HEPATITIS C GENOTYPE-3 SPECIFIC MECHANISM OF HYPOCHOLESTEROLEMIA. EFFECT OF LONG-TERM SUSTAINED VIROLOGICAL RESPONSE

C.M. Fernandez-Rodriguez¹, P. Lopez Serrano¹, M.L. Gutierrez¹, S. Alonso¹, M. Nevado², J.L. Lledo¹

¹Gastroenterology and Hepatology Unit, Fundacion Hospital Alcorcon, Madrid, Spain ²Pathology Unit, Fundacion Hospital Alcorcon, Madrid, Spain

Introduction

Hepatic steatosis associated to genotype 3 HCV is associated to low serum cholesterol and may be mediated by a protein-core direct cytopathic effect. Reversal of this lipid metabolic disturbance in long-term virological sustained responders is less-well known.

Aims

To examine the serum colesterol levels of HCV patients infected with genotype-3 chronic, its relationship with liver steatosis and the long-term effect of sustained virological response (SVR) on hypocholesterolemia as compared with non-responders and with patients with genotype-1.

Methods

Two hundred and fifteen consecutive untreated patients with chronic hepatitis C referred to our institution for assessing antiviral treatment have been studied (genotype 1, n = 158; genotype 2, n =4; genotype 3, n =41 and genotypes 4 y 5, n=12). Data on virological response 6 months after the end of treatment were available in 160 patients.

Results

Patients infected by genotype 3 showed lower age-adjusted serum cholesterol levels and more frequent moderate to severe hepatic steatosis than those infected by non-3 genotypes (P<0.001). There was an inverse correlation between the degree of steatosis and serum cholesterol in patients with genotype-3 (p>0.01) but not in patients with genotype 1. In patients with genotype-3 and SVR, serum cholesterol raised from 140 mg/dl (IC 120-151) to 185 mg/dl (IC 171-199) six months after the end of treatment (p: 0. 0001). By contrast, serum cholesterol did not change in non-responders: 143 mg/dl (IC 99-187) to 140 mg/dl(IC 111-169). In patients infected with genotype 1, regardless of virological sustained response, serum cholesterol remained unchanged: From 196 mg/dl (181-211) to 204 (193-215) in SVR and from 180 (167-192) to 170 (160-181) in non-responders.

Conclusions

In addition to cause hepatic steatosis, genotype-3 of HCV, but not other genotypes, decreases serum cholesterol which was inversely proportional to the degree of hepatic steatosis. This interference with the metabolic lipid pathway is reversible with sustained virological response.

LEPTIN, LEPTIN-ADIPONECTIN RATIO AND INSULIN RESISTANCE ARE RELATED WITH STEATOSIS BUT NOT FIBROSIS IN HCV CHRONIC HEPATITIS

G. Venezia¹, O. Lo Iacono¹, S. Petta¹, M. Amato², V. Rodolico³, A. Mattina², C. Giordano², V. Di Marco¹, C. Mineo¹, S. De Lisi¹, P. Almasio¹, A. Craxì¹

¹Gastroenterology, University of Palermo, Palermo, Italy ²Endocrinology, University of Palermo, Palermo, Italy ³Pathological Anatony, University of Palermo, Palermo, Italy

BACKGROUND

Steatosis is commonly present in chronic hepatitis C (CHC); however the pathophysiology and metabolic association of steatosis and its role in disease progression have not been established. Leptin “resistance” and low levels of adiponectin play a role in the pathogenesis of hepatic steatosis and insulin resistance.

AIM

To evaluate the presence of insulin resistance, levels of leptin, adiponectin and resistin and their possible relationship with steatosis and fibrosis in CHC.

METHODS

We studied fifty-five naïve patients with biopsy-proven CHC (age: 51 ± 12 years; gender: 33M/22F). METAVIR and Brunt classifications and the ATP III metabolic syndrome definition were applied. BMI, fasting glucose, insulin, C-peptide, resistin, leptin, adiponectin, lipoprotein, apo-β was performed.

