Time-Varying mHAP-III Is the Most Accurate Predictor of Survival in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

INTRODUCTION: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). METHODS: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. RESULTS: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10-1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. CONCLUSION: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.

Transjugular intrahepatic portosystemic shunt (TIPS): current indications and strategies to improve the outcomes.

Transjugular intrahepatic portosystemic shunt (TIPS) represents a very effective treatment of complications of portal hypertension. Established indications to TIPS in cirrhotic patients include portal hypertensive bleeding and refractory ascites. Over the years additional indications have been proposed, such as the treatment of vascular disease of the liver, hepatic hydrothorax, hepatorenal syndrome and bleeding from ectopic varices. Indications under evaluation include treatment of portal hypertension prior to major abdominal surgery and treatment of portal vein thrombosis. In spite of these advances, there are still uncertainties regarding the appropriate workup for patients to be scheduled for TIPS. Moreover, prevention and management of post-TIPS complications including hepatic encephalopathy and heart failure are still suboptimal. These issues are particularly relevant considering aging in TIPS candidates in Western countries. Correct selection of patients is mandatory to prevent complications which may eventually frustrate the good hemodynamic results and worsen the patient's quality of life or even life expectancy. The possible role of small diameter TIPS to prevent post-procedural complications is discussed.

Epidemiological, demographic and clinical data on chronic viral hepatitis C in Tuscany.

BACKGROUND: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries' economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy. METHODS: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress. RESULTS: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44 ± 15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin's lymphoma in 10.5%). CONCLUSIONS: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.

Aldoxorubicin and Temozolomide combination in a xenograft mice model of human glioblastoma.

Glioblastoma Multiforme (GBM) is still an incurable disease. The front-line Temozolomide (TMZ)-based therapy suffers from poor efficacy, underlining the need of new therapies. Preclinically, Aldoxorubicin (Aldox), a novel prodrug of Doxorubicin (Dox), has been successfully tested against GBM, encouraging the study of its association with other agents. For the first time, we evaluated the effectiveness of Aldox combined to TMZ in preclinical models of GBM. Our in vitro results demonstrated that the anti-glioma effect of Aldox was more marked than TMZ and their combination increased the killing effect of the anthracycline in TMZ-resistant GBM cells. Moreover, unlike Dox, Aldox was able to accumulate in P-glycoprotein (P-gp)-overexpressed cells due to a negative regulation of the P-gp function. We also compared efficacy and safety of weekly administrations of Aldox (16 mg/kg), with or without TMZ (0.9 mg/kg, daily injections), in the U87 xenograft mouse model. Aldox therapy induced a moderate tumor volume inhibition (TVI) and an increased survival rate (+12.5% vs vehicle). On the other hand, when combined to TMZ, Aldox caused a significant TVI (P=0.0175 vs vehicle) and delayed the mortality during the experimental period, although TVI and endpoint survival percentage (+37.5% vs vehicle) were not significantly different from TMZ alone. Our preliminary data showed that Aldox exerts anti-glioma effects in vitro and in vivo. It also enhances its antitumor activity when combined with TMZ, resulting in a superior efficacy compared to the single agents, without adverse side effects.

Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma.

Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months. Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ. The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy. The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models. The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB. In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM. Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy. Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments. In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy.

Non-invasive assessment of liver fibrosis in patients with HBV-related chronic liver disease undergoing antiviral treatment: A preliminary study.

In chronic hepatitis B (CHB) patients, fibrosis assessment during antiviral treatment is a key step in the clinical management. Aim of this study was to evaluate the performance of elastography in assessing fibrosis stage in CHB before and after two years of nucleoside/nucleotide analogues (NUC) treatment in comparison with indirect serum markers. CHB diagnosis was made according to standard criteria. A clinical and virological evaluation was performed at baseline and again at 3, 6, 9, 12 18, and 24 months during treatment. Fibrosis was evaluated by liver biopsy, elastography and indirect serum markers. Of 75 patients, 50 had CHB, HBeAg negative and were deemed eligible for this study. Of these, 22 underwent liver biopsy. Mean histo-morphometric values of fibrotic tissue differed significantly in the stage < S3 vs. stage ≥S3: 2.01±2.62% vs. 12.85±7.31% (p=0.03), respectively. At 18 and 24 months, stiffness values were statistically reduced from those previously observed (P=0.03 and P<0.001). At 24 months the values of APRI, FIB-4 and LOK were not different from baseline values, while the value of FORNS score at 24 months was the only one statistically reduced. In two patients with fibrosis stage S3 and S6, respectively, fibrosis regressed to stage S2 and S5. In conclusion, the results of the present study show that liver histology, stiffness and FORNS score improve significantly during a long-term follow-up of HBV patients successfully treated with NUC. These results strongly suggest that the non-invasive evaluation of liver fibrosis represents a key step in the management and treatment of chronic HBV hepatitis.

