Silvia Leone

Alcohol and hepatocellular carcinoma:A review and a point of view

It is well recognized that one cause of chronic liver disease and hepatocellular carcinoma (HCC) is alcohol consumption. Research in Italy and the United States concludes that the most common cause of HCC (responsible for 32% to 45% of HCC) is alcohol. It has recently been shown that a significant relationship between alcohol intake, metabolic changes, and hepatitis virus infection does exist. Alcohol may be a factor in the development of HCC via direct (genotoxic) and indirect mechanisms (cirrhosis). There is only one way of diagnosing HCC, which is early identification through surveillance, when curative treatments become possible. After stopping alcohol intake the risk of liver cancer decreases by 6% to 7% a year, and an estimated time period of 23 years is also needed. Therefore, surveillance is also important in former drinkers and, in our opinion, independently from the presence of compensated cirrhosis. In cases of very early stage (VES) and early stage with portal hypertension, liver transplantation is the optimal option; and in cases of associated disease, percutaneous ethanol injections, radiofrequency and microwave ablation are the ideal treatments. Despite the possibility of detecting microvascular invasion with HR, several studies and some randomized controlled trials revealed that overall survival and DSF rates in patients with VES HCC are much the same after ablation and HR. Therefore, ablation can be regarded as a first-line choice for patients with VES HCC. It is important to emphasize that the choice of treatment should be weighed carefully in the context of a multidisciplinary cancer team.

Liver Disease and Hepatocellular Carcinoma in Alcoholics: The Role of Anticraving Therapy.

Alcohol is the main risk factor for death and disability. The treatment of alcohol dependence (AD) is a complex activity as the variables are numerous; however, those which must necessarily be taken into account are the type of AD, the internal comorbidities and the presence of any psychiatric comorbidity. Liver problems are one of the most common causes of alcohol-related liver damage. 45% of deaths from cirrhosis are alcohol-related. Thus, the treatment of AD must often deal with a more or less severe liver disease, which influences the choice of anticraving drug. As chronic liver disease is often present, and as in a substantial proportion of cases, because there is a correlation with viral infections or with hepatocellular carcinoma (HCC), it is clear that hepatologists should make use of nonhepatotoxic molecules. In cases of mild liver disease, all available drugs might be used, but we recommend caution because the liver is usually fragile due to the harmful abuse of alcohol. In the advanced liver disease, the choice of treatment is reduced. A psychosocial approach such as attending support groups could be the first choice. In cases of compensated cirrhosis with or without HCC, or in cases of HCC without cirrhosis, metadoxine, acamprosate and baclofen can be used. In decompensated forms the only drug tested to date has been baclofen. In alcohol-related liver disease a professional team with hepato-alcohologists is also necessary, especially for liver transplantation programs.

Alcohol and Liver Transplantation

We agree with the recommendation to assess consumption of alcohol carefully even for patients on a waiting list for a liver transplant (LT) who have non-alcohol-related cirrhosis (Russ et al ., 2016). It often happens that only alcohol addiction is seen as a problem, while moderate consumption (which may be hazardous/harmful) is underestimated by both patients (as they consider their own drinking to be moderate) and their healthcare providers. This is not the case for smoking. All transplant centers require patients to stop smoking completely before they can go on a waiting list for LT. The identification of moderate consumption of alcohol is important for several reasons. First, after LT, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) often develop. NAFLD is present …

[Alcohol, cardiovascular prevention and cancer].

It is well known that light to moderate drinking (10-25 g/day) has a protective effect on ischaemic heart disease. This effect seems independent of the type of alcoholic beverage. Recently, the International Agency for Research on Cancer (World Health Organization) stated that alcoholic beverages are carcinogenic for human (oral cavity, pharynx, larynx, oesophagus, colorectum, liver and breast). There is a dose-response relationship between alcohol and cancer in that the risk of cancer increases proportionally with alcohol consumption. Low doses of alcohol (10 g/day) are associated with an increased risk for oral cavity, pharynx, larynx, oesophagus and breast cancer. Therefore, a physically active lifestyle and a healthy diet are more effective in preventing ischaemic heart disease than a low level of alcohol consumption.

Alcohol and liver transplantation: the 6‐month abstinence rule is not a dogma

We have read with interest the excellent paper by Kollmann et al. [1]. The authors affirm that alcohol relapse did not have a statistically significant effect on patient survival. Pfitzmann et al. [2] claim that post-transplant survival is significantly lower in patients undergoing a true relapse than in abstainers or in those with minor lapses, otherwise transplants for alcoholic liver disease (ALD) have mortality rates that are equal to or minor in comparison with transplants for all other causes. Besides, mortality due to relapse of the disease is very low; the leading causes of death are due to cardiovascular diseases and tumors [3]. It is well known that the 6-month rule is an arbitrary threshold and the correlation between 6 months abstention and alcohol relapse is weak [3,4]. A new way of working is needed to improve the results [3]. An Italian position statement affirms that the 6-month rule is not an evidence-based practice [5] and suggests the following criteria: 1 Screening of novo tumors after liver transplantation (LT) (ethanol is present in group 1 of the International Agency for Research on Cancer) [6] and prevention of metabolic syndrome; 2 In cases of end-stage liver disease (ESLD) with a model for end-stage liver disease (MELD) <19, a 6-month period of abstinence could be required; 3 In cases of progressive ESLD with MELD >19, 3 months of abstinence are more ideal in selected patients who are particularly compliant. ESLD alcoholics who do not recover within the first 3 months of abstinence die in high percentages [5,7]; 4 In cases of severe acute alcoholic hepatitis (MELD > 20) not responding to steroidal treatment, LT is mandatory in selected patients, independent of the sober period achieved. The transplant team must include an addiction specialist (AS)/hepato-alcohologist, and patients in the post-transplant period have to participate in self-help groups (SHGs). The important role of addiction specialists and SHGs was observed in our retrospective experience [8]. This casuistry (2005–2010) was revised more recently (unpublished data). Seventy four young alcoholic patients with ALD were quickly enrolled and put onto a multidisciplinary care pathway with an addiction specialist and regular attendance at an SHG. The team was accompanied by an SHG. This group was compared with 157 young patients who for various reasons followed a traditional route with or without irregular attendance at an SHG. The AS was not present on the traditional route. After a period of 5–10 years (age: 25– 35 years), univariate and multiple logistic regression analyses were performed (JMP SA, NC, Cary, USA). Regular attendance at an SHG will guarantee a longer period of sobriety in years than in a group with conventional treatment: 6 (4–7) vs. 3 (3–6) (P < 0.0001). Cases of cirrhosis (9.4% vs. 31%; P < 0.0001) and hepatocellular carcinoma (4% vs. 14.6%) tend to be lower. Therefore, an AS and participation in an SHG may be determinant during the post-transplant period in the absence of a specified period of pretransplant alcohol abstinence [5,9,10].

Antiviral therapy and hepatocellular carcinogenesis.

We have read with great interest the excellent review by Li et al. The authors claim that even in subjects who have achieved a sustained virological response with interferon or pegylated interferon therapy, the risk of hepatocellular carcinoma (HCC) remains, especially in those with advanced fibrosis. Our previous experience has shown how interferon treatment, which compensates hepatitis C virus cirrhosis, reduces the negative clinical evolution independently of the type of laboratory and virological response, but it is barely useful in the prevention of HCC because cirrhosis itself represents a risk of cancer. We evidenced that the cumulative probabilities of developing HCC were not significantly higher in untreated patients versus interferon-treated cases when they were assessed with Kaplan-Meier and log-rank tests (P> .05). Some experience has shown how interferon prevents or delays the development of HCC, but the magnitude of the overall effect is low, and the observed benefits might be due to false associations. Moreover, during the course of cirrhosis associated with diabetes mellitus type 2 or the consumption of alcohol, the risk of HCC can survive even in the absence of direct (overexpression of hepatitis C virus proteins, nonstructural protein 5B–retinoblastoma interaction, and expression of microRNA 122) or indirect effects of hepatitis C virus (continuous stimulus of proinflammatory, proapoptotic, and proliferative signals). Sixty to eight percent of patients with cirrhosis develop hyperinsulinemia, and approximately 20% develop diabetes mellitus type 2. The presence of hyperinsulinemia favors the onset of HCC and exacerbates its progression. One must also carefully consider that with respect to the consumption of ethanol during the course of liver cirrhosis, it is known that dosages that do not correlate with alcohol dependence may increase the risk of mortality. The European Association for the Study of the Liver affirms that if there is a threshold, it is very low and difficult to detect because of the difficulties in measuring a daily intake less than 10 to 12 g. It could be the case that more moderate consumption might play a more significant role in hepatic carcinogenesis than is currently thought. Recently, Persson et al. evidenced how the consumption of 3 drinks per day is positively associated with the occurrence of both HCC and liver disease mortality. Ethanol, in fact, has been included in International Agency for Research on Cancer Group 1 with a direct genotoxic capacity. It should also be noted that the risk for HCC actually decreases by 6% to 7% per year after an individual gives up alcohol. From these considerations, there follows the need for a careful metabolic evaluation, and the consumption of alcohol during the course of cirrhosis must definitely not be recommended because there is no safe threshold. In the presence of alcohol dependence, however, the patient should be seen by a hepatologist team specializing in alcohology. Even with the introduction of direct-acting antiviral agents, the ongoing surveillance of liver cirrhosis should be performed every 6 months by a sonographyexperienced hepatologist despite the achievement of a sustained virological response.

Fibrosis progression in patients treated for hepatitis C recurrence

is influenced by oxidative stress and FFA through independent mechanisms (3). Thus, it cannot also be excluded with certainty a direct effect of oxidative stress on circulating IMA levels. However, on a clinical point of view, we emphasize that, regardless the underlying molecular mechanisms, the main finding of our study resides on the association between IMA elevation and localized bacterial infections, which was supported by the experiments performed in cirrhotic rats exposed to acute endotoxin administration.