background and aims. Recurrence of hepatocellular carcinoma (HCC) after two years from resection (late recurrence) is considered a de novo HCC. Nonetheless, annual incidence is speculated to remain higher than first HCC in the cirrhotic general population, but never compared in detail. Aims of the present study were to assess incidence and risk factors of HCC recurrence and to compare it with non HCC cirrhotics. Methods. Retrospective analysis of cirrhotic patients with HCC submitted to resection (n = 205) and cirrhotics undergoing surveillance with ultrasonography (n = 150). Results. Resected patients showed higher prevalence of male gender and higher alpha-fetoprotein (AFP) (P < 0.05). Risk factors for early (<2 years) recurrence (incidence = 21.8%/year) were higher AFP, poorly tumour differentiation and presence of microvascular invasion (p < 0.05), all suggesting a metastatic cause for recurrence. Risk factors for both late recurrence (18.4%/year) and first HCC occurrence (3.3%/year) were male gender, older age and higher serum transaminase (suggesting de novo HCC); multiple primary tumours and higher AFP were additional risk factors for respectively late recurrence and first HCC (p < 0.05). Resected patients with ≤1 risk factors for late recurrence showed similar annual incidence of HCC (6.2%/year) to controls with >1 risk factors (6.3%/year; p = 0.919). Conclusion. HCC annual incidence remains higher than in cirrhosis even after two years from resection. However, in low risk resected HCC the incidence is similar to that of cirrhotic controls. The assessment of such characteristics in resected patients could address tailored post-operative follow-up schedules or, in the liver transplantation setting, modify allocation priority in HCC patients (maintaining or preserving priority). doi:10.1016/j.dld.2007.12.067 EFFICACY AND SAFETY OF TREATMENT WITH PEGYLATED INTERFERON AND RIBAVIRIN FOR HEPATITIS C VIRUS-ASSOCIATED CRYOGLOBULINEMIA: A MULTICENTER STUDY C. Mazzaro a , A.M. Baragiotta c , G. Pozzato b , G. Monti d , D. Filippini e , C. Donada f , A. Tellan a , A. Gabrielli g , S. De Vita h , GISC Gruppo Italiano Studio Crioglobulinemia (GISC) a
Department of Medicine, Pordenone General Hospital, Italy of Medicine University, Trieste, Italy c Gastroenterology, Pordenone General Hospital, Italy d Department of Medicine, Saronno General Hospital, Italy e Rheumatology, Milano General Hospital, Italy f Department of Medicine, Gorizia General Hospital, Italy g Rheumatology, University, Ancona, Italy h Rheumatology, University Udine, Italy b Department
Abstracts / Digestive and Liver Disease 40 (2008) A1–A40
Background. Limited data are available regarding the treatment of patients with HCV-related mixed cryoglobulinemia. Aim. The objective of this study was to evaluate the efficacy and safety of therapy with peginterferon alfa-2b plus ribavirin (RBV) in patients with chronic hepatitis C related MC. Methods. 66 consecutive pts with MC were recruited in this study (34 F and 32 M, median age 55). A liver biopsy was performed before therapy (83%). A chronic liver disease of variable severity (from A1F0 to A3F4) was found in 94% of these patients. In four (6%) patients liver cirrhosis was observed. Fourteen patients (21%) presented with peripheral neuropathy s-m; five patients (8%) were affected by nephropathy and five (8%) had B cell lymphoma. All cases were HCV–RNA positive, genotype 1 (52%), or non-1 genotypes (48%). All patients were treated with Peginterferon alfa2b 1.5 mcg/kg/week for 48 week plus RBV 1000–1200 mg/daily for 48 weeks in genotype 1 and for 24 weeks in Genotype 2 or 3 associated with Prednisone: 0.2–0.5 mg/kg/daily for 4 weeks. All patients were followed for at least 24 weeks after the end of the therapy. The response to treatment was analysed by comparing clinical, immunologic, virologic and biochemical parameters at the initial evaluation with those observed during follow-up. Results. Relevant variables at enrolment, end of treatment (EOT) and the end follow-up (EFU)
A25
OLDER DONOR AGE IS ASSOCIATED WITH INCREASED DONOR OXIDATIVE STRESS AND FAILURE TO RESTORE BASAL TOTAL PROTEIN GRAFT CONTENT AFTER ISCHEMIA REPERFUSION INJURY IN HUMAN LIVER TRANSPLANTATION S. Ginanni Corradini a , A. Molinaro a , M. Siciliano a , E. Costi c , R. Monticolo c , C. Pirazzi a , M.A. Burza a , M. Merli a , A.F. Attili a , G.L. Mennini b , P. Berloco b , M. Rossi b , L. Iuliano c a
Div. Gastro Dip Med Clinica, Italy Chir. Generale “Paride Stefanini”, Italy c Dip. Med. Int., Universita’ “La Sapienza” Roma, Italy b Dip.
