Elisa Fumolo

IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: Role in the course of chronic viral hepatitis and the development of HCC

BACKGROUND & AIMS A single nucleotide polymorphism (rs12979860 C/T) 3kb upstream of the interleukin 28B (IL-28B) gene was shown to be associated with hepatitis C clearance. We verified whether this association also translates into a different genotype distribution at the end of the disease trajectory. METHODS A RFLP-PCR technique was used to genotype 412 patients with cirrhosis due to hepatitis C (n=199), hepatitis B (n=75), alcohol (n=110), and other causes (n=28), of whom 256 underwent liver transplantation (OLT). Hepatocellular carcinoma (HCC) was demonstrated in the native liver of 85 OLT patients, 52 with viral cirrhosis, and 33 with non-viral cirrhosis respectively. A group of 292 patients (235 HCV and 57 HBV positive) with mild chronic hepatitis and 344 healthy subjects served as controls. RESULTS A significant difference (p=0.0005) was observed in IL-28B rs12979860 genotype frequencies between patients with viral cirrhosis (C/C=99, C/T=137, T/T=38) and those with non-viral cirrhosis (C/C=72, C/T=58, T/T=8). Patients with HCV related cirrhosis carried more frequently the T/T genotype in comparison to mild hepatitis C or HBV-related cirrhosis. IL-28B rs12979860 genotype frequencies were C/C=23, C/T=50, T/T=12 among OLT patients with cirrhosis complicated by HCC, and C/C=79, C/T=78, T/T=14 among patients with cirrhosis not complicated by HCC (p<0.005). CONCLUSIONS IL-28B rs12979860 C/T polymorphism T allele is more prevalent in patients with viral cirrhosis due to HCV in comparison to other aetiologies and to patients with mild chronic hepatitis C. Among OLT patients, carriage of this allele seems to augment the risk of developing HCC.

Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.

In immune‐competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty‐two consecutive patients were treated for RHC with combination therapy with INF‐α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤10 ng/ml) patients, in 6/20 deficient (>10 and ≤20 ng/ml) and in 6/12 with near normal (>20 ng/ml) 25‐OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi‐square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi‐square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.

PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence.

Background and aim: The PNPLA3 rs738409 C>G polymorphism has been found to be strongly associated with non‐alcoholic fatty liver disease and with alcoholic liver disease. Whether the PNPLA3 rs738409 polymorphism could be a risk factor for the development of hepatocellular carcinoma (HCC) in cirrhosis patients is unknown.

Vitamin D and the risk of acute allograft rejection following human liver transplantation

Background: Vitamin D may act as an immune modulator in experimental and human organ transplantation, but these data are yet to be confirmed in human liver transplantation (LT).

Role of Interleukin 28B rs12979860 C/T Polymorphism on the Histological Outcome of Chronic Hepatitis C: Relationship with Gender and Viral Genotype

BackgroundThis study aimed to determine whether the single-nucleotide polymorphism (rs12979860 C/T) of the interleukin 28B (IL-28B) gene, which is associated with hepatitis C virus (HCV) clearance, is also associated with fibrosis in chronic HCV infection.MethodsAn RFLP-PCR technique was used to genotype 629 HCV-positive patients (200 with cirrhosis) and 428 healthy control subjects.ResultsThe genotype frequencies in the controls and chronic hepatitis C patients were as follows: C/C 47.0% vs. 32.6%, C/T 41.8% vs. 52.8% and T/T 11.2% vs. 14.6% (p < 0.0001). The C allele frequency was higher in HCV-2- (0.635) and 3- (0.692) infected patients in comparison to those infected with HCV-1 (0.550) or 4–5 (0.600) (p < 0.001). Infected T/T homozygotes had a mean staging score higher than other patients (3.50 vs. 3.04, p < 0.05).ConclusionsIL-28B rs12979860 C/T polymorphism is associated with a greater likelihood of HCV persistence, particularly in HCV genotypes 1 and 4. The T allele affects the severity of liver fibrosis.