RESULTS

Thirty-three (60%) patients had genotype 1b and 4 (8%) genotype 3a; 20 (36%) had histological steatosis with grade 2 or 3 (>33% hepatocytes involved). Patients with CHC and steatosis grade 2 or 3 were older (p=0.018), had higher staging (p=0.047). Metabolic syndrome was present in 7/20 (35%) pts with steatosis and in 4/35 (11%) without (p= 0.036). BMI (25.1±3.1 vs 28.0±5.1; p=0.034), serum triglycerides concentration (91±41 vs 128±74; p=0.018), insulin level (11.6±11.4 vs 13.8±5.0 p=0.014), HOMA (3.0±3.6 vs 3.3±1.4; p=0.016), fasting glucose insulin ratio (11.7±7.4 vs 7.9±3.0 p= 0.034), leptin (14.7±10.1 vs 25.6±11.3 p=0.003) and leptin/adiponectin ratio (0.6±0.4 vs 1.3±08 p= 0.002) were statistical associated with steatosis. No statistical association was found for grading, ALT, GGT, glucose, cholesterol and HDL concentration, lipoprotein, apo-β and adiponectin, resistin and C-peptide. However no statistical correlation was found between fibrosis and leptin, adiponectin and its ratio.

CONCLUSION

In HCV infected patients high serum levels of leptin and ratio leptin/adiponectin are related to severe steatosis, but not with liver fibrosis; reflect their potential role in insulin resistance and the importance of antisteatotic regulatory mechanisms

SIGNIFICANT IMPROVEMENT IN THE OUTCOME OF HCV-INFECTED TRANSPLANT RECIPIENTS FOLLOWING THE IMPLEMENTATION OF SIMPLE MEASURES

M. Berenguer¹, V. Aguilera¹, M. Prieto¹, F. San Juan², S. Benlloch¹, J.M. Rayón³, J. Berenguer¹

¹Hepatogastroenterology Department Hospital Universitario La Fe, Valencia, Spain ²Liver Unit, Surgery Department, Hospital Universitario La Fe, Valencia, Spain ³Pathology Department Hospital Universitario La Fe, Valencia, Spain

Background

Recurrent HCV-cirrhosis occurs in a substantial proportion of recipients, with higher rates reported in patients transplanted recently. Both the aging of the donors and over-immunosuppression have been implicated in this worse outcome. In addition, controversial results have been reported with regards to the role of specific calcineurin-inhibitors.

Aims

To determine (1) whether the implementation of specific measures aimed at reducing or avoiding the negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C; (2) whether there are differences in outcome based on the induction immunosuppression (tacrolimus vs cyclosporine-based).

Methods

Comparative study between a cohort of patients transplanted recently (2001-2003) and a control group of HCV-infected patients transplanted before the implementation of three simple measures (1999-2000): (i) use dual immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) Slow steroid tapering; and (iii) selection, whenever possible, of organs from younger donors for HCV-candidates; (2) Prospective randomized trial comparing fibrosis progression and rate of HCV-related severe disease (F3, F4, cholestatic hepatitis) between tacrolimus and cyclosporine-based immunosuppressed using the most recent cohort. Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study.

Results

Severe disease (defined as bridging fibrosis, cirrhosis, or fibrosing cholestatic hepatitis in the first two years) was significantly lower in this cohort compared to the control group (13/42, 31 % vs 26/47, 50%; p=.02). While the age of the donor had not changed significantly between the two cohorts, the proportion of patients on triple-quadriple regimes was lower and the duration of prednisone therapy longer in patients transplanted more recently. Cyclosporine (n=26) and tacrolimus (n=16) patients were similar with regards to demographics, donor age and sex, duration of prednisone, rejection, methyl-prednisolone boluses, surgical-related variables and follow-up. The percentage of patients developing severe disease was not statistically different between the cyclosporine and tacrolimus groups (27% vs 37.5%).

Conclusions

Improving the outcome of recurrent hepatitis C might be achieved by reducing overall immunosuppression and avoiding abrupt changes in immunosuppression.

Liver Transplantation – Special Populations - Children

FUNCTIONAL RESULTS OF LIVER TRANSPLANTATION IN CHILDREN WITH 5 TO 14 YEARS OF FOLLOW UP

F. Lacaille¹, Y. Revillon¹, D. Jan¹, J. Pawlowska², M. Marcellini³

¹Hôpital Necker-Enfants Malades, paris, France ²Centrum Zdrowia Dziecka, Warsaw, Poland ³Ospedale Bambino Gesu, Rome, Italy

Introduction

The prevention of long term complications is a major concern in children after liver transplantation (LT).

