Treatment of alcohol dependence: recent progress and reduction of consumption.

Alcohol dependence (AD) is a major public health problem. Currently, three drugs for the treatment of AD have been approved by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA): acamprosate, disulfiram, and oral naltrexone. The FDA also approved the use of long-acting injectable naltrexone. In Austria and in Italy sodium oxybate is also approved. The EMA's Committee for Medicinal Products for Human Use has recently granted marketing authorization for nalmefene for the reduction of alcohol consumption. Many patients, while accepting the problem, are unable or unwilling to completely stop consuming alcohol, leading to an inevitable deterioration over time of their psycho-physical state, and social and family relationships. It is appropriate to offer these patients the opportunity to significantly reduce their consumption of alcohol. The reduction may be an opportunity to prepare the individual for achieving complete abstinence. Abstinence should always be the main goal. Currently, nalmefene is the only drug that has been authorized for the reduction of alcohol consumption. Its association with psycho-social support is mandatory; it is taken on an "as-needed" basis, which should preferably be 1-2 hours before the possible intake of alcohol. The trials showed a significant reduction in alcohol consumption, which resulted in a significant reduction in morbidity and mortality. Reducing consumption allows a decrease in the progression of numerous alcohol-induced chronic diseases, as well as a reduction in psycho-physical damage, acts of violence, motor vehicle accidents, and accidents at work, which in turn means fewer healthcare costs.

Silymarin and S-adenosyl-L-methionine (SAMe): two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view.

The alcoholic liver disease (ALD) is the leading cause of death from liver failure in Italy and worldwide. Ethanol abstention, a healthy diet, and a significant improvement of life-style are the mainstay of treatment for this disease. Currently, we do not have effective therapeutic options are at our disposal to restore and maintain an improved clinical status. Silymarin is a complementary and alternative medicine often prescribed and self-prescribed; it has anti-oxidant, anti-inflammatory, anti-fibrotic, and metabolic properties. It improves the laboratoristic values and the ultrasonographic grading of liver disease in case of steatosis/steatohepatitis. S-adenosyl-L-methionine (SAMe) is the principal biological methyl donor, and it is also a precursor of glutathione (GSH), essential for the anti-oxidant pathways. SAMe is particularly important for opposing the toxicity of free radicals generated by various toxins, including alcohol. An association between Silymarin and SAMe (labelled as a dietary supplement) has been recently brought to market, and seems to be promising. It could be beneficial in such cases of alcoholic hepathopathies. New therapeutic options are needed by hepatologists to successfully overcome a constantly growing disease.

Recurrent hepatitis C and non-alcoholic fatty liver disease in transplanted patients: a review.

Non-alcoholic fatty liver disease (NAFLD) is a common occurrence after orthotopic liver transplantation (OLT). The association steatosis/HCV determines important implications for clinical practice: steatosis accelerates the progression of fibrosis and reduces the likelihood of obtaining a sustained virological response (SVR) with antiviral therapy. In post-transplant HCV patients we have evidenced a strong correlation between body mass index (BMI), cholesterol, triglycerides (TGC) and hepatic percentage of steatosis. In subjects with BMI <25 and TGC <160 ng/mL, the chance of SVR was 48 times higher than that of non response. The chances of SVR and sustained biochemical response for patients with percentage of steatosis <15 were 12 times higher than that with higher percentage of steatosis. We can conclude how the amount of steatosis be noted specifically in biopsy examination reports of patients with relapse chronic hepatitis C and how the management of dismetabolism, diet and exercise therapy can improve BMI, liver histology and the response to antiviral therapy.

Severe acute alcoholic hepatitis and hepatorenal syndrome: role of transjugular intrahepatic portosystemic stent shunt.