MTHFR C677T Polymorphism and Risk of HCC in Patients With Liver Cirrhosis: Role of Male Gender and Alcohol Consumption

BACKGROUND A single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified. The TT or CT genotypes show a marked reduction of the enzyme activity; this causes higher homocysteine levels and alterations of folate metabolism. Folate metabolism is essential for DNA synthesis and methylation, crucial steps in carcinogenesis. In this paper, we investigated whether the MTHFR C677T SNP could influence the occurrence of hepatocellular carcinoma (HCC) in a cohort of patients transplanted for end stage liver disease of different etiologies. METHODS Two hundred and twelve consecutive patients who underwent liver transplantation for end stage liver disease due to hepatitis B or C, alcoholic liver disease, and other causes were studied. Two hundred and thirty-six blood donors served as controls. Focal hepatic lesions were searched in the sectioned explanted livers. The presence of the MTHFR C677T SNP was determined via polymerase chain reaction amplification. RESULTS Among the 65 patients with HCC, 22 had the CC genotype, 30 the CT, and 13 the TT genotype. Only in patients with alcoholic liver disease was a significant association detected between the TT genotype and the presence of liver cancer (6/17 vs. 5/46, p < 0.05). At stepwise logistic regression analysis the independent selected predictors of HCC were found: age at transplantation >55 years (p < 0.001) and the association among male gender, alcoholic liver disease, and MTHFR TT genotype (p = 0.002). CONCLUSIONS The present study suggests that male TT carriers with alcoholic cirrhosis bear an increased risk of developing HCC.

Interleukin-6 Polymorphisms and Gender: Relationship with the Occurrence of Hepatocellular Carcinoma in Patients with End-Stage Liver Disease

Objective: To investigate whether interleukin-6 (IL-6) polymorphisms could be associated with the occurrence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and whether this influence could act synergistically with the gender of the patient. Methods: We studied 219 consecutive patients who underwent liver transplantation for liver cirrhosis. All total hepatectomy specimens were sectioned at intervals of 1 cm in search for suspicious focal hepatic lesions. Genotyping for the IL-6 –1363 G>T, –597 G>A, –572 G>C, –174 G>C and +2954 G>C polymorphisms was performed by restriction fragment length polymorphism. Results: A significant association was found between the presence of the A-C/A-C low producer diplotype (–597 G>A/–174 G>C loci) and absence of HCC (18/153 vs. 1/66, p < 0.02). With respect to the IL-6 A-C/A-C low producer phenotype (n = 19), females (n = 60) and males (n = 140) with the high producer phenotypes had an adjusted odds ratio for the presence of HCC of 3.74 and 14.8, respectively (p < 0.001). Conclusions: Polymorphisms of IL-6, by determining differences in its expression, are associated with HCC occurrence among patients with liver cirrhosis. The protective effect of female gender against the occurrence of HCC occurs mainly among carriers of IL-6 high producer phenotypes.

Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti‐core antibodies may develop overt “de novo” HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O‐HBV). In the native liver, 8/30 patients had detectable O‐HBV; during the follow‐up, O‐HBV infection was demonstrated in 14 graft specimens. Graft O‐HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O‐HBV and no O‐HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post‐transplant O‐HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O‐HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.

Prevalence and Risk Factors for Delayed Adrenal Insufficiency After Liver Transplantation

Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid‐free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end‐stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained <20 μg/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P < 0.01), the increase in the body mass index after LT (P < 0.01), a low serum cholesterol concentration (P = 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P < 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Factors associated with FAGA include the cumulative steroid dose, weight changes after LT, and ACTH and cholesterol levels at the time of steroid withdrawal. Liver Transpl 14:1014–1019, 2008.

Antiviral treatment in patients with hepatitis C virus-related cirrhosis awaiting liver transplantation.

End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.