Trends in liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. AIM: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. METHODS: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. RESULTS: From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). CONCLUSIONS: Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death.

Mycophenolate Interruption Restores Anti-SARS-CoV-2 Vaccine Immunogenicity in Unresponsive Liver Transplant Recipients.

BACKGROUND & AIMS: The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve the immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. METHODS: LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T-cell responses were measured before and 2 months following the fourth vaccine dose, and anti-SARS-CoV-2 s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. RESULTS: Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2 s-RBD antibodies. The mean antibody titer was 8944 UI/mL. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T-cell response. Two patients (one positive for T-cell response) developed a self-limited SARS-CoV-2 infection. CONCLUSIONS: Suspending MMF prior to the fourth dose of the anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients.

Baseline Predictors of the Long-Term Insufficient Biochemical Response in Patients with Autoimmune Hepatitis: A Single Center Experience.

The treatment response criteria in autoimmune hepatitis (AIH) have been recently updated. This study aimed to assess treatment responses in 39 (16 males) patients with AIH confirmed by histology. Prednisone added to azathioprine or mycophenolate was the most frequent first-line treatment. Serum alanine aminotransferase (ALT) levels were periodically checked for a median of 45 months. Eight (20.5%) patients presented 4 weeks non-response (NR). Baseline lower multiples of ALT above the upper normal limit (UNL) (p = 0.005), Ishak liver fibrosis score > 3 (p = 0.029), and less frequent confluent necrosis > 2 (p < 0.001) were independent predictors of NR. 24 (61.5%) patients achieved complete biochemical response (CBR) at six months. Ishak liver fibrosis score ≤ 3 (p < 0.001), lobular eosinophilic infiltrate (p < 0.001), and ≥50% decrease in serum ALT levels at week 4 (p < 0.001) were independent predictors of CBR. In addition, the GLUCRE score, derived from the multiplication of serum creatinine (mg/dL) and glucose (mg/dL) levels, were identified. A baseline GLUCRE value > 100 strongly predicted CBR failure (p = 0.003) at a follow-up greater than 12 months. In conclusion, the absence of cirrhosis and a ≥50% UNL decrease in serum ALT levels were independent predictors for CBR. A baseline GLUCRE score may help identify patients maintaining longer CBR.

Immunogenicity and safety of a third dose of anti-SARS-CoV-2 BNT16b2 vaccine in liver transplant recipients.

BACKGROUND & AIMS: A strategy to improve the low rate of anti-SARS-CoV-2 mRNA vaccine-induced immunogenicity in liver transplant recipients (LTs) is urgently needed. METHODS: We analysed the rate of positive (≥0.8 U/ml) anti-SARS-CoV-2 receptor domain-binding protein (RBD) antibody response 2 months after a third dose of the BNT16b2 vaccine in 107 LTs who completed the second vaccine dose 7 months earlier. RESULTS: A positive anti-SARS-CoV-2-s-RBD antibody response after the third vaccine dose was detected in 98 (91.6%) LTs compared to 82 (76.6%) after the second vaccine dose (p = .003). The median of anti-SARS-CoV-2 RBD antibody titres increased from 22.9 U/ml 6 months after the second to 3500 U/ml 2 months after the third vaccine dose (p < .001). Fourteen (14.3%) responder patients presented antibody titres <100 U/ml, 57 (58.2%) between 100 and 9999 U/ml and 27 (27.6%) ≥10 000 U/ml. Seropositivity after the second dose was maintained after the third dose. Independent predictors of antibody response failure after the third vaccine dose were taking a higher daily dose of mycophenolate mofetil (MMF, p < .001) and had a lower (<60 ml/min/1.73 m2 ) estimated glomerular filtration rate (p = .007). Nine (9.1%) LTs experienced symptomatic SARS-CoV-2 infection after the third vaccine dose. Median antibody titres were not statistically different between infected and not infected LTs (1325 vs 3515 U/ml, p = .678). CONCLUSIONS: The third dose of the BNT16b2 vaccine increased the number of LTs who developed a positive anti-SARS-CoV-2 s-RBD antibody response. A proportion of patients remained unresponsive, mainly for modifiable factors, such as the use of MMF or multiple immunosuppressants.

Low risk of nosocomial severe acute respiratory syndrome-coronavirus-2 infection in patients with liver disease admitted to a hepatology unit at an academic hospital: A single-center experience.