Assessment of liver fibrosis in primary biliary cholangitis: Comparison between indirect serum markers and fibrosis morphometry.

BACKGROUND: The accuracy of non-invasive methods for the quantification of liver fibrosis in primary biliary cholangitis (PBC) is still debated. AIMS: To determine the histo-morphometric measurement of fibrotic tissue and to explore the possible association between indirect markers (APRI, FORNS, FIB-4, and Lok) and morphometry. METHODS: Retrospective analysis of medical data from patients with PBC, on whom needle liver biopsy was performed as part of the diagnostic assessment. One section of each biopsy stained with Sirius red was used for calculating the percentage of collagen. Quantitative measure of fibrotic tissue (fibrosis morphometry) was calculated as a percentage of collagen content by digital image analysis. Morphometry results were divided into four groups reflecting Ludwig's staging and compared with values for indirect serum markers. RESULTS: 50 PBC patients were enrolled (86% females, mean age 57 ± 12.30 years), 19 were Ludwig's stage I (38%), 14 stage II (28%), 12 stage III (24%), and five stage IV (10%). Morphometry results were significantly different among Ludwig stages (p<0.05). No significant differences were found for indirect serum markers. A significant correlation was found between morphometry results and indirect serum markers tested (p<0.05). CONCLUSION: In our cohort, the histo-morphometric values of fibrotic tissue increased progressively with Ludwig's stages of PBC, while non-invasive markers did not.

Screening of distress among hospitalized patients in a department of internal medicine.

A psychosomatic approach to the basic screening of distress for patient care in hospitals and other health services is presented. The aims of this study were to verify association between: (1) medical illnesses and distress; (2) patients' needs and distress; (3) type of illness and patients' needs; (4) patients' needs and sense of coherence. One hundred and eighty-nine patients (78 F and 111 M, average age 65 years±8.43) were assessed by self-report questionnaires. We found that higher anxiety and/or depression levels were associated with urogenital (p=0.026), rheumatologic (p=0.006), oncological (p=0.011), neurological (p=0.026) and respiratory (p=0.013) illnesses. Higher distress scoring was associated with rheumatologic illnesses (p=0.024) and illnesses of the liver and digestive system (p=0.037) while a higher severity of distress was associated with oncological illnesses (p=0.011). Depression/anxiety were associated with the need to speak to a psychologist (p=0.050), to a spiritual advisor (p=0.009), to be more reassured by relatives (p=0.017), to feel less abandoned (p=0.036). Only low sense of coherence was associated with the need for greater dialogue with physicians (p=0.012), the need to participate less in treatment decisions (p=0.041), the need to feel less left to one's own devices (p=0.023). Several needs are associated with medical illnesses. In conclusion, these results indicate that early psychological screening could be important to avoid worse or chronic distress.

Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study.

AIM: To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. METHODS: LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. RESULTS: LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. CONCLUSION: Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.

Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study.

UNLABELLED: Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV(+) patients belonging to the following groups: MC syndrome (MCS)-HCV (121 patients with symptomatic MC), MC-HCV (132 patients with asymptomatic MC), and HCV (158 patients without MC). Pegylated interferon plus ribavirin treatment was administered according to standard protocols. Posttreatment follow-up ranged from 35 to 124 months (mean 92.5 months). A significant difference was observed in the rate of sustained virological response between the HCV group and both the MC-HCV (P = 0.009) and MC-HCV+MCS-HCV (P = 0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of nonresponse. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with sustained virological response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virological response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virological nonresponders were also clinical nonresponders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of interferon-based therapy on HCV patients with and without MC and with and without symptoms, as well as the long-term effects of viral eradication on MC. CONCLUSION: MC is a negative prognostic factor of virological response. Clearance of HCV led to persistent resolution or improvement of MCS, strongly suggesting the need for a next generation of highly effective antiviral drugs.

Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib.

AIM: To investigate in greater detail the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma (HCC) in patients with established cirrhosis. METHODS: From October 2009 to July 2012 patients with an established diagnosis of cirrhosis and HCC treated with sorafenib were consecutively enrolled. According to the Barcelona Clinic Liver Cancer (BCLC) classification, patients were in the advanced stage (BCLC-C) or in the intermediate stage (BCLC-B) but unfit or unresponsive to other therapeutic strategies. Treatment was evaluated performing a 4-phase computed tomography or magnetic resonance imaging scan every 2-3 mo, and analyzed according to the modified Response Evaluation Criteria in Solid Tumors. Sorafenib was administered at 800 mg/d, until radiological progression or occurrence of unacceptable adverse events (AEs). Univariate and multivariate analyses identified predictors of 16-wk clinical benefit and overall survival. RESULTS: Forty-four patients were enrolled, 15 had intermediate HCC and 14 a Child-Pugh score of B7. AEs caused treatment interruption in 19 patients (43%), and median treatment duration was shorter in this subset (5 wk vs 19 wk, P < 0.001) and in the BCLC-C subgroup (13 wk vs 40 wk, P = 0.015). No significant differences in the reason for treatment interruption or in treatment duration were found comparing patients in Child-Pugh class A vs B or in patients older or younger than 70 years. After 16 wk of treatment, 18 patients (41%) had stable disease or partial response. Patients with viral infection or BCLC-C were at higher risk of disease progression. ECOG, extrahepatic spread, macrovascular invasion, alpha-fetoprotein or alkaline phosphatase levels at admission were independent predictors of overall survival. CONCLUSION: In patients with cirrhosis and HCC treated with sorafenib, AEs are a common cause of early treatment withdrawal. Vascular invasion and extrahepatic spread condition early response to treatment and survival. Baseline biochemical parameters may be helpful to identify patients at higher risk of shorter overall survival.

Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment.

INTRODUCTION: Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. MATERIALS AND METHODS: Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. RESULTS: MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. CONCLUSION: This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion.

Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C.

BACKGROUND: Liver stiffness has been suggested as a parameter of fibrosis progression/regression in hepatitis C virus (HCV) patients. AIM: To evaluate stiffness before and after peginterferon-ribavirin treatment. METHODS: Stiffness was prospectively measured in 74 HCV patients, 32 genotypes 1/4 (43.25%) and 42 genotypes 2/3 (56.75%), before, at end of treatment, and after 3 years of follow-up (49 patients). On the same study day, 21 patients underwent liver biopsy. RESULTS: In 55 patients with sustained virological response (74.32%), liver stiffness decreased significantly at end of therapy (6.8±4.9kPa) vs. baseline (9.5±6.9kPa, p=0.04). The decrease vs. baseline was maintained in 30 sustained virological response patients after 3 years follow-up (6.8±4.6kPa vs. 10.8±8.5kPa, p=0.0141). No difference was found at end of treatment vs. baseline (10.1±4.7kPa vs. 9.7±4.2kPa, p=0.825) and after 3 years of follow-up vs. baseline (10.2±3.4kPa vs. 9.7±4.2kPa, p=0.765) in null responders. Similar results were found in relapsers at end of treatment vs. baseline (13.7±7.7kPa vs. 15.2±8.2kPa, p=0.74), and after 3 years of follow-up vs. baseline (16.9±10.0kPa vs. 15.2±8.2kPa, p=0.734). Pre-treatment stiffness >12kPa was significantly associated with no SVR (p<0.025), RR=2.44 (95%C.I. 1.17-5.07). CONCLUSION: Liver stiffness may be useful to assess long-term antiviral treatment response.

Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia.

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin's lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders.

Diffusion-weighted imaging of the liver: a comprehensive review.

Diffusion-weighted magnetic resonance imaging is based on the Brownian motion of water and enables quantification of the apparent diffusion coefficient throughout the body. This article discusses the principles of diffusion-weighted magnetic resonance imaging, as well as the possible applications and limitations as they apply to liver imaging. This will introduce the readers to this novel magnetic resonance imaging tool, which has a promising future.

The hepatitis C virus infection as a systemic disease.

Hepatitis C Virus (HCV) is a major health problem, infecting about 3 % of people worldwide and leading to liver as well as extrahepatic diseases. This justifies the definition of HCV infection as a systemic disease. Based on available data, the link between the virus and some of these extrahepatic disorders is certain, whereas for some others needs further confirmation. HCV-related lymphoproliferative disorders, ranging from benign, but pre-lymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas, represent the extrahepatic manifestations most closely related to HCV. The primary involvement of the liver and lymphatic system corresponds to the double viral tropism, being HCV able to infect both hepatic and lymphatic cells. Other HCV-associated disorders include renal, endocrine, dermatological, cardiovascular, rheumatologic and central nervous system diseases. On the whole, the HCV disease appears a very important, mainly hidden, public health problem leading to heavy direct and indirect costs. The possibility that HCV may be eradicated following antiviral therapy is important for both the therapeutic and preventive points of view, making the HCV disease an ideal model for pathogenetic studies.

Glycogenic hepatopathy associated with type 1 diabetes mellitus as a cause of recurrent liver damage.