Aim

To evaluate the medium term results, we studied 53 children (20 boys), who survived more than 5 years after LT. Patients : they are 6 to 24 year-old, the median follow-up is 7.5 y (5-14.5). They received LT at a mean age of 3.5 y (11 m-14.5 y), for chronic cholestasis in 41. Two were retransplanted (1 primary non-function, 1 biliary complications). Graft was living-related in 37, a reduced liver in 6, a split liver in 2, a whole liver in 10.

Results

2 children died, 5 y (cystic fibrosis), and 10 y (awaiting retransplantation) after LT. All others have a normal daily function. The 6 older ones are students or employed, the other ones attend school, only 2 being backward. Immunosuppression is ciclosporine in 39, tacrolimus in 14, 32 off prednisone. Height is > 85% mean for age except in 2 (Alagille, propionic acidemia). One child only weighs more than 125% of mean weight for height. Liver tests are abnormal in 13. Two patients have hepatitis B and 3 hepatitis C. One has arterial thrombosis and chronic biliary problems. Biliary stenosis necessitated surgery 2 to 7 y after LT in 4. Liver biopsy was performed in 29, and is normal only in 2 : lesions are ductular proliferation (3), rejection (19, mild in 18), related to hepatitis C (3). The immunosuppression was changed in 10 after the biopsy. Renal clearance was controlled in 24 : it is > 70 ml/mn/1.73 m2 in 18, 60-70 in 4, < 60 in 2. Five are treated for high blood pressure. Blood lipids are normal in all. Cardiac ultrasonography is normal in 13/15.

Conclusions

The medium term functional results of LT are good, the patients leading a near-normal life. Growth is satisfactory, overweight is not a major problem. However liver histology is seldom normal. Kidney function is already borderline in some patients and could be improved by a change of immunosuppression. Heart function should be followed, due to complications of hypertension, tacrolimus toxicity, or hypercholesterolemia.

HEPATIC STEATOSIS AFTER LIVER TRANSPLANTATION: PREVALENCE AND ASSOCIATED FACTORS

G. Nicolini¹, F. Gentili¹, A. Onetti Muda³, A. De Santis¹, S. Ginanni Corradini¹, O. Riggio¹, S. Natalizi³, M. Iappelli², M. Rossi², A.F. Attili¹, M. Merli¹

¹II Gastroenterologia, Università di Roma 'La Sapienza', Rome, Italy ²II Clinica Chirurgica, Università di Roma 'La Sapienza', Rome, Italy ³Anatomia Patologica, Università di Roma 'La Sapienza', Rome, Italy

Introduction

Hepatic steatosis has been described after liver transplantation (LT) and mostly associated with hepatitis C reinfection. Other factors, often present in transplanted patients, are associated with steatosis: overweight/obesity, diabetes, hypertension, hypertrigliceridemia, alcohol consumption. Moreover, donor characteristics and liver perfusion may contribute to the occurrence of post-LT steatosis.

Aim

Our study was aimed at defining the prevalence and factors associated to post-LT steatosis.

Methods

Among 107 consecutive patients transplanted at our University from January 2001 to January 2004, forty-two (29M/13F;mean age:55±8years) performed one or more liver biopsies, during follow-up. The main indication for biopsies was alteration in liver enzymes, but also protocol biopsies were included. Sixty-seven percent of patients were HCV-RNA positive. Steatosis was defined as mild-moderate (involving<60% of hepatocytes) or severe (>/=60%).

Results

The overall prevalence of steatosis was 60%, while severe steatosis was present in 6 patients (14%). Patients’ characteristics at time of biopsy are reported in Table. Post-LT steatosis is related to hepatitis C recurrence; severe steatosis was associated with genotype 3. BMI, diabetes, hypertension, hypertrigliceridemia and donor steatosis were not associated with post-LT steatosis. A decreased arterial blood flow in the allograft seems to contribute to post-LT steatosis.

ARE THERE ADDITIONAL RISK FACTORS BEYOND MELD-SCORE TO PREDICT DEATH ON THE WAITING LIST?

G.R. Silberhumer¹, H. Hetz², S. Rockenschaub¹, B.A. Berlakovich¹, R. Steininger¹, F. Muehlbacher¹

¹Medical University Vienna, Department for Transplantsurgery, Vienna, Austria ²Medical University Vienna, Department for Anesthesiology, Vienna, Austria

Backround

Model for End-stage Liver Disease (MELD) score has emerged as a useful tool in predicting mortality in patients awaiting liver transplantation. There is still the discussion, if further parameters could improve the sensitivity and specificity of the MELD score.

