Andrea Marengo

Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis

The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlying this complex relationship.

Progression and Natural History of Nonalcoholic Fatty Liver Disease in Adults

Liver-related mortality is the third cause of death in patients with nonalcoholic fatty liver disease, but the long-term prognosis basically depends on the presence and severity of liver damage. Thus, life expectancy in patients with simple steatosis is not different from the general population, but liver-related mortality is significantly higher in patients with nonalcoholic steatohepatitis (NASH), particularly in those with advanced fibrosis. Progression of liver disease is observed in up to one-third of patients with NASH. The long-term hepatic prognosis mostly depends on the histologic stage at initial liver biopsy, but multiple risk factors may concur.

Hepatitis B Virus Reactivation and Efficacy of Prophylaxis with Lamivudine in Patients Undergoing Allogeneic Stem Cell Transplantation

Patients previously infected with hepatitis B virus (HBV) undergoing an allograft and recipients from HBV carrier donors are at risk of posttransplant viral reactivation. The role of prophylaxis with lamivudine remains unclear. One hundred seventeen patients, with a median age of 52 years (20-67 years), with various hematologic malignancies transplanted between 1999 and 2007 entered the study. Eighty-seven recipients negative for HBV surface antigen (HBsAg), antihepatitis B core antigen antibodies (anti-HBc), and HBV-DNA with HBsAg and HBV-DNA negative donors were defined as at low risk of HBV reactivation, whereas all the remaining 30 patients were defined as at high risk. Patients at high risk transplanted in 2005 or after received lamivudine to prevent HBV reactivation as per the Italian guidelines by the Associazione Italiana per lo Studio del Fegato (AISF). Patients at low risk did not experience HBV reactivation/hepatitis. Among the recipients at high risk, 11 of 25 anti-HBc positive, those HBsAg positive (2 of 2) or negative but transplanted from HBsAg positive donors (3 of 3) were treated with lamivudine. None of these developed HBV reactivation/hepatitis after a median follow-up of 40 months (17-55 months). Hepatitis developed in 3 anti-HBc positive untreated patients conditioned with a reduced-intensity regimen. Hepatitis B was not observed in recipients at low risk, transplanted from HBsAg negative/anti-HBc positive or negative donors. Lamivudine was effective in controlling reactivation in: HBsAg positive recipients, in patients transplanted from HBsAg positive donors and in HBsAg negative/antiHBc positive recipients, who showed a significant risk of reactivation if not given prophylaxis (NCT 00876148).

Lactic acidosis during Entecavir treatment in decompensated hepatitis B virus-related cirrhosis

Lactic acidosis (LA) may be observed in cirrhotics hepatitis B irus (HBV) patients with impaired liver function during Entecavir ETV) treatment and Model for End stage Liver Disease (MELD) core has been suggested to directly correlate with LA development 1]. However some recent studies [2–4] reported a high efficacy and afety of ETV in decompensated cirrhosis. Thus the risk of LA with nucleos(t)ide analogues (NUCs) remains ontroversial and very few data are available about LA in HBV and on-HBV related cirrhosis with high MELD score and multi-organ ailure (MOF), expressed by Sequential Organ Failure Assessment SOFA) score. In our study we retrospectively evaluated the emergence of LA uring ETV in a small series of HBV decompensated cirrhotics with igh MELD score and MOF, comparing the results with a second roup of patients with non-HBV decompensated cirrhosis and simlar clinical features. Six naïve HBV decompensated patients were analysed (Group ). These 6 patients were matched with 6 non-HBV decompensated atients (Group B). LA was defined as hyperlactataemia (serum actate level > 2 mmol/L) with arterial pH < 7.30. The main clinical haracteristics of the patients are reported in Table 1.

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 years

BACKGROUND & AIMS In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. METHODS One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. RESULTS One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. CONCLUSIONS In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander.