BACKGROUND: Patients with liver disease may be at increased risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection due to immune dysfunction. However, the risk of nosocomial SARS-CoV-2 infection in these patients remains unknown. This study aimed to determine whether patients with liver disease are at an increased risk of nosocomial transmission of SARS-CoV-2 infection upon admission to the hospital for diagnostic or therapeutic procedures. METHODS: The study prospectively enrolled 143 patients who were admitted at least once to the hepatology unit at our hospital; 95 patients (66%) were admitted at least twice during the study period. History of past symptomatic SARS-CoV-2 exposure was assessed on the day before hospital admission via an interview. Patients were evaluated for active SARS-CoV-2 infection via real-time reverse transcription-polymerase chain reaction (RT-PCR) performed on nasopharyngeal swabs and tests for serum anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. RESULTS: None of the patients enrolled tested positive for SARS-CoV-2 infection by RT-PCR at the first or the second clinical evaluation. One patient who had previously received a liver transplant and who had a history of symptomatic SARS-CoV-2 infection that occurred 4 months before hospital admission tested positive for anti-SARS-CoV-2 IgG but not IgM antibodies at each of the two hospital admissions. CONCLUSIONS: The results of our study suggest that patients with liver disease are at no increased risk of nosocomial SARS-CoV-2 infection. These data support the policy of maintaining clinical hospital checks that will be necessary until or possibly even after the completion of the current SARS-CoV-2 vaccination campaign.

Past COVID-19 and immunosuppressive regimens affect the long-term response to anti-SARS-CoV-2 vaccination in liver transplant recipients.

BACKGROUND & AIMS: The long-term immunogenicity of anti-SARS-CoV-2 vaccines in liver transplant (LT) recipients is unknown. We aimed to assess the long-term antibody response of the Pfizer-BioNTech® BNT162b2 vaccine in LT recipients compared to controls. METHODS: LT recipients underwent anti-SARS-CoV-2 anti-receptor-binding domain protein IgG (anti-RBD) and anti-nucleocapsid protein IgG antibody (anti-N) measurements at the first and 1, 4 and 6 months after the second vaccination dose. RESULTS: One hundred forty-three LT recipients and 58 controls were enrolled. At baseline, 131/143 (91.6%) LT recipients tested anti-N negative (COVID-19 naïve), and 12/143 (8.4%) tested positive (COVID-19 recovered) compared to negative controls. Among COVID-19 naïve, 22.1% were anti-RBD positives 1 month after the first vaccine dose, while 66.4%, 77%, and 78.8% were 1, 4 and 6 months following the second vaccine dose. In contrast, 100% of controls were positive at 4 months (p <0.001). The median anti-RBD titer 4 months after the second vaccine dose was significantly lower (32 U/ml) in COVID-19 naïve than in controls (852 U/ml, p <0.0001). A higher daily dose of mycophenolate mofetil (MMF) (p <0.001), higher frequency of ascites (p = 0.012), and lower serum leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at 6 months. All COVID-19 recovered patients tested positive for anti-RBD at each time point. The median antibody titer was similar in those taking MMF (9,400 U/ml, 11,925 U/ml, 13,305 U/ml, and 10,095 U/ml) or not taking MMF (13,950 U/ml, 9,575 U/ml, 3,500 U/ml, 2,835 U/ml, p = NS) 3 weeks after the first and 1, 4 and 6 months after the second vaccine dose, respectively. CONCLUSIONS: In COVID-19-naïve LT recipients, the immunogenicity of anti-SARS-CoV-2 vaccination was significantly lower than that in controls. MMF was the main determinant of vaccination failure in SARS-CoV-2-naïve patients. LAY SUMMARY: The immunogenicity of anti-SARS-CoV-2 vaccination in liver transplant recipients is currently unknown. Herein, we show that liver transplant recipients who have not previously had COVID-19 are less likely to mount effective antibody responses to vaccination than a control population. The main determinant of vaccination failure was the use of the immunosuppressive drug mycophenolate mofetil.

An Essential Guide for Managing Post-Liver Transplant Patients: What Primary Care Physicians Should Know.

With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.

Liver Transplantation in Patients with Hepatocellular Carcinoma beyond the Milan Criteria: A Comprehensive Review.

The Milan criteria (MC) were developed more than 20 years ago and are still considered the benchmark for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). However, the strict application of MC might exclude some patients who may receive a clinical benefit of LT. Several expanded criteria have been proposed. Some of these consider pretransplant morphological and biological variables of the tumor, others consider post-LT variables such as the histology of the tumor, and others combine pre- and post-LT variables. More recently, the HCC response to locoregional treatments before transplantation emerged as a surrogate marker of the biological aggressiveness of the tumor to be used as a better selection criterion for LT in patients beyond the MC at presentation. This essential review aims to present the current data on the pretransplant selection criteria for LT in patients with HCC exceeding the MC at presentation based on morphological and histological characteristics of the tumor and to critically discuss those that have been validated in clinical practice. Moreover, the role of HCC biological markers and the tumor response to downstaging procedures as new tools for selecting patients with a tumor burden outside of the MC for LT is evaluated.

Recurrent and Treatment-Unresponsive Spontaneous Bacterial Peritonitis Worsens survival in Decompensated Liver Cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) remains a major complication of cirrhosis. However, the incidence and the real impact of SBP in determining patient survival rates remain unclear. This study aims to evaluate the incidence and risk factors for SBP development and the role of SBP in predicting transplant-free survival. METHODS: Two hundred two consecutive patients underwent 492 paracenteses with biochemical and microbiological analysis of the ascitic fluid. When multiple paracenteses had been performed on a given patient, the first SBP-positive paracentesis or the first paracentesis conducted when none was diagnostic for SBP was included in the study. RESULTS: SBP was detected in 28 of 202 (13.9%) patients; in 26 of 28 patients, the neutrophil count in the ascitic fluid was ≥250 cells/µl, and in 15 of 28 patients, the cultures were positive. Variables independently associated with SBP were as follows: a higher model of end-stage liver disease (MELD) score, the serum glucose value, elevated CRP serum levels, and higher potassium serum levels. Overall, the median (range) transplant-free survival was 289 (54-1253) days. One hundred (49.5%) patients died, whereas 35 patients (17.3%) underwent liver transplantation. Independent predictors of death or liver transplantation were a higher MELD score and the development of SBP, especially if it was antibiotic-resistant or recurrent SBP. CONCLUSION: The occurrence of SBP is associated with more severe liver dysfunction in conjunction with the presence of inflammation. Unlike the occurrence of SBP per se, failure of first-line antibiotic treatment and SBP recurrence appear to strongly influence the mortality rate.

Challenges and future developments in liver transplantation.

Liver transplantation (LT) has become the treatment of choice for a wide range of liver diseases in both adult and pediatric patients. Until recently, the largest proportion of LT in adults, were performed in patients with hepatitis C (HCV) related cirrhosis. The recent availability of safe and effective direct antiviral agents to cure HCV infection in almost all patients whatever the HCV genotype and severity of liver disease, will reduce the need for LT in this category of recipients. Thus, it is presumed that in the next 1 to 2 decades HCV related liver disease will diminish substantially, whereas non-alcoholic steato-hepatitis (NASH) will correspondingly escalate as an indication for LT. The greatest challenges facing LT remain the limited supply of donor organs, and the need for chronic immunosuppression, which represent the true obstacles to the greater application and durable success of the LT procedure. This review aimed to highlight, in different sections, the main open issues and future developments in LT. These will be focused to explore current and future strategies to maximize the use of limited organs, to offer an update on potential new approaches to immunosuppression and to imagine new indications for LT when the number of patients awaiting transplants for HCV related liver disease is reduced.

[New organ allocation criteria in liver transplantation.] / Trapianto di fegato: nuovi criteri di allocazione.

The organ allocation modality in the liver transplant represents a fundamental step for the correct success of the transplantation procedure. The practical effects deriving from the adoption of the organ allocation models do not imply only clinical repercussions but also concern important ethical aspects. Alongside the general principles of fairness, justice and transparency, the organ allocation models should be aimed at providing for each patient who waits for an organ, the possibility of accessing it, preserving and maximizing the outcome of the transplant in terms of survival and quality of life. Balancing successfully the clinical and ethical aspects in an allocation model is particularly difficult and probably not completely feasible. In this brief review, the general principles governing the different models of organ allocation in liver transplantation are addressed. A particular description of the decision-making process that led to the sharing in Italy of a new allocation model based on the concept of the transplant benefit is illustrated. In this model we have tried to combine the two fundamental principles that for many years have guided the choice of allocation models, respectively based on the criteria of urgency and utility.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.

UNLABELLED: Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 µg thrice daily and up to 200 µg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. CONCLUSION: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

Vitamin A deficiency is associated with hepatitis C virus chronic infection and with unresponsiveness to interferon-based antiviral therapy.

