Marsha Y. Morgan

The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: Results of a meta-analysis

BACKGROUND A number of clinical trials have been undertaken to determine the efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals. However, the reported differences in patient populations, treatment duration, and study endpoints make comparisons difficult. An assessment of the efficacy of treatment with acamprosate was, therefore, undertaken using meta-analytical techniques. METHODS All randomized, placebo-controlled trials (RCTs) that fulfilled predetermined criteria were identified using (1) a language unrestricted search of 10 electronic databases; (2) a manual search of relevant journals, symposia, and conference proceedings; (3) cross-referencing of all identified publications; (4) personal communications with investigators; and (5) scrutiny of Merck-Santés internal reports of all European trials. Study quality was assessed, independently, by three blinded workers. Key outcome data were identified; some outcome variables were recalculated to ensure consistency across trials. The primary outcome measure was continuous abstinence at 6 months; abstinence rates were determined by estimating Relative Benefit (RB). RESULTS A total of 19 published 1 unpublished RCTs were identified that fulfilled the selection criteria; 3 were excluded because the documentation available was insufficient to allow adequate assessment. The remaining 17 studies, which included 4087 individuals, 53% of whom received active drug, were of good quality and were otherwise reasonably comparable. There was no evidence of publication bias. Continuous abstinence rates at 6 months were significantly higher in the acamprosate-treated patients (acamprosate, 36.1%; placebo, 23.4%; RB, 1.47; [95% confidence intervals (CI): 1.29-1.69]; p < 0.001). This effect was observed independently of the method used for assigning missing data. The effect sizes in abstinent rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. At 12 months, the overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI, 7.8-18.7%; number needed to treat, 7.5). Acamprosate also had a modest but significant beneficial effect on retention (6.01%; [95% CI, 2.90-8.82]; p = 0.0106). CONCLUSION Acamprosate has a significant beneficial effect in enhancing abstinence in recently detoxified, alcohol-dependent individuals.

Sex-related differences among 100 patients with alcoholic liver disease.

During 1975 we studied 100 patients--77 men and 23 women--who had a history of alcohol abuse and disturbed liver function test results. On presentation the women were less likely to be suspected of alcohol abuse (9; 38%) than the men (59; 77%). Although the quantity of alcohol consumed and length of history of alcohol abuse were similar for men and women, the incidence of chronic advanced liver disease was higher among women (86%) than among men (65%). Women, however, were less likely to have developed primary liver cell cancer. Overall the women had a higher incidence of other alcohol-related disorders and were less likely to stop abusing alcohol (2; 9%) than were their male counterparts (22; 29%). Women seem to be more susceptible to alcohol-related disease.

Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement

Aliment Pharmacol Ther 2011; 33: 739–747

Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis.

Liver iron concentrations were determined in 60 alcoholics with liver disease of varying severity, 15 patients with untreated idiopathic hemochromatosis, and 16 control subjects with biliary tract disease. Mean liver iron concentrations (μg/100 mg dry weight) were significantly greater in the alcoholics (156.4±7.8 (sem);P<0.05) and in patients with idiopathic hemochromatosis (2094.5±230.7;P<0.01) than in control subjects (53.0±7.0). Liver iron concentrations of >140 μg/100 mg were found in 17 alcoholics (29%) and in all 15 patients with idiopathic hemochromatosis. Liver iron concentrations >1000 μg/100 mg were found in all patients with idiopathic hemochromatosis but in none of the alcoholics. In the alcoholics no relationship existed between liver iron concentrations and the amount of alcohol consumed daily, the length of the drinking history, the amount of beverage iron consumed daily, or the severity of the liver disease. Serum ferritin concentrations reflected iron stores in patients with hemochromatosis and in alcoholics with minimal liver disease. However, in alcoholics with significant liver disease serum ferritin concentrations did not reflect iron stores accurately, although with normal values iron overload is unlikely. Serum iron concentration and percentage saturation of total iron-binding capacity were of little value in assessing iron status in either alcoholics or patients with hemochromatosis. Measurement of the liver iron concentration clearly differentiates between alcoholics with significant siderosis and patients with idiopathic hemochromatosis.

Plasma ratio of valine, leucine and isoleucine to phenylalanine and tyrosine in liver disease.

The molar ratio valine + leucine + isoleucine/phenylalanine + tyrosine was determined in the plasma of patients with liver disease of varying aetiology and severity and in an age and sex matched control group. In the control group of 58 subjects the mean ratio was 3.3 +/- 0.5 (ISD). The mean ratio was significantly lowered in groups of 25 patients with alcoholic cirrhosis (P less than 0.001), 25 patients with chronic active hepatitis (P less than 0.001), 23 patients with primary biliary cirrhosis (P less than 0.001), and 11 patients with cryptogenic cirrhosis (P less than 0.001). In a group of 50 patients with cirrhosis, the ratio was significantly lowered (P less than 0.001) irrespective of the presence of hepatic encephalopathy. A good correlation existed between the value of the ratio and the severity of the liver disease as judged histologically, with values of the ratio appearing to reflect histological change irrespective of the patients clinical condition. There was no significant diurnal variation in the value of the ratio. Lowering of this plasma amino acid ratio appears to be secondary to liver disease and quite independent of the presence of hepatic encephalopathy.

The nutritional management of hepatic encephalopathy in patients with cirrhosis: International society for hepatic encephalopathy and nitrogen metabolism consensus

Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex‐related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35‐45 kcal/g and 1.2‐1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late‐night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short‐term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE. (Hepatology 2013)

Plasma amino-acid patterns in liver disease

Plasma amino-acid concentrations were measured in 167 patients with liver disease of varying aetiology and severity, all free of encephalopathy, and the results compared with those in 57 control subjects matched for age and sex. In the four groups of patients with chronic liver disease (26 patients with chronic active hepatitis, 23 with primary biliary cirrhosis, 11 with cryptogenic cirrhosis, and 48 with alcoholic hepatitis +/- cirrhosis) plasma concentrations of methionine were significantly increased, while concentrations of the three branched chain amino-acids were significantly reduced. In the first three groups of patients plasma concentrations of aspartate, serine, and one or both of the aromatic amino-acids tyrosine and phenylalanine were also significantly increased, while in the patients with alcoholic hepatitis +/- cirrhosis plasma concentrations of glycine, alanine, and phenylalanine were significantly reduced. In the three groups of patients with minimal, potentially reversible liver disease (31 patients with alcoholic fatty liver, 10 with viral hepatitis, and 18 with biliary disease) plasma concentrations of proline and the three branched chain amino-acids were significantly reduced. Patients with alcoholic fatty liver also showed significantly reduced plasma phenylalanine values. Most changes in plasma amino-acid concentrations in patients with chronic liver disease may be explained on the basis of impaired hepatic function, portal-systemic shunting of blood, and hyperinsulinaemia and hyperglucagonaemia. The changes in patients with minimal liver disease are less easily explained.

Regional variations in cerebral proton spectroscopy in patients with chronic hepatic encephalopathy

Regional variations in proton magnetic resonance spectroscopy (MRS) were assessed in 26 patients and 14 healthy volunteers using a two dimensional chemical shift imaging technique. Patients were classified as being neuropsychiatrically unimpaired, or as having subclinical or overt chronic hepatic encephalopathy (CHE). Peak area ratios of choline (Cho), glutamine and glutamate (Glx) and N-acetylaspartate (NAA) relative to creatine (Cr) were measured. Significant reductions in mean Cho/Cr and elevations in mean Glx/Cr were observed in the patient population, which correlated with the severity of CHE. There were significant regional variations in these metabolite ratios with the mean Cho/Cr lowest in the occipital cortex and the mean Glx/Cr highest in the basal ganglia. NAA/Cr remained relatively constant in all areas of the brain analysed. The regional variation in the metabolite ratios suggests that spectral information from more than one voxel may be useful in the assessment of patients with CHE.

Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients: A randomised, cross-over study

Fourteen patients with cirrhosis and subclinical hepatic encephalopathy were randomised to treatment with lactitol or lactulose for a 2-month period during which they were monitored clinically, by electroencephalography and by manually administered and computer-based psychometric testing. Following a washout period of 4-6 weeks patients were crossed-over to treatment with the alternative sugar for a similar period of monitoring. None of the patients showed evidence of overt hepatic encephalopathy and only one showed slowing of the electroencephalogram mean cycle frequency at the onset of the trial. However, significant impairment was observed in the group as a whole in the performance of all three manually administered psychometric tests and in four of the ten computer-based test variables. No changes were observed in clinical status or in electroencephalogram mean cycle frequency during treatment with either lactitol or lactulose. However, psychometric performance improved consistently, and to the same degree, during treatment with both sugars. Patients required a mean of 26 g (range 8-36) of lactitol and 25 ml (10-60) of lactulose to achieve two semi-soft stools per day. The majority of patients complained of flatulence during treatment with both sugars but this tended to resolve with continued treatment. Diarrhoea developed in a small number of patients during both treatment periods but this was invariably dose-related. Patients were equally divided in their preference for the two sugars. Patients with subclinical hepatic encephalopathy benefit from treatment with lactitol and lactulose in terms of their psychometric performance. The feasibility and benefits of long-term treatment for this condition need to be elucidated.

Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: A multidimensional approach

There is no “gold standard” for diagnosing hepatic encephalopathy in patients with cirrhosis. In consequence, the presence of this condition, unless floridly overt, is often missed. As a result, the majority of patients are denied the benefits of treatment. There are a number of individual techniques, which access different aspects of cerebral function that can be used, singly or in combination, to provide diagnostic information in this condition, including mental state assessment, psychometric testing, electroencephalography, sensory and cognitive evoked potentials, and neuroimaging. These have been variously applied to the study of hepatic encephalopathy but fundamental differences in the essential aims of the studies, as well as differences in the patient populations and the acquisition and analysis of the data, have made comparisons difficult. Thus, there is no clear consensus as to the sensitivity, specificity, or validity of these tests when used alone or in combination. There are, however, a number of additional methods that could be used to analyze the electrophysiological data, and a number of alternative evoked potentials that could be measured to provide better diagnostic information. In addition, there are a number of techniques, such as critical flicker frequency and smooth pursuit eye movements, which have not yet been applied systematically in this condition and which may provide useful diagnostic information. Clearly the methods for assessing hepatic encephalopathy need to be reviewed, newer methods for analyzing the electrophysiological data and newer techniques for assessing alternative aspects of cerebral function need to be explored for their diagnostic utility. This process should aim at developing a multidimensional diagnostic tool.