Emiliano Giostra

Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3.

BACKGROUND/AIMS Patients infected with the hepatitis C virus (HCV) often have liver steatosis, suggesting the possibility of a viral cytopathic effect. The aim of this study was to correlate the occurrence and severity of liver steatosis with HCV RNA type, level and sequence of the core-encoding region. METHODS We scored the liver steatosis in 101 HCV-infected individuals carefully selected to exclude other risk factors of a fatty liver. Results were compared with HCV RNA genotype and level in serum and liver. In selected patients, we assessed the effect of antiviral therapy on steatosis and the relationship between nucleocapsid sequence heterogeneity and fat infiltration. RESULTS Steatosis was found in 41 (40.6%) patients, irrespective of sex, age or route of infection. HCV genotype 3 was associated with higher steatosis scores than other genotypes. A significant correlation between steatosis score and titer of intrahepatic HCV RNA was found in patients infected with genotype 3, but not in those infected with genotype 1. In selected patients, response to alpha-interferon was associated with the disappearance of steatosis. Analysis of the nucleocapsid of 14 HCV isolates failed to identify a sequence specifically associated with the development of steatosis. CONCLUSIONS We provide virological and clinical evidence that the steatosis of the liver is the morphological expression of a viral cytopathic effect in patients infected with HCV genotype 3. At variance with published evidence from experimental models, the HCV nucleocapsid protein does not seem to fully explain the lipid accumulation in these patients.

Performance of endosonography-guided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions

OBJECTIVE:Preoperative diagnosis of cystic lesions of the pancreas remains difficult despite improvement in imaging modalities and cystic fluid analysis. The aim of our study was to assess the performance of endoscopic ultrasonography (EUS) and EUS-guided fine needle aspiration (FNA) in the diagnosis of pancreatic cystic lesions.METHODS:Data from a series of 127 consecutive patients with pancreatic cystic lesions were prospectively studied. EUS and EUS-guided FNA were performed in all patients, and cystic material was used for cytological and histological analysis as well as for biochemical and tumor markers analysis. Performance of EUS diagnosis, biochemical and tumor markers, and FNA diagnosis were compared with the final histological diagnosis obtained at surgery or postmortem examination. Sixty-seven patients underwent surgery and therefore constituted our study group.RESULTS:EUS provided a tentative diagnosis in 113 cases (89%). Cytohistological FNA provided a diagnosis in 98 cases (77%). When the results of EUS and EUS-guided FNA were compared with the final diagnosis (67 cases), EUS correctly identified 49 cases (73%), whereas FNA correctly identified 65 cases (97%). Sensitivity, specificity, positive predictive value, and negative predictive value of EUS and EUS-guided FNA to indicate whether a lesion needed further surgery were 71% and 97%, 30% and 100%, 49% and 100%, and 40% and 95%, respectively. Carbohydrate antigen 19–9 > 50,000 U/ml had a 15% sensitivity and a 81% specificity to distinguish mucinous cysts from other cystic lesions, whereas it had a 86% sensitivity and a 85% specificity to distinguish cystadenocarcinoma from other cystic lesions.CONCLUSIONS:EUS-guided FNA is a valuable tool in the preoperative diagnostic assessment of pancreatic cystic lesions.

Steatosis affects chronic hepatitis C progression in a genotype specific way

Background and aims: Liver steatosis is frequent in chronic hepatitis C, particularly in patients infected with hepatitis C virus (HCV) genotype 3. The aim of this study was to determine the relationship between steatosis and fibrosis in chronic hepatitis C as a function of viral genotype. Methods: A multivariable logistic regression analysis was carried out in 755 chronic hepatitis C patients (mean body mass index (BMI) 24.11 kg/m2; 178 with genotype 3), consecutively admitted to three referral hospitals. Liver histology showed steatosis in 315 and fibrosis in 605 patients, of whom 187 had cirrhosis (78 compensated and 109 decompensated). Results: Steatosis was independently associated with fibrosis (p<0.001), genotype 3 (p<0.001), BMI (p<0.001), ongoing alcohol abuse (p<0.001), and age (p = 0.001). Fibrosis was associated with the Metavir activity score (p<0.001), age (p<0.001), steatosis (p = 0.001), past alcohol abuse for >5 years (p = 0.015), and BMI (p = 0.034). When regression analysis was repeated on patients divided according to viral genotype (that is, 3 v non-3) to identify type specific risk factors, steatosis was associated with ongoing alcohol abuse (p<0.001) and age (p = 0.01) only in non-3 genotype infected patients and with Metavir activity (p = 0.044) only in genotype 3 infected patients. Similarly, fibrosis was associated with steatosis only in genotype 3 infected individuals (p = 0.018), and with past alcohol abuse (p = 0.003) and (marginally) diabetes (p = 0.078) only in non-3 genotype infected patients. Conclusions: Steatosis influences chronic hepatitis C progression in a genotype specific way. Patients infected with genotype 3 and histologically confirmed steatosis should not be deferred from effective antiviral therapy.

Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial

Background: In chronic pancreatitis, obstruction of the main pancreatic duct (MPD) may contribute to the pathogenesis of pain. Pilot studies suggest that extracorporeal shock wave lithotripsy (ESWL) alone relieves pain in calcified chronic pancreatitis. Aim: To compare ESWL alone with ESWL and endoscopic drainage of the MPD for treatment of pain in chronic pancreatitis. Subjects: Patients with uncomplicated painful chronic pancreatitis and calcifications obstructing the MPD. Methods: 55 patients were randomised to ESWL alone (n = 26) or ESWL combined with endoscopy (n = 29). Results: 2 years after trial intervention, 10 (38%) and 13 (45%) patients of the ESWL alone and ESWL combined with endoscopy group, respectively, had presented pain relapse (primary outcome) (OR 0.77; 95% CI 0.23 to 2.57). In both groups, a similar decrease was seen after treatment in the MPD diameter (mean decrease 1.7 mm; 95% CI 0.9 to 2.6; p<0.001), and in the number of pain episodes/year (mean decrease, 3.7; 95% CI 2.6 to 4.9; p<0.001). Treatment costs per patient were three times higher in the ESWL combined with endoscopy group compared with the ESWL alone group (p = 0.001). The median delay between the onset of chronic pancreatitis and persistent pain relief for both groups was 1.1 year (95% CI 0.7 to 1.6), as compared with 4 years (95% CI 3 to 4) for the natural history of chronic pancreatitis in a reference cohort (p<0.001). Conclusions: ESWL is a safe and effective preferred treatment for selected patients with painful calcified chronic pancreatitis. Combining systematic endoscopy with ESWL adds to the cost of patient care, without improving the outcome of pancreatic pain.

Hepatitis associated with Kava, a herbal remedy for anxiety.

Kava, the rhizome of the pepper plant Piper methysticum , has been widely used in the South Pacific as a narcotic drink. Lactones, the major constituents of kava, are considered to be pharmacologically active and are sold in Europe and the United States as standardised extracts for anxiety and tension. A 50 year old man presented to his doctor because of jaundice. He had noticed fatigue for a month, a “tanned” skin, and dark urine. The medical history was unremarkable …

‘Liver First’ Approach in the Treatment of Colorectal Cancer with Synchronous Liver Metastases

Background: In patients with synchronous colorectal liver metastases, an approach reversing the traditional therapeutic order – i.e. starting with chemotherapy first, doing the liver surgery second, and performing the colorectal surgery last – is theoretically appealing as it avoids the risk of metastatic progression during treatment of the primary tumor. The present series updates on a previously reported pilot experience. Patients and Methods: 35 patients with advanced synchronous colorectal metastases and nonobstructive colorectal tumors were treated with the reversed approach. Data were collected in a prospective database. Results: The median number of metastases was 6, the median size of the largest metastasis was 6 cm. Five patients could not complete the program (one death from sepsis during chemotherapy, 3 cases of progressive disease under treatment, and one case of vanishing liver metastases). The remaining 30 patients responded and underwent R0 liver resections with no major complications. One patient needed a Hartmann’s procedure for obstruction after a first-step hepatectomy, and 1 patient had a rectal anastomotic leak. Median survival was 44 months. Overall survival rates of the 30 patients who completed the program at 1, 2, 3, 4 and 5 years were 100, 89, 60, 44 and 31%. Conclusions: The reverse approach appeared feasible and safe, with operability and survival rates better than expected for patients with similar severity. Potential problems, in particular regrowth of vanishing metastases and primary tumors, chemotherapy-associated liver damage, and large bowel obstruction, can be minimized by careful multidisciplinary selection, planning and execution.