UNLABELLED: Recent data suggest that vitamin A modulates the expression of type I interferon receptor enhancing the antireplication effect of interferon-α on hepatitis C virus (HCV). This study aimed to investigate the prevalence of vitamin A deficiency among patients with chronic HCV infection and to assess whether vitamin A deficiency could be associated with unresponsiveness to interferon-based antiviral therapy. The analysis included 199 consecutive treatment-naïve chronic HCV patients in whom pretreatment serum vitamin A and 25-OH vitamin D were measured; 119 healthy blood donors were used as controls. Median (interquartile range) serum vitamin A in HCV-positive patients was significantly lower than in controls: 256 ng/mL (128-440) versus 742 (624-942, P<0.0001). Overall sustained viral response was achieved in 122/199 patients, 46/109 infected by difficult to treat HCV genotypes. In these latter, 39/104 (37.5%) were nonresponders. At multivariate analysis, nonresponse to antiviral therapy was predicted by carriage of interleukin (IL)-28B T/* genotypes, baseline serum levels of γGT>60 IU/mL, of HCV RNA>600,000 IU/mL, of vitamin A≤100 ng/mL, and a cumulative dose of ribavirin≤80%. Seventeen patients (9.0%) had both serum levels of vitamin A≤100 ng/mL and of vitamin D≤20 ng/mL; the presence of a combined vitamin A and D deficiency was found to be a strong independent predictor of nonresponse to antiviral therapy. CONCLUSION: A high percentage of patients with chronic HCV infection have serum vitamin A deficiency. This condition is associated with nonresponse to antiviral therapy.

Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C.

UNLABELLED: Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after antiviral treatment in hepatitis C virus (HCV) difficult-to-treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of antiviral responses in patients affected by chronic hepatitis C. In all, 206 HCV patients treated with a combination therapy of pegylated (PEG)-interferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A, and IL-28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G = 64 (31.1%), G/T = 100 (48.5%), T/T = 42 (20.4%) and C/C = 108 (52.4%), C/A = 84 (40.8%), A/A = 14 (6.8%). Patients were divided into those carrying ≥3 major alleles (wildtype [WT]+: G-C/G-C, G-C/T-C, G-C/G-A, N = 100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N = 106). Four groups were identified: vitamin D ≤20 ng/mL and WT-, vitamin D ≤20 and WT+, vitamin D >20 and WT-, vitamin D >20 and WT+. In difficult-to-treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (P = 0.003). At multivariate analysis, having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (odds ratio 4.52, P = 0.015). CONCLUSION: In difficult-to-treat HCV genotypes, simultaneous pretreatment normal serum vitamin D levels and the carriage of GC-globulin WT isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy.

Recipient interleukin-28B Rs12979860 C/T polymorphism and acute cellular rejection after liver transplantation: role of the calcineurin inhibitor used.

BACKGROUND: Interleukin-28 (IL-28B) rs12979860 C/T polymorphism is known to predict the outcome of antiviral therapy in hepatitis C. In addition to its interferon-like and antiviral functions, IL-28B possesses the ability to modulate CD8 T cells function. This study aimed to investigate whether recipient IL-28B polymorphism may have a role in predicting the occurrence of acute cellular rejection (ACR) after liver transplantation (LT). METHODS: Two hundred fifty-one consecutive LT recipients were enrolled. All the patients underwent per protocol liver biopsies at 1, 3, and 12 months after LT. ACR episodes in the first post-LT year were recorded and graded according to the Banff score. RESULTS: At least one moderate to severe (Banff score ≥ 5) ACR episode was reported in 75 patients (29.9%). ACR was associated with IL-28B polymorphism: C/C=21/102 (20.6%), C/T=43/126 (34.1%), and T/T=11/23 (47.8%) (P=0.003). At logistic regression analysis, IL-28B polymorphism was found to be a predictor of ACR (P=0.012) together with cytomegalovirus reactivation (P=0.023). The association between IL-28B polymorphism and ACR occurrence was evident in tacrolimus but not in cyclosporine-treated patients. ACR episodes occurred more frequently from hepatitis C virus (HCV) negatives carrying the IL-28B C/C genotype (17.8%) to HCV negatives carrying at least one T allele or HCV positives carrying at least one C allele (33.3%) to HCV positives carrying the T/T genotype (50.0%, P=0.002). CONCLUSIONS: HCV etiology in association with the carriage of IL-28B T/T genotype predicted the highest frequency of ACR. Recipient's IL-28B genotyping could be a useful tool in individualizing immunosuppressive therapy according to the risk of ACR occurrence.

Association between vitamin D receptor genetic polymorphisms and acute cellular rejection in liver-transplanted patients.

Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver-transplanted patients surviving at least 1month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P=0.017) and TaqI (T: 0.667 vs. 0.543, P=0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P=0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P=0.006), with CMV reactivation (OR 2.34, P=0.033) and HCV aetiology (OR 1.86, P=0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy.

Association between the epidermal growth factor rs4444903 G/G genotype and advanced fibrosis at a young age in chronic hepatitis C.

BACKGROUND: The epidermal growth factor (EGF) rs4444903 A>G polymorphism has been associated with the development of liver cancer, which commonly complicates cirrhosis of viral origin; however, whether this polymorphism might be associated with fibrosis progression in chronic viral hepatitis is unknown. The present study was performed to assess the allelic and genotypic frequencies of the rs4444903 A>G polymorphism in patients with chronic hepatitis C virus HCV infection and to ascertain whether this polymorphism might be an independent predictor of the degree of fibrosis. METHODS: An RFLP-PCR technique was used to genotype 645 patients (211 with cirrhosis); 528 were referred for the diagnosis and treatment of chronic hepatitis C, and 117 were transplanted for HCV-related end stage liver disease. A group of 428 healthy subjects served as a control. All the subjects were of Caucasian ethnicity. RESULTS: The EGF rs4444903 A>G polymorphism genotype frequencies in HCV chronic infected patients were as follows: A/A=227 (35.3%), A/G=328 (50.9%), and G/G=90 (14.8%). Genotype frequencies were found to differ between patients with an Ishak staging score⩽2 (A/A=117, A/G=157, G/G=34) and patients with a score>2 (A/A=110, A/G=171, G/G=56, p=0.038). A highly significant linear relationship between increasing stage scores and EGF genotype was detected in younger patients (A/A: 2.02±0.18, A/G: 2.55±0.17, G/G: 3.00±0.32, p=0.008). However, no significant association was detected between the stage score and EGF genotype in older patients (A/A: 3.79±0.19, A/G: 3.64±0.15, G/G: 3.98±0.30 p=0.579). CONCLUSIONS: The EGF rs4444903 A>G polymorphism may facilitate liver fibrosis progression in Caucasian patients with chronic hepatitis C, especially in younger patients.

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. METHODS: This study included 483 (344 males) consecutive Italian patients of Caucasian ethnicity affected by cirrhosis, of whom 279 had undergone transplantation for end-stage liver disease while 204 had been referred to our liver and transplant unit for the diagnosis of cirrhosis. The aetiologies were hepatitis C virus=209, hepatitis B virus=76, alcohol=166, metabolic=32. Ile148Met rs738409 transversion was genotyped using an restriction fragment length polymorphism-based assay. RESULTS: The genotype frequencies of the rs738409 polymorphism were distributed differently in patients with cirrhosis C/C=168, C/G=220, G/G=95 vs controls C/C=218, C/G=175, G/G=35 (P<0.0001). Among cirrhotics, the G allele was over-represented in alcoholic/metabolic (0.505) vs viral (0.368, P<0.001) liver disease. Patients with cirrhosis complicated by HCC were more likely to be G/G homozygotes (38/141) than the remaining patients (57/342, P<0.02). At multivariate analysis, the PNPLA3 rs738409 polymorphism was confirmed to be an independent predictor of HCC occurrence (odds ratio 1.76, 95% confidence interval 1.06-2.92, P<0.05). HCC rates increased from 13/116 (11.2%; female C/(*) carriers), to 97/295 (32.9%; male C/(*) carriers and female G/G homozygotes), to 31/72 (43.1%; male G/G homozygotes) (P<0.0001). CONCLUSIONS: The PNPLA3 rs738409 C>G polymorphism is associated with cirrhosis. In synergy with gender, this polymorphism is a strong predictor of HCC occurrence among patients with cirrhosis.

Role of interleukin 28B rs12979860 C/T polymorphism on the histological outcome of chronic hepatitis C: relationship with gender and viral genotype.

BACKGROUND: This 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. METHODS: An RFLP-PCR technique was used to genotype 629 HCV-positive patients (200 with cirrhosis) and 428 healthy control subjects. RESULTS: The 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). CONCLUSIONS: IL-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.