Acute Alcoholic Hepatitis (AAH) is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. Mild to moderate forms of AAH frequently respond to alcoholic abstinence, whereas severe AAH is characterized by a poor prognosis. Up to 40% of these patients die within 6 months upon symptoms onset. This high rate of mortality is due to different factors: liver failure, severe infections, and portal hypertension with variceal bleeding and hepatorenal syndrome (HRS). In AAH, HRS is a common complication that leads to the death of more than 90% of the patients within 3 months, unless they had been liver transplanted. Transjugular Intrahepatic Portosystemic Stent Shunt (TIPS) has been increasingly used in the management of portal hypertension and its complications, and, it might become a valuable option in patients with HRS awaiting LT. This study has taken into consideration 9 consecutive patients affected by severe AHH with HRS suitable for TIPS. We have determined serum creatinine, blood urea nitrogen, serum sodium, sodium urinary excretion and urine volume in all patients, before the intervention, 7 days and 30 days after TIPS. Seven patients were transplanted within 6 months. After TIPS, the renal function improved with significant reduction in serum creatinine and increase in urine volume. We can conclude that TIPS is a valuable option in patients with severe AAH complicated by HRS and are waiting for liver transplantation.

Human carcinogenesis and alcohol in hepato-gastroenterology.

Alcohol consumption is one of the top-10 risks for worldwide burden of disease. The International Agency for Research for Cancer affirmed that there was evidence for the carcinogenicity of ethanol in animals and classified alcohol consumption as carcinogenic for humans. Alcohol consumption causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver, pancreas and female breast. 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. Given the linear dose-response relation between alcohol intake and risk of cancer, control of heavy drinking remains the main target for cancer control. European Code Against Cancer recommends keeping daily consumption within two drinks (20 g [corrected] of alcohol/day) for man and one drink for women and US Department of Health and Human Services suggest as a low risk, a maximum of 10 g [corrected] of alcohol a day in man and half of this in women.

Noninvasive ratio indexes to evaluate fibrosis staging in chronic hepatitis C: role of platelet count/spleen diameter ratio index.

OBJECTIVES: Noninvasive evaluation of fibrosis is an on-going effort in the management of chronic hepatitis C. This study was planned to noninvasively evaluate fibrosis staging. DESIGN: We evaluated the biochemical, functional [aminopyrine breath test (ABT)] and ultrasonographic variables of 75 chronic hepatitis C patients. RESULTS: Clinical [body mass index (BMI)], biochemical [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT)] and ratio indexes, together with the ABT, showed a higher relationship with fibrosis: initial (score2) fibrosis: BMI (24+/-2 vs. 26+/-2, P=0.0007), AST (56+/-36 vs. 88+/-65, P=0.0159), ALT (92+/-54 vs. 139+/-108, P=0.0290), PLT (220+/-64 vs. 173+/-61, P=0.0007), PLT/spleen diameter ratio (PLT/SPD) (2133+/-786 vs. 1540+/-681, P=0.0003), AST/platelet count ratio index (APRI) (0.80+/-0.87 vs. 1.51+/-1.47, P=0.0010), ABT%d/h30 min (10.8+/-4.5 vs. 7.6+/-3.8, P=0.0007), ABT%d/cum120 min (8.9+/-3.3 vs. 6.5+/-3.1, P=0.0007). Considering the differences between fibrosis score 2 and 3 patients, BMI, ABT and PLT/SPD ratio proved to be statistically significant. Multivariate stepwise analysis (with and without BMI) identified two models for distinguishing between initial and evident fibrosis: Model 1: -0.569+(BMIx0.107)+(APRIx0.169)-(PLT/SPDx0.304), and Model 2: 2.376+( APRIx0.152)-(ABTd/h30x0.043)-(PLT/SPDx0.249). These models showed concordance in identifying or ruling out evident fibrosis in 76% and 78.7% of the patients respectively. The PLT/SPD ratio also showed 78.7% concordance with the histological score. CONCLUSION: These results suggest that noninvasive evaluation of fibrosis in chronic hepatitis C may be considered an effective tool thanks to the use of an inexpensive, reproducible ratio index.

Application of the platelet count/spleen diameter ratio to rule out the presence of oesophageal varices in patients with cirrhosis: a validation study based on follow-up.