In summary, at the end of the follow-up, 40 (61%) had a clinical and biochemical response and 31 patients (46%) had a virological response, but among them 23 (35%) had also a sustained immunological response. Conclusions. This study shows that this treatment is safe and well tolerated and adverse events are comparable to standard interferon plus RBV.
Background and aim. Although advanced donor age is considered one of the characteristics of the expanded criteria donor for liver transplantation, it is not clear the mechanism by which older donor age predisposes to inferior liver transplant outcomes. Proteolysis occurs in the graft during ischemia, and post-reperfusion protein synthesis restores hepatic protein content. However, hepatic ischemia reperfusion injury is characterized by oxidative stress and endoplasmic reticulum stress which lead to reduced graft protein synthesis eventually associated with impaired survival. We investigated the degree of liver donor systemic oxidative stress and early changes of liver graft total protein and ATP content during liver transplantation according to donor age. Methods. Blood and liver graft (BxT1 ) samples were obtained from heartbeating donors before the aorta was clamped. A second liver graft sample was obtained 2 h after reperfusion in the recipient (BxT2 ) during 49 consecutive primary non urgent whole organ liver transplantations. Plasma oxysterols (7 OH-cholesterol and 7 keto-cholesterol) were measured by mass spectrometry. Total hepatic protein (Bio-Rad protein assay method) and ATP content (chemiluminescence) were measured in liver homogenates. The differences between BxT1 and BxT2 of total protein (P) and of ATP (ATP) hepatic contents were considered expression of the degree of post-reperfusion graft protein and ATP recovery impairment. Hepatic steatosis was evaluated semiquantitatively. The data were evaluated by comparing donors older (OD; n = 14; mean age 71.1 ± 5.7 years) and younger (YD; n = 35 mean age 37.5 ± 13.7 years) than 65 years. Results. OD had a significantly (P < 0.05) higher P than YD (82.3 ± 77.0 vs. 7.4 ± 118.6 g/mg dry liver, respectively), while no intergroup difference in ATP and in BxT1 graft steatosis was found. Plasma oxysterol concentration was significantly (p < 0.005) higher in OD than in YD (168.6 ± 65.6 vs. 64.2 ± 41.5 ng/ml, respectively). Conclusions. Older donor age is associated with increased donor systemic oxidative stress and reduced graft postreperfusion protein recovery after ischemia reperfusion injury in human liver transplantation.
doi:10.1016/j.dld.2007.12.068
doi:10.1016/j.dld.2007.12.069
Variable
Enrolment
EOT
EFU
HCV-RNA positivity ALT (>53 IU/l) Cryocrit (%) Rheumatoid Factor (>25 IU/ml) Purpura
66 (100%) 55 (83%) 66 (100%) 60 (91%) 59 (89%)
19 (29%) 16 (24%) 42 (64%) 60 (91%) 10 (15%)
35 (54%) 23 (33%) 43 (65%) 59 (89%) 26 (39%)
Efficacy of antiviral treatment in the 66 patients wit HCVrelated MC. Response
EOT
EFU
Virological Clinical Immunological Biochemical
47 (71%) 55 (85%) 24 (36%) 39 (71%)
31 (46%) 40 (61%) 23 (35%) 33 (60%)
Side effects. Neutropenia Thrombocitopenia Ribavirin dose reduction because anaemia* Interrupted therapy because depression Interrupted therapy because thrombocitopenia with neutropenia * Two
4 (6%) 4 (6%) 8 (12%) 2 (3%) 1 (2%)
patients EPO.