Antonio Molinaro

Glial fibrillary acidic protein as an early marker of hepatic stellate cell activation in chronic and posttransplant recurrent hepatitis C

Activated alpha‐smooth muscle actin (α‐SMA)–positive hepatic stellate cells (HSCs) are pericytes responsible for fibrosis in chronic liver injury. The glial fibrillary acidic protein (GFAP), commonly expressed by astrocytes in the central nervous system, is expressed in vivo in the liver in a subpopulation of quiescent stellate cells. In the rat, increased GFAP expression in the acute response to injury and down‐regulation in the chronic response have been observed, whereas reports concerning GFAP expression in human liver are still conflicting. We investigated the utility of GFAP compared to α‐SMA as an immunohistochemical marker of early activated HSCs in chronic and posttransplant recurrent hepatitis C and correlated GFAP expression with vascular remodeling and fibrosis progression. With immunohistochemistry and a semiquantitative scoring system, the expression of GFAP and α‐SMA in HSCs and the microvessel density were analyzed in biopsies from normal livers obtained from cadaveric donors [donor liver (DL); n = 21] and from livers from posttransplant hepatitis C virus recurrent hepatitis (HCV‐PTR) patients (n = 19), hepatitis C virus chronic hepatitis (HCV‐CH) patients, (n = 12), and hepatitis C virus cirrhosis (HCV‐C) patients (n = 16). The percentage of α‐SMA–positive HSCs was significantly higher in the HCV‐PTR, HCV‐CH, and HCV‐C groups compared to the DL group (P < 0.01). The percentage of GFAP‐positive HSCs was significantly higher in the HCV‐PTR group compared to the DL, HCV‐C (P < 0.01), and HCV‐CH (P < 0.05) groups and in the HCV‐CH group compared to the DL group (P < 0.01), inversely correlating with the extent of fibrosis and microvessel density (P < 0.01). In the HCV‐PTR group, the percentage of GFAP‐positive HSCs correlated with fibrosis progression (P < 0.01). In conclusion, GFAP could represent a useful marker of early activation of HSCs in HCV‐CH and seems to predict fibrosis progression in HCV‐PTR. Liver Transpl 14:806–814, 2008.

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis

Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at‐risk alcohol consumption are available. Moreover, patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross‐sectional studies. The aim of this study was to investigate the role of age at onset of at‐risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence.

Preoperative donor scores and postoperative early measures of graft function: relevance to the outcome of liver transplantation.

BACKGROUND Several donor and recipient parameters play a role in the determination of post-liver transplant allograft function. The identification of prognostic indices presents great implications for correct allocation of donors and more targeted recipient management. The aim of our review was to detect the role of preoperative scoring systems and early postoperative measures of graft function as predictive factors for the development of graft failure and recipient death. METHODS We stratified a cohort of 97 patients in two groups according to a 1-year functional (Group A; n = 72) versus non-functional (Group B; n = 25) status of the allograft. RESULTS Patients in group B showed higher preoperative Model for End-stage Liver Disease (MELD) values, longer warm ischemia times, reduced bile outputs and increased peak values of transaminases and INR content within the first 3 days after transplantation. Group B showed 48% of patients with initial poor graft function. The parameters which resulted in a significant prediction of graft loss by multivariate analysis were MELD (P = .012); postoperative day 1 serum alanine aminotransferase (ALT) (P < .0001) and day 3 ALT (P = .003). The predictive factors for patient death were postoperative day 1 serum ALT (P < .0001) and day 3 ALT (P = .001). CONCLUSIONS MELD score was a useful preoperative parameter for the prediction of post-transplant graft survival. Early ALT values predicted both graft and recipient survivals. Minimization of parameters related to their peaks (warm ischemia time) may improve graft and patients survival rates.

D-Lactic acidosis 25 years after bariatric surgery due to Salmonella enteritidis

D-Lactic acidosis is a rare complication that occurs in patients with short bowel syndrome due to surgical intestine resection for treatment of obesity. The clinical presentation is characterized by neurologic symptoms and high anion gap metabolic acidosis. The incidence of this syndrome is unknown, probably because of misdiagnosis and sometimes symptoms may be incorrectly attributed to other causes. Therapy is based on low carbohydrate diet, sodium bicarbonate intravenous, rehydratation, antiobiotics, and probiotics that only produce L-lactate. In the case we describe, D-lactic acidosis encephalopathy occurred 25 y after bypass jejunoileal, due to Salmonella enteriditis infection.