BACKGROUND: Screening for oesophageal varices represents an important part of the diagnostic work-up of cirrhotic patients. We have previously shown that the platelet count/spleen diameter ratio is a parameter that can rule out the presence of oesophageal varices safely and in a cost-effective fashion. AIM: To evaluate the prognostic and diagnostic accuracy of the platelet count/spleen diameter ratio for ruling out the presence of oesophageal varices in the follow-up of a cohort of cirrhotic patients without oesophageal varices at inclusion. METHODS: After initial endoscopy, the 106 cirrhotic patients without oesophageal varices who participated in our previous study were followed-up with annual or biannual surveillance endoscopy. Patients were censored at the time of diagnosis of oesophageal varices or at their last visit, and at that time platelet count and spleen diameter were recorded. Sixty-eight patients made up the study cohort after excluding patients who were lost to follow-up or died before undergoing control endoscopy. RESULTS: During the follow-up, 27 patients (40%) developed oesophageal varices. Patients with higher baseline platelet count/spleen diameter ratios (p<0.0001) as well as a ratio above 909 were less likely to develop oesophageal varices (p<0.0005). At follow-up, a platelet count/spleen diameter ratio < or = 909 had 100% negative predictive value and 84% efficiency in identifying the presence of oesophageal varices. CONCLUSIONS: The use of the platelet count/spleen diameter ratio proved to be an effective means for ruling out the presence of oesophageal varices even in the longitudinal follow-up of patients.

Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.

BACKGROUND AND AIMS: Cirrhotic patients frequently undergo screening endoscopy for the presence of oesophageal varices (OV). In the future, this social and medical burden will increase due to the greater number of patients with chronic liver disease and their improved survival. In this study, our aims were (1) to identify clinical, biochemical, and ultrasonographic parameters which might non-invasively predict the presence of OV in patients with liver cirrhosis; (2) to evaluate the reproducibility of the obtained results in a different, although related, further group of patients; and (3) to assess the predictiveness of the identified rules in patients with compensated cirrhosis. METHODS: In the first part of the study we retrospectively evaluated the presence of OV in 145 cirrhotic patients, and in the second part we evaluated the reproducibility of the study results in a subsequent group of 121 patients. Finally, we evaluated these parameters in a subgroup of 145 patients with compensated disease. All 266 patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio was calculated for all patients. RESULTS: The prevalence rates of OV were 61% and 58% in the first and second groups of patients, respectively. In the first part of the study, we found that platelet count, spleen diameter, platelet count/spleen diameter ratio, and Child- Pugh class were significantly different among patients with or without OV, although the platelet count/spleen diameter ratio was the only parameter which was independently associated with the presence of OV in a multivariate analysis. A platelet count/spleen diameter ratio cut off value of 909 had 100% negative predictive value for a diagnosis of OV. This result was reproduced in the second group of patients as well as in patients with compensated disease. In a cost-benefit analysis, screening cirrhotic patients according to the "platelet count/spleen diameter ratio strategy" was far more cost effective compared with the "scope all strategy". CONCLUSIONS: The platelet count/spleen diameter ratio is the only parameter which is independently associated with the presence of OV, and its negative predictive value is reproducible. Its use is of value even in the subgroup of patients with compensated disease, and it is also cost effective.

Stool antigen assay (HpSA) is less reliable than urea breath test for post-treatment diagnosis of Helicobacter pylori infection.