Granulocyte-Colony Stimulating Factor Induces Proliferation of Hepatic Progenitors in Alcoholic Steatohepatitis : A Randomized Trial

Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte‐colony stimulating factor (G‐CSF) mobilizes hematopoietic stem cells, induces liver regeneration, and improves survival. We studied the short‐term effects of G‐CSF on CD34+ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty‐four patients (mean age 54 years) with alcoholic cirrhosis [Child‐Turcotte‐Pugh score 10 (7–12)] and concomitant biopsy‐proven ASH [Maddrey score 36 (21‐60)] were randomized to standard care associated with 5 days of G‐CSF (10 μg/kg/day, group A, n = 13) or standard care alone (group B, n = 11). Serial measurement of CD34+ cells, liver tests, cytokines [hepatocyte growth factor (HGF); tumor necrosis factor α; tumor necrosis factor‐R1; interleukin‐6; alfa‐fetoprotein], and 13C‐aminopyrine breath tests were performed. Proliferating hepatic progenitor cells [HPC; double immunostaining (Ki67/cytokeratin 7)], histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G‐CSF was well tolerated. At day 7, both CD34+ cells (+747% versus −6%, P < 0.003), and HGF (+212% versus −7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67+/cytokeratin 7+ cells correlated with changes in CD34+ cells (r = 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups. Conclusion: G‐CSF mobilizes CD34+ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function. (HEPATOLOGY 2008.)

Non-Alcoholic Fatty Liver Disease in Liver Transplant Recipients: Another Story of “Seed and Soil”

OBJECTIVES:Fatty liver disease is a potential long-term complication of liver transplantation (LT). We therefore aimed to determine the prevalence and risk factors of liver steatosis in a large population of adult post-LT patients.METHODS:We evaluated the clinical, biological, histological, and evolutive features of patients with a diagnosis of steatosis made at liver biopsy examination during post-LT follow-up. Risk factors were analyzed by univariate and multivariate analysis.RESULTS:In total, 1,596 liver biopsies from 599 patients were available. Recurrent liver disease was present in 178 patients. A histological diagnosis of steatosis was made in 131 (31.1%) of the remaining 421 patients (51.1% had normal liver tests): 53% had grade 1, 31% grade 2, and 16% grade 3 steatosis. Perisinusoidal fibrosis was present in 38 patients (29.0%). Histological lesions were consistent with the diagnosis of non-alcoholic steatohepatitis (NASH) in 5 patients (3.8%). At the end of follow-up, cirrhosis or extensive fibrosis was observed in 3 patients (2.25%). Multivariate analysis showed that seven factors (post-LT obesity, tacrolimus-based regimen, diabetes mellitus, hyperlipidemia, arterial hypertension, alcoholic cirrhosis as primary indication for LT, and pre-transplant liver graft steatosis) were risk factors for post-LT steatosis. When zero, one, two, three, four, five, and six factors were present, steatosis occurred in 6.0, 12.0, 22.1, 29.9, 65.5, 81.5, and 100.0%, respectively.CONCLUSIONS:Liver steatosis is a frequent late complication of LT; its development depends on a combination of host and graft factors. LT is therefore an interesting model to study the natural history and the determinants of liver steatosis.

Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication

HCV infection has a severe course of disease in HIV/HCV co‐infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV‐specific T‐cell responses in 86 HCV mono‐infected patients, 48 HIV/HCV co‐infected patients and 42 liver transplant recipients. IFN‐γ and IL‐2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV‐derived peptides. We observed that HCV‐specific T‐cell responses were polyfunctional in HCV mono‐infected patients, with presence of proliferating single IL‐2‐, dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD4+ and dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD8+ cells. In contrast, HCV‐specific T‐cell responses had an effector profile in HIV/HCV co‐infected individuals and liver transplant recipients with absence of single IL‐2‐producing HCV‐specific CD4+ and dual IL‐2/IFN‐γ‐producing CD8+ T cells. In addition, HCV‐specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co‐infected patients and liver transplant recipients. Importantly, “only effector” T‐cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune‐based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV‐1 co‐infection and liver transplantation.

Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study.

BACKGROUND & AIMS Complications and technical problems of paracentesis in cirrhotic patients are infrequent. However, the severity and the incidence of these events and their risk factors have not been assessed prospectively. METHODS Cirrhotic patients (n = 171) undergoing paracentesis were included. Of the 515 paracenteses, 8.8% were diagnostic, and 91.2% were therapeutic. Technical features, demographic data, and adverse events during a period of 72 hours after the procedure were examined. RESULTS Major complications occurred in 1.6% of procedures and included 5 bleedings and 3 infections, resulting in death in 2 cases. Major complications were associated with therapeutic but not diagnostic procedures and tended to be more prevalent in patients with low platelet count (<50 10(9)/L), Child-Pugh stage C, and in alcoholic cirrhosis patients. Technical problems occurred in 5.6%. The most frequent complication was a leak of ascites at the puncture site (5.0%), and in 89.5% there were no complications. CONCLUSIONS The safety of paracentesis in cirrhotic patients might be decreased if risk factors, which depend on the characteristics of the patient and of the procedure itself, are present.