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.

Does Caval Reconstruction Technique Affect Early Graft Function after Liver Transplantation? A Preliminary Analysis

BACKGROUND In the past decades, the inferior vena cava (IVC) reconstruction technique has undergone several evolutions, such as biopump, piggyback technique (PB), and laterolateral approach (LLPB). Several advantages are reported comparing the PB technique to biopump use. However, comparison between PB and LLPB has not been as well investigated. The aim of this study was to compare the results in terms of immediate graft function and intermediate graft survival among 3 subgroups characterized by distinct caval reconstruction techniques. METHODS We retrospectively analyzed a cohort of 200 consecutive adult patients who underwent liver transplantation from January 2001 to December 2009. The patients were stratified according to 3 caval reconstructive techniques: biopump (n=135), PB (n=32) and LLPB (n=33). RESULTS The LLPB group showed the shortest cold and warm ischemia times and the best immediate postoperative graft function. Survival analysis revealed LLPB patients to present the best 1-year graft survival rates: namely, 90.9% versus 75.0% and 74.1% among the PB and biopump groups, respectively (log-rank tests: LLPB vs biopump: P=.03; LLPB vs PB: P=.05). In our experience, LLPB showed the best graft survivals with an evident reduction in both cold and warm ischemia times. However, it is hard to obtain an irrefutable conclusion owing to the retrospective nature of this study, the small sample, and the different periods in which the groups were transplanted. CONCLUSIONS LLPB technique was a safe procedure that minimized the sequelal of ischemia-reperfusion damage. This technique yielded results superior to venovenous bypass. No definitive conclusions can to be obtained in this study comparing classic PB or LLPB.

Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation

BACKGROUND Knowledge regarding the plasma fatty acid (FA) pattern in patients with liver cirrhosis is fragmentary. OBJECTIVE We evaluated plasma FA lipidome and its association with the prognosis of cirrhosis and severity of liver graft damage after transplantation. DESIGN In this observational study, plasma FA lipidome was investigated in 51 cirrhotic patients before liver transplantation and in 90 age- and sex-matched healthy control subjects. In addition, we studied ischemia-reperfusion damage in the liver of 38 patients for whom a graft biopsy was available at transplantation. With the use of logistic regression, we modeled the presence of cirrhosis, the dichotomized model for end-stage liver disease score below and above the median, and the presence of severe liver graft ischemia-reperfusion damage. RESULTS The FA pattern was markedly altered in cirrhotic patients, who showed, compared with healthy controls, higher monounsaturated FAs, lower n-6 and n-3 polyunsaturated FAs, and undetectable cerotic acid. Plasma di-homo-γ-linolenic acid was independently associated with the presence of cirrhosis (OR: 0.026; 95% CI: 0.004, 0.196; P < 0.0001), severity of its prognosis (OR: 0.041; 95% CI:0.005, 0.376; P = 0.006), postreperfusion graft hepatocellular necrosis (OR: 0.921; 95% CI: 0.851, 0.997; P = 0.043), and sinusoidal congestion (OR: 0.954; 95% CI: 0.912, 0.998; P = 0.039). Associations of di-homo-γ-linolenic acid with the presence of cirrhosis and severity of its prognosis were confirmed also after false discovery rate correction. CONCLUSIONS Cerotic and di-homo-γ-linolenic acids may serve as markers of disease and prognosis in liver cirrhosis. Dietary supplementation with di-homo-γ-linolenic acid could be a reasonable interventional strategy to delay disease progression in liver cirrhosis.

Differential vascular endothelial growth factor A protein expression between small hepatocellular carcinoma and cirrhosis correlates with serum vascular endothelial growth factor A and α‐fetoprotein

Background/Aims: Drugs with antivascular endothelial growth factor A (anti‐VEGF‐A) action are under clinical evaluation with encouraging results in advanced hepatocellular carcinoma (HCC). The relative VEGF‐A protein expression in non‐advanced HCC and in the cirrhotic non‐tumoral tissue in the same patient, a variable that could be important for treatment efficacy, has been investigated with conflicting results, only using the cirrhotic tissue surrounding the neoplasm (CS).

Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome

We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome.

Corrigendum: PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease.

Corrigendum: PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease