Gianni Testino

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.

Dna damage in peripheral blood lymphocytes of patients with cirrhosis related to alcohol abuse or to hepatitis B and C viruses

Background Both alcohol abuse and hepatitis B or C virus infections are implicated in the development of hepatocellular carcinoma, but it is still controversial whether the pathogenetic mechanism is epigenetic or genotoxic. Aim Considering that alcohol promotes the generation of reactive oxygen species and both viruses infect peripheral lymphocytes, in this study we investigated the occurrence of DNA fragmentation in peripheral blood lymphocytes from patients with alcoholic cirrhosis and from patients with cirrhosis related to B and C viruses, and analyzed the correlation between the degree of DNA fragmentation and the Child–Pugh score used to assess the degree of hepatic insufficiency. Methods The study population consisted of two groups: group I involved 12 patients with alcoholic cirrhosis; group II involved 25 patients with hepatic B virus or hepatic C virus cirrhosis. The control group involved 20 healthy individuals. The degree of DNA fragmentation in peripheral blood lymphocytes was determined with the alkaline Comet assay that provides two indexes of the frequency of DNA single-strand breaks and alkali-labile sites, the tail length and the tail moment. Results Mean values of both tail length and tail moment were significantly increased (P<0.001) in lymphocytes from 12 patients with alcoholic cirrhosis and in lymphocytes from 25 patients with HBV or HCV cirrhosis, as compared with average tail length and tail moment values of lymphocytes from 20 healthy individuals. A significant positive correlation was found to exist between the degree of DNA fragmentation present in lymphocytes of each of the 37 patients with alcoholic or viral cirrhosis and the corresponding value of the Child–Pugh score. Conclusion The occurrence of DNA fragmentation in peripheral blood lymphocytes reflects a direct genotoxic effect of either alcohol or HBV and HCV and suggests that the same genotoxic effect may operate in the liver and contribute to hepatocarcinogenesis.

Altered oxidative stress/antioxidant status in blood of alcoholic subjects is associated with alcoholic liver disease

BACKGROUND Oxidative stress is implicated in pathogenesis of alcoholic liver disease (ALD). This study investigated the possible correlation among the erythrocyte indices of oxidative stress, the leukocyte panels of antioxidant proteins (metallothioneins), the serum biochemical parameters and the liver steatosis grade. METHODS A total of 118 cases including 60 alcoholic subjects and 58 controls were enrolled. All the alcoholic subjects were screened for body mass index (BMI), liver steatosis, and blood chemistry and serology. The level of oxidative stress and oxidative stress-related parameters were measured in the blood and correlated with clinical findings. RESULTS Alcoholic subjects showed higher BMI, moderate/severe hepatic steatosis, increase in the levels of triglycerides, cholesterol, glucose, γ-glutamyl-transpeptidase (GGT), alanine aminotransferase (ALT), bilirubin, alpha 1 and beta 2 globulins, iron and a decrease in the levels of aspartate aminotransferase (AST) and beta 1 globulin with respect to the reference values. Moreover, alcoholic subjects showed: (i) an increase in Thiobarbituric Acid Reactive Substance (TBARS) content representing a good estimation of global oxidative stress; (ii) a stimulation of the activities of the antioxidant enzymes catalase and SOD; (iii) a modulation of expression of metallothioneins, with a down-regulation of MT-1A and an up-regulation of MT-1E isoforms. CONCLUSIONS Our data suggest that alcoholism is strongly associated with altered pattern of blood metallothioneins; this parameter combined with the score calculated by an ad hoc implemented algorithm (HePaTest) could offer a non-invasive alternative approach for evaluating alcohol-related damages and could be used in follow-up of alcoholic patients.

Alcohol and gastrointestinal oncology

Results from several large epidemiological studies have firmly established that alcohol is associated with elevated cancer incidence and mortality. Recently the International Agency for Cancer Research stated that acetaldehyde associated with alcoholic beverages is carcinogenic to humans and confirmed the Group 1 classification of alcohol consumption and of ethanol in alcoholic beverages. Alcohol consumption causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver, pancreas and female breast. The frequency of most alcohol-induced diseases increases in a linear fashion as intake increases: oral, oesophagus and colon cancer fall into this pattern. Very little is known about safe margins of alcohol consumption. US Department of Health and Human Services suggest a maximum of 28 g of alcohol a day in man and half of this in women.

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.

Helicobacter pylori and gastric cancer

1. Locke GR, Zinsmeister AR, Talley NJ, et al. Risk factor for irritable bowel syndrome: Role of analgesic and food sensitivities. Am J Gastroenterol 2000;95:157–65. 2. Zwetchkenbaum JF, Burakoff R. Food allergy and the irritable bowel syndrome. Am J Gastroenterol 1988;83:901–4. 3. Alun Jones A, Shorthouse M, MacLoughlan P, et al. Food intolerance: A major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982;2:1115–7. 4. Addolorato G, Gasbarrini G, Marsigli L, et al. Irritable bowel syndrome and food allergy: An association via anxiety and depression? Gastroenterology 1996;111:833–4. 5. Addolorato G, Marsigli L, Capristo E, et al. Anxiety and depression: A common feature of health care seeking patients with irritable bowel syndrome and food allergy. Hepato-Gastroenterology 1998;45:1559–64. 6. Stead RH, Dixon MF, Bramwell NH, et al. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 1989;97:1212–9.

Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis.

Interferon (IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma (HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus (HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer. Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated (PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.

Helicobacter pylori, cell proliferation, and carcinogenesis

TO THE EDITOR: I have read with interest the excellent article by Hua-Xiang Xia and Talley (1). The authors hypothesized that Helicobacter pylori–induced apoptosis may play a key role in gastric carcinogenesis by increasing cell proliferation and/or resulting in gastric atrophy. I agree with the authors that H. pylori has a decisive role, and I too agree with them in saying that the chronic inflammation alone is not sufficient to induce increased gastric epithelial cell turnover; H. pylori is required. My colleagues and I have written on this subject in this very journal. It is well known how H. pylori, by means of various mechanisms acting in correspondence with the stem cells, contributes to induce hyperproliferation. An evident morphological manifestation of such conditions in the initial phases is the expansion of the mucopeptic compartment (presence of anti–pepsinogen A and PASpositive cellular elements) in the superficial-foveolar site. This expansion has been observed in about 72% of H. pylori positive superficial chronic gastritis (SCG) cases. This phenomenon has been observed neither in subjects with H. pylori negative SCG nor in those with normal gastric mucosa (2, 3). Furthermore, as a reduction of the cellular proliferation has been demonstrated already after eradication of H. pylori, a reduction/disappearance of the expansion of the mucopeptic compartment can be noted also (4). Cellular differentiation is displayed, with the progressive increase of immature elements that progress to the more or less total disappearance of differentiated gastric cells or differentiating ones, with formation of metaplastic/dysplastic clones or even neoplastic ones, naturally in the presence of an individual host genetic susceptibility (5). As for the relation H. pylori/atrophy/carcinogenesis, in our opinion there are some obstacles to an exclusive acceptance of the idea that the relation of H. pylori with the preneoplastic/neoplastic modifications solely develops by means of the chronic gastritis with its atrophic evolution and achlorydria. The presence of multifocal atrophy in many cases is mostly linked to the damage in the glandular necks’ stead in time, but in reality, metaplastic and/or dysplastic modifications may have started in a previous period and are not linked to secretory alterations. The continuous increase in cellular turnover in correspondence with the glandular necks may contribute, on one hand, to a loss of the glands with atrophic evolution and, on the other, by means of hyperproliferation, to the contemporary promotion/progression of the metaplastic, dysplastic, and neoplastic clones (6, 7). Therefore, H. pylori, by means of alteration of cellular cynetics, could probably act as a promoter in the progression toward neoplasia in subjects with genetic predisposition independent of the presence of atrophy (8, 9).

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 …

Surveillance for Hepatocellular Carcinoma in Alcoholic Patients

To the Editor: we have read the excellent letter to the editor by Giannini and Trevisani ( 1 ). Th e Authors do not agree with Singal et al. ’ ( 2 ) consideration for reintroducing serum alpha-feto-protein (AFP) in the surveillance armamentarium for hepatocellular carcinoma (HCC). Alcohol has been recently inserted in the Group 1 International Agency for Research on Cancer (IARC — World Health Organization). It has been confi rmed a causal link between alcohol consumption and HCC. In Europe among men and women, 33 % (11 – 54 % ) and 18 % (3 – 38 % ) of the incidence of the total HCC was attributable to former and current alcohol consumption ( 3 ). Moreover, a meta-analysis suggests that the risk of liver cancer does indeed fall aft er cessation by 6 – 7 % a year. It is estimated that a time period of 23 years is required aft er drinking cessation, with a correspondingly large 95 % confi dence interval of 14 – 70 years, for the risk of liver cancer to be equal to that of never drinkers ( 4 ). It emerges the necessity of a strict follow-up every 6 or 12 months in relation with the clinical features of the alcoholic patients. In our Regional Alcoholic Unit in 2012, we identifi ed 12 HCC in Child A alcoholic cirrhosis (four females, average age: 55 ± 6.5) without viral infection. Th e identifi cation was eff ected with ultrasound and confi rmed with contrastenhanced ultrasound. All nodules were identifi ed with a diameter inferior to 3 cm. Eleven patients had AFP in the normal range (1 – 8 ng / ml). In one patient the value was 15 ng / ml. Successively, the patients were treated with resection or percutaneous ablation. Th e role of AFP in the diagnosis and surveillance of HCC has decreased during the past few years. Th e cut-off usually found to be useful in discriminating between highand low-risk groups has been 20 ng / ml. In the experience of Mancebo et al. ( 5 ), only three patients (3 / 62: 4.8 % ) had baseline AFP values greater than 20 ng / ml and for that reason it is not surprising that the initial value of AFP had not been found to be a risk factor for HCC. It seems to suggest that baseline AFP level could have a role as a predictive factor for HCC in viral cirrhosis, but not in the case of alcoholic cirrhosis. In our opinion, the combined use of ultrasound and serum AFP has both direct and indirect costs for each early detection of HCC, which are too expensive. According to Giannini and Trevisani, ( 1 ) there is evidence that a well-conducted surveillance based on ultrasound performed by expert operator can detect most HCCs at an early stage. Th erefore, in our opinion ultrasound performed by expert is suffi cient if the operator is also an experted hepatologist.