The top three leading causes of death in patients with nonalcoholic fatty liver disease (NAFLD) in descending order are cardiovascular disease, cancer, and liver disease. It is clear now that the increased risk of metabolic and macro- and microvascular complications in NAFLD stems from the associated features of metabolic syndrome. However, NAFLD itself may contribute to the spectrum of risk factors associated with insulin resistance. The primary focus of this review is to summarize the main systemic associations of NAFLD, as well as to discuss the mechanisms that link them to NAFLD. Hepatic lipid accumulation in NAFLD impairs hepatic glucose and lipid metabolism further increasing the risk of type 2 diabetes mellitus and of cardiovascular disease, independently of established risk factors. The incidence, prevalence, and severity of these complications are proportional to the histological severity of liver damage suggesting that NAFLD, but particularly nonalcoholic steatohepatitis, can also contribute to the low-grade inflammatory state through the systemic release of several markers of inflammation, oxidative stress, and of procoagulant factors. The clinical implication of these findings is that patients with NAFLD require a multidisciplinary evaluation, with a major focus on type 2 diabetes mellitus and cardiovascular disease complications and may benefit from more intensive surveillance and early treatment interventions to decrease the risk for cardiovascular and kidney complications.

Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6‐D2‐glucose and U‐13C‐glucose) in the basal state and during an oral glucose tolerance test. The best‐performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test‐derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61‐0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63‐0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45‐0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). Conclusion: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD. (Hepatology 2016;63:107–116)

Clinical impact of A/H1/N1/09 influenza in patients with cirrhosis: Experience from a nosocomial cluster of infection†‡

A/H1N1/09 influenza is associated with a high risk of complications in patients with chronic diseases, but data on morbidity and mortality in patients with cirrhosis are limited. A cluster of A/H1N1/09 infection in 48 patients admitted to a Gastro‐Hepatology Unit is reported. Nosocomial spread, clinical outcome, and viral characteristics of A/H1N1/09 strains from a study group of 48 inpatients (21 and 27 with and without cirrhosis, respectively) were compared with those from a control group of 44 outpatients with mild influenza‐like illness and without cirrhosis. A/H1N1/09 infection was confirmed in 8/48 (17%) inpatients. A/H1N1/09 infection rate did not differ in patients with and without cirrhosis (4/21, 19%; 4/27, 15%), but three patients with cirrhosis died of pneumonia and acute respiratory distress syndrome, with fungal or bacterial superinfection in two cases, despite antiviral treatment. None of patients without cirrhosis died. Viral sequences showed the presence of hemagglutinin mutation D222G in two out of three fatal cases and S183P in seven out of eight infected patients. These mutants were not detected in the outpatients group. Even if A/H1N1/09 infection rate in hospitalized patients with and without cirrhosis was not significantly different, cirrhosis and D222G/S183P substitutions were significantly associated with severe disease and poor outcome, also suggesting fungal or bacterial superinfection and portal hypertension as risk factors for A/H1N1/09 disease severity in patients with cirrhosis. Vaccination, preventive and early treatment and a strict control of nosocomial spread should be activated carefully in patients with cirrhosis during epidemics influenza. J. Med. Virol. 85:1–7, 2012.

Glucocorticoids and antivirals for HBV reactivation in onco-hematologic patients

Patients with inactive or occult hepatitis B virus infection and onco-hematological malignancies are at risk of hepatitis flare, hepatic failure and death due to chemotherapy-mediated reactivation. Nucleot(s)ide analogues can reduce reactivation risks and/or hepatitis. However, immuno-mediated phenomena combine to determine liver damage and clinical outcome. We describe in this report two patients with onco-hematological malignancies and hepatitis B reactivation after chemotherapy in whom glucocorticoids were added to nucleot(s)ide. Antiviral therapy was effective on replication, while glucocorticoids managed hyperergic response. One patient without underlying liver disease survived, while the second died and the autopsy demonstrated cirrhosis undetected before death. This clinical trial suggests that in patients with onco-hematological malignancies and altered liver function tests in spite of effective antiviral response, glucocorticoids could control the effects of immune response. However prognosis and survival are related to the underlying liver status.

Prophylaxis and treatment of Hepatitis B in immunocompromised patients

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.