Methods

From 1997 to 2003 622 adult patients with End Stage Liver Disease were listed for orthotopic liver transplantation (OLT). 388 patients were transplanted, 131 died on list, 55 were removed from the waiting list due to tumor progression (n=11), poor condition (n=6), non compliance (n=7), clinical improvement (n=28) or technical reasons (n=3). 48 patients are still awaiting OLT. All patients were categorized according to the MELD Score.

Results

Patients who died on list showed a significant increase of their MELD score during waiting time (On list MELD: 21±7 vs. Off list MELD: 28±9) as well as a significant higher MELD score at listing compared to patients who were transplanted (On list MELD: 16±5 vs. Off list MELD: 17±7) or removed (On list MELD: 16±6 vs. Off list MELD: 12±3). Multivariate analysis (Cox Model) identified MELD score at listing (p<0,001), ascites (p<0,001) and spontaneous bacterial infection (p=0,003) as independent risk factors for death on the waiting list. Patient survival estimated by Kaplan Meier method was similar at 3, 6 and 12 months after transplantation regardless of the MELD Score. However, patients with a MELD Score >=25 showed a trend towards a lower survival at 3 years (62% versus 80%, p=0.08). A further detail of interest in this analysis was the fact that patients with MELD Score <11 showed a higher risk for death after OLT (89% survival) than on waiting list (98% survival) at three months.

Conclusion

Our study demonstrated that MELD Score is a strong predictor for death on the waiting list. It enables listing patients depending on their disease severity and uses only routine blood tests without any subjective parameters. Additionally we evaluated refractory ascites and recurrent infection as independent risk factors, too. These complications of portal hypertension have to be treated adequately, especially in patients with lower MELD Scores.

INCREASING DONOR AGE REDUCES SURVIVAL FOLLOWING LIVER TRANSPLANTATION (LT) IN PATIENTS WITH CHRONIC HCV WITHOUT AFFECTING THE SEVERITY OF DISEASE RECURRENCE

N. Yilmaz¹, M.L. Shiffman¹, R.T. Stravitz¹, R.K. Sterling¹, V.A. Luketic¹, A.J. Sanyal¹, M.J. Contos², A.S. Mills², A. Cotterell³, D. Maluf³, M.P. Posner³, R.A. Fisher³

¹Hepatology Section, VCU Medical Center, Virginia Commonwealth University Medical Center, Richmond VA, USA ²Department of Pathology, VCU Medical Center, Virginia Commonwealth University Medical Center, Richmond VA, USA ³Division of Transplant Surgery, VCU Medical Center, Richmond VA, USA

INTRODUCTION

It has been suggested that patients with HCV who underwent LT in recent years had reduced survival and this was secondary to more aggressive recurrent disease, especially in those patients who received and older donor organ.

STUDY AIMS

To determine the impact of donor age on LT survival and disease recurrence in patients with chronic HCV.

METHODS

222 patients underwent LT for HCV cirrhosis between 1991-2004; mean age 50 years; 75% male; 84% Caucasian. 30% had received interferon (IFN) prior to LT. Immunosuppression varied considerably over 13 years and included, OKT3(14%), ATG(2%), cyclosporine/Neoral(55%), tacrolimus(12%), azathioprine(14%), MMF(85%), sirolimus(41%) and prednisone(100%). Donor age ranged from 6-76 years; 10% were >60 years. All patients underwent protocol liver biopsy (LBX) 6 months after LT and at 1-2 year intervals thereafter. Rejection was always confirmed by LBX.

RESULTS

Patient survival at 1, 3 and 5 years was 86%, 82% and 74% when LT was performed between 1991-00; graft survival was 83%, 79% and 70%. In contrast, a significant (p<0.001) decline in patient and graft survival was observed when LT was performed between 2001-03; 81%, 68% and 50% and 80%, 66% and 48% at 1, 2 and 3 years respectively. Between 1991-00 the use of donor organs >60 years was <7% compared to 15% during 2001-03 (p<0.01). The 5 year patient and graft survival after LT when the donor was <60 years was 69% and 64% respectively versus only 42% when donor age was >60 years (p<0.001). In contrast, increasing donor age was not associated with more severe recurrent HCV. After 5 years 23% of grafts from donors <20 years had developed bridging fibrosis or cirrhosis compared to 25% from donors >60 years. No specific immunosuppression medication, acute rejection (20-30% over the 13 years) or treatment with IFN prior to LT appeared to affect patient or graft survival.

CONCLUSIONS