 Aminotransferase elevation is a frequent cause of consultation for the Hepatologist, in both the outpatient and inpatient settings, but identifying the origin of these biochemical alterations may be challenging. Here we report a case where acute elevation of aminotransferases, associated with abdominal symptoms, was the cause of two hospitalizations in a short period of time. As the patient suffered from type 1 diabetes, celiac disease, and autoimmune thyroiditis, several potential causes of damage could be hypothesized, including celiac hepatitis, fatty liver, and autoimmune hepatitis. A liver biopsy performed in the occasion of the second hospitalization allowed to rule out autoimmune hepatitis and celiac hepatitis, showing mild signs of fatty infiltration. Staining with periodic acid-Schiff with or without diastase showed a marked accumulation of glycogen, indicating the presence of a glycogenic hepatopathy associated with poorly controlled type 1 diabetes. This condition may be a cause of liver damage in patients with type 1 and occasionally type 2 diabetes, but its occurrence is often overlooked. This case report illustrates the fact that glycogenic hepatopathy may relapse, and prompts the clinician to take into account this condition in the differential diagnosis of causes of liver injury.

Hepato-systemic gradient of carbon monoxide in cirrhosis.

BACKGROUND AND AIMS: Experimental data suggest that in liver cirrhosis splanchnic and systemic vasculature exhibit marked endothelial Carbon monoxide (CO) overproduction, while recent data demonstrated heme oxygenase (HO) hyperactivity in the liver of rats with cirrhosis. No data are so far available on CO levels in the hepatic veins of cirrhotic patients. We aimed at evaluating whether plasma CO levels differ between systemic (peripheral vein) and hepatic (hepatic vein) circulation in patients with viral cirrhosis with and without ascites. METHODS: We enrolled 31 consecutive non-smoking in- or outpatients with liver cirrhosis. We measured wedge (occluded, WHVP) and free hepatic venous pressures (FHVP) and hepatic-vein pressure gradient (HVPG) was the calculated. Plasma level of NO and plasma CO concentration were determined both in peripheral vein and in the hepatic vein in cirrhotics. RESULTS: In cirrhotic patients plasma CO levels were significantly higher in the hepatic vein (16.66±10.71 p.p.m.) than in the peripheral vein (11.71±7.00 p.p.m). Plasma NO levels were significantly higher in peripheral vein (97.02±21.11 µmol/ml) than in the hepatic vein (60.76±22.93 µmol/ml). CONCLUSIONS: In patients with liver cirrhosis we documented a hepato-systemic CO gradient as inferred by the higher CO values in the hepatic vein than in the peripheral vein. In cirrhotic patients, CO and NO exhibit opposite behavior in the liver, while both molecules show increased values in the systemic circulation. It can be speculated that increased intra-hepatic CO levels might represent a counterbalancing response to reduced NO intra-hepatic levels in human liver cirrhosis.

Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcγ receptors.

OBJECTIVE: Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related immune complex disorder. Only some HCV-infected patients develop MC, which suggests that the genetic background of the host plays a key role. This study was undertaken to evaluate the contribution of host genetic factors in the pathogenesis of HCV-associated MC (HCV-MC) by analyzing allelic variants of low-affinity Fcγ receptor (FcγR) genes and BAFF promoter. METHODS: FcγR polymorphisms (FCGR2A 131 R/H, FCGR2B 232 I/T, FCGR3A 176 V/F, and FCGR3B NA1/NA2) and BAFF promoter polymorphism -871 C/T were analyzed in 102 patients with HCV-MC and 108 patients with HCV without MC, using polymerase chain reaction-based techniques. RESULTS: A higher prevalence of -871 T/T homozygosity (31% versus 16%; P = 0.001) and a greater frequency of T alleles of the BAFF promoter (80% versus 57%; P = 0.004) were found in the HCV-MC group than in the HCV group. A significant increase in serum BAFF concentration was significantly associated with the higher frequency of the T allele in HCV-MC (mean ± SD 4.12 ± 1.29 versus 2.09 ± 0.81 ng/ml; P < 0.0005). The distribution of the FcγR genotypes was not significantly different. In the 21 HCV-MC patients treated with rituximab, the response was strictly related to F allele homozygosity (significantly reduced in 5 of 5 patients with the FCGR3A F/F genotype versus 4 of 16 with V/V or V/F; P < 0.0005). CONCLUSION: These results indicate the importance of host genetic background in the development of HCV-MC, suggesting that mechanisms enhancing Ig production and B cell survival may play a relevant role. Genetic FcγR variants seem to be crucial to the effectiveness of rituximab therapy.

Non-invasive assessment of fibrosis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children and adolescents. The resulting increase in the number of patients with NAFLD is expected to translate into increased numbers of patients with liver cirrhosis, and hepatocellular carcinoma. In this context, it is particularly important to identify patients at risk for progressive chronic liver disease. Currently, liver biopsy is the gold standard to diagnose non-alcoholic steatohepatitis (NASH) and to establish the presence and stage of fibrosis. Due to the remarkable increase in the prevalence of NAFLD and the concomitant efforts in developing novel therapies for patients with NASH, non-invasive, simple, reproducible, and reliable non-invasive methodologies are needed. This paper provides a concise overview of the role of non-invasive diagnostic tools for the determination of presence and extent of fibrosis in NAFLD patients, with particular emphasis on the methods currently available in clinical practice.