BACKGROUND: The diagnostic yield of the stool antigen test (HpSA) in evaluating the results of Helicobacter pylori eradication therapy is controversial, but many studies have used only the 13C-urea breath test (13C-UBT) as a gold standard which has greatly reduced their relevance. AIM: To compare the reliability of HpSA and 13C-UBT in patients post-treatment using biopsy-based methods as reference tests. METHODS: A total of 100 consecutive dyspeptic patients (42 male and 58 female; mean age, 56 +/- 18 years) were enrolled in our study. All patients were H. pylori positive on the basis of at least two biopsy-based methods, and underwent 1 week of treatment with various triple therapies. They were again endoscoped 4 weeks after completing therapy and six biopsy specimens were taken from the gastric antrum and corpus for rapid urease test, histology and culture. HpSA and 13C-UBT were also performed within 3 days of the second endoscopy. RESULTS: On the basis of biopsy-based tests, infection was eradicated in 77 patients but continued in 23. Three false negatives were observed with HpSA and two with 13C-UBT. In contrast, the number of false positives was significantly higher (P < 0.01) with HpSA than with 13C-UBT (nine vs. one), confirming the lower specificity of the former test. The overall accuracy of HpSA was 88% vs. 97% for 13C-UBT (P < 0.02). CONCLUSIONS: HpSA has lower diagnostic value than 13C-UBT in the evaluation of the outcome of anti-H. pylori therapy. 13C-UBT remains the first-line diagnostic method to monitor eradication results. The use of HpSA should be reserved for those settings in which 13C-UBT is not available.

Influence of mastication on gastric emptying.

The role of mastication on digestion efficiency remains to be demonstrated. This study investigates whether masticatory function influences gastric emptying rate. Twelve normal volunteers were studied on two occasions after ingestion of the same test meal containing ham cubes, crackers, and egg (mixed with 13C-octanoic acid), chewed, in random order, either with 50 masticatory cycles or with 25 cycles, swallowing ham cubes whole. Lag phase (Tlag) and gastric half-emptying time (T1/2) were measured by means of the 13C-octanoic acid breath test. Trituration performance was assessed by the sieve test, and was expressed as the percentage of ham particles < or = 1 mm after 50 masticatory cycles. Tlag and T1/2 were significantly shorter when the meal was chewed with 50 cycles than with 25 cycles (Tlag 25.9+/-3.8 vs. 36.4+/-4.1 min, p=0.017; T1/2 49.1+/-5.7 vs. 62.5+/-6 min, p=0.009). Trituration performance was inversely related to both Tlag (r=0.621, p=0.031) and T1/2 (r=0.699, p=0.012). Comminution of food influences significantly gastric emptying rates.

Impairment of cytochrome P-450-dependent liver activity in cirrhotic patients with Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori gastric infection has been associated with various digestive and extra-digestive diseases. The systemic influence of gastric H. pylori infection seems to be mediated by the release of various cytokines. In liver disease, bacterial infections have been associated with the impairment of liver metabolic function. AIMS: To evaluate the influence of H. pylori infection on liver function as assessed by means of the monoethylglycinexylidide test, which depends upon liver blood flow and cytochrome P-450 activity, and the 13C-galactose breath test, which depends on cytosolic enzymatic activity and is correlated with hepatic functional mass. Moreover, to evaluate whether H. pylori-associated modifications of liver function may be related to tumour necrosis factor-alpha serum levels. PATIENTS AND METHODS: Thirty-five patients with liver cirrhosis of various aetiologies, who underwent monoethylglycinexylidide and 13C-galactose breath tests, were retrospectively evaluated for H. pylori infection by means of anti-H. pylori immunoglobulin G. The main clinical, biochemical and functional characteristics of the patients as well as their tumour necrosis factor-alpha serum levels were then analysed on the basis of the presence of H. pylori infection. RESULTS: Twenty-one patients tested positive for H. pylori infection (60%), and 11 tested negative (31.4%). No clinical or biochemical differences were observed between H. pylori-infected and non-infected patients. H. pylori infection showed no difference in distribution according to Child-Pugh classes (A, 55%; B and C, 67%). The monoethylglycinexylidide test results were significantly lower at each sampling time in H. pylori-positive patients compared to H. pylori-negative patients (MEGX15, P=0.027; MEGX30, P=0.014; MEGX60, P=0.028), while 13C-galactose breath test showed no significant differences considering both cumulative percentage dose and percentage dose/h. The median tumour necrosis factor-alpha serum levels were no different between H. pylori-positive (16.1 pg/mL, 95% confidence interval, 8.7-28.7) and H. pylori-negative (12.3 pg/mL, 95% confidence interval, 8.7-23.4) patients. CONCLUSIONS: In cirrhotic patients, H. pylori infection seems to selectively affect cytochrome P-450 liver activity, while hepatic functional mass does not seem to be impaired. Tumour necrosis factor-alpha does not seem to be the mediator of this impairment. Further studies are needed to evaluate the impact of H. pylori eradication on parameters of liver function.

Does surveillance for hepatocellular carcinoma in HCV cirrhotic patients improve treatment outcome mainly due to better clinical status at diagnosis?

BACKGROUND/AIMS: Cirrhotic patients with hepatitis C virus infection are a group at higher risk for hepatocellular carcinoma. Conventional screening programs detect only few early hepatocellular carcinomas that are eligible for radical treatment. Our aim was to compare characteristics of patients, modality of treatment, and outcome in anti-HCV positive cirrhotics with hepatocellular carcinoma diagnosed during follow-up, or incidentally. METHODOLOGY: Sixty-one hepatocellular carcinomas were consecutively diagnosed in cirrhotic anti-HCV patients from 1993-1998 among which 34 during biannual ultrasonographic-biochemical follow-up and the others incidentally. Child-Pugh's score, alpha-fetoprotein levels, uni- or multifocality of the tumor, and treatment and survival of the patients were then analyzed on the basis of modality of diagnosis. RESULTS: Surgical treatment was feasible only in a minority of patients. Radical and palliative treatment was more frequent among patients with HCC diagnosed during follow-up. Child-Pugh's score was lower in these patients, moreover their survival rate was better. Analysis of survival of patients treated with the same procedure and grouped by modality of diagnosis did not demonstrate any differences. Regression analysis showed that patients with a lower Child-Pugh's score, one nodule, with a tumor diagnosed during follow-up and who were treated had a better survival rate. CONCLUSIONS: In our population surveillance did not detect a higher percentage of curable HCC. Nevertheless the results of palliative treatment and of curative treatment overlapped. Overall better outcome was observed in patients with preserved liver function whatever the treatment. Surveillance allowed us to diagnose HCC in patients with these characteristics thus leading to an improved survival rate.

Cholestasis is the main determinant of abnormal CA 19-9 levels in patients with liver cirrhosis.

BACKGROUND/AIMS: Altered CA19-9 levels are commonly found in patients with liver cirrhosis though a clear explanation for this finding has not yet been given. The aim of this study was to investigate whether CA19-9 levels might be related to alterations in biochemical parameters and/or to functional impairment in cirrhotic patients with and without hepatocellular carcinoma. METHODS: We studied 126 patients with liver cirrhosis, 60 of whom also had hepatocellular carcinoma. CA19-9 values were related to clinical, biochemical and functional parameters. In half of the patients CA19-9 levels were related to the monoethylglycinexylidide test, which is a dynamic liver function test. RESULTS: In more than half the cases CA19-9 values were above the upper limit. Liver function worsening as assessed by Child-Pugh's score and monoethylglycinexylidide test did not seem to influence the alteration of the marker. By contrast, in univariate analysis CA19-9 correlated with aminotransferases, gamma-glutamyltransferase and alkaline phosphatase. Multivariate analysis showed that besides alkaline phosphatase also the presence of hepatocellular carcinoma might influence the alteration of CA19-9, although the marker was of no use for the diagnosis of liver cancer in patients with altered though not diagnostic alpha-fetoprotein levels. CONCLUSIONS: In our study we confirmed the correlation of CA19-9 levels with cholestasis and cytolysis parameters. Moreover, we found no association between CA19-9 levels and impaired liver function as assessed by means of the Child-Pugh's score and the monoethylglycinexylidide test, which is cholestasis-independent and explores liver metabolic and clearance activities. The cholestatic picture that characterizes liver cirrhosis might enhance the expression and passage of the marker from the bile to the blood. The addition of CA19-9 assessment is not useful for the diagnosis of hepatocellular carcinoma in patients with non-diagnostic levels of alpha-fetoprotein. Caution should therefore be used when evaluating CA19-9 in cirrhotic patients with cholestasis, since false positive results may occur.

The impact of antibiotic resistance on the efficacy of three 7-day regimens against Helicobacter pylori.

BACKGROUND: Antibiotic resistance affects the success of anti-Helicobacter pylori therapies and varies greatly from country to country. AIM: To compare the efficacy of three short-term triple regimens in relation to H. pylori primary resistance in our region. METHODS: We enrolled 210 H. pylori-positive dyspeptic patients for this randomized, open, parallel-group study. Three arms of 70 patients each received the following 1-week regimens: (1) ranitidine bismuth citrate 400 mg b.d. + clarithromycin 250 mg b.d. + metronidazole 500 mg b.d. (RCM); (2) bismuth subcitrate 240 mg b.d. + amoxycillin 1000 mg b.d. + metronidazole 500 mg b.d. (BAM); (3) omeprazole 20 mg o.d. + clarithromycin 250 mg b.d. + metronidazole 500 mg b.d. (OCM). H. pylori was assessed by CLO-test and histology before and 4 weeks after therapy. Antibiotic resistance was assessed by E-test. RESULTS: On intention-to-treat analysis RCM was more effective than OCM (84% vs. 69%; P < 0.03) and BAM (84% vs. 63%; P < 0.004). MIC determination was successful in 117 out of 210 patients (55%); metronidazole resistance was present in 52 out of 117 patients (44%) and clarithromycin resistance was present in 17 out of 117 patients (14%). Excellent cure rates were achieved when strains were sensitive to both antibiotics (100% with RCM and BAM and 90% with OCM), whereas RCM was superior to OCM (P=0.009) and BAM (P=0.001) with respect to overall resistant strains (94% vs. 57% and 38%, respectively). CONCLUSIONS: One-week RCM is the best regimen to eradicate H. pylori in our geographical area. This seems to be linked to the better ability of RCM compared to OCM and BAM in overcoming the high prevalence of H. pylori resistance to both metronidazole and clarithromycin in our region.

Comparative effects of levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia and gastroparesis.

BACKGROUND: The efficacy of several prokinetic drugs on dyspeptic symptoms and on gastric emptying rates are well-established in patients with functional dyspepsia, but formal studies comparing different prokinetic drugs are lacking. AIM: To compare the effects of chronic oral administration of cisapride and levosulpiride in patients with functional dyspepsia and delayed gastric emptying. METHODS: In a double-blind crossover comparison, the effects of a 4-week administration of levosulpiride (25 mg t.d.s.) and cisapride (10 mg t.d.s.) on the gastric emptying rate and on symptoms were evaluated in 30 dyspeptic patients with functional gastroparesis. At the beginning of the study and after levosulpiride or cisapride treatment, the gastric emptying time of a standard meal was measured by 13C-octanoic acid breath test. Gastrointestinal symptom scores were also evaluated. RESULTS: The efficacy of levosulpiride was similar to that of cisapride in significantly shortening (P < 0.001) the t1/2 of gastric emptying. No significant differences were observed between the two treatments with regards to improvements in total symptom scores. However, levosulpiride was significantly more effective (P < 0.01) than cisapride in improving the impact of symptoms on the patients' every-day activities and in improving individual symptoms such as nausea, vomiting and early postprandial satiety. CONCLUSION: The efficacy of levosulpiride and cisapride in reducing gastric emptying times with no relevant side-effects is similar. The impact of symptoms on patients' everyday activities and the improvement of some symptoms such as nausea, vomiting and early satiety was more evident with levosulpiride than cisapride.

Data integration to assist gastric emptying data analysis.

The diagnosis of dyspepsia is very difficult because the symptoms are clinically aspecific and the gastric emptying time tests are of complex interpretation. An integrated and automated analysis of clinical and instrumental data may improve the diagnostic process. We present a system to collect data on dyspeptic patient from different sources which has been set up to assist the clinician in the diagnosis of dyspepsia. The data base integrates a wide set of symptoms with data coming from laboratory tests. Moreover, we assess the feasibility of classifying gastric emptying profiles using both octanoid acid excretion data and electrogastrography.