The appropriateness of current UK training in acute internal medicine.

Doctors training in Acute Internal Medicine (AIM) need to provide evidence that they can effectively manage 20 'top' and 40 'other important' acute medical presentations. However, the presentations considered important in the AIM curriculum do not have an empirical evidence base. This study compared real-life presentations against those in the AIM curriculum. Data on all presentations to the acute medical service at The Royal Free Hospital, London, were collected retrospectively for five non-consecutive weeks and prospectively for one week. Five frequently encountered presentations viz: cough, nausea and vomiting, dizziness, hyperglycaemia and lethargy were not amongst those listed as 'top' or 'other important' in the AIM curriculum. Hence, demonstration of competency in these presentations is currently not an explicit requirement.

Review article: pharmacotherapy for alcohol dependence - the why, the what and the wherefore.

BACKGROUND: The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended. AIM: To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors' unwillingness to prescribe these agents, will be explored. METHODS: Relevant papers were selected for review following extensive, language- and date-unrestricted, electronic and manual searches of the literature. RESULTS: Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost-effectiveness while the risks associated with the use of disulfiram are well-known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co-occurring drug-related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine. CONCLUSION: Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition.

Non-invasive diagnostic assessment tools for the detection of liver fibrosis in patients with suspected alcohol-related liver disease: a systematic review and economic evaluation.

BACKGROUND: Excessive alcohol consumption may lead to the development of alcohol-related liver disease (ALD). Liver biopsy may be used in patients with suspected ALD to confirm the diagnosis, exclude other or additional liver pathologies, and provide accurate staging of the degree of liver injury in order to enable the prediction of prognosis and inform treatment decisions. However, as it is an invasive procedure that carries the risk of morbidity and mortality, current UK guidance recommends that biopsy is not required to confirm the diagnosis in patients with a high clinical suspicion of ALD in whom blood tests have excluded other causes of liver disease, unless it is necessary to confirm a diagnosis of acute alcoholic hepatitis in order to inform specific treatment decisions. OBJECTIVES: To evaluate the diagnostic accuracy, cost-effectiveness, and effect on patient outcomes of four non-invasive tests for liver fibrosis [the Enhanced Liver Fibrosis (ELF™) test (Siemens Healthcare Diagnostic Inc., Tarrytown, NY, USA), FibroTest (BioPredictive, Paris, France), FibroMAX (BioPredictive, Paris, France) and transient elastography (FibroScan(®); produced by EchoSens, Paris, France and distributed in the UK by Artemis Medical Ltd, Kent, UK)] in patients suspected of having ALD. DATA SOURCES: A systematic review was undertaken to identify studies reporting the diagnostic and prognostic accuracy of the ELF test, FibroTest, FibroMAX, and FibroScan for the identification of liver fibrosis and associated conditions in patients with suspected ALD. The following databases were searched in January 2010: MEDLINE (from 1950 to January 2010), MEDLINE In-Process & Other Non-Indexed Citations (from 1950 to January 2010), EMBASE (from 1980 to January 2010), Cochrane Database of Systematic Reviews (from 1996 to January 2010), Cochrane Central Register of Controlled Trials (from 1898 to January 2010), Cochrane Methodology Register (from 1904 to January 2010), Database of Abstracts of Reviews of Effects (from 1995 to January 2010), HTA Database (from 1995 to January 2010), NHS Economic Evaluation Database (from 1995 to January 2010), Cumulative Index to Nursing and Allied Health Literature (from 1982 to January 2010), Web of Knowledge and Science Citation Index (from 1969 to January 2010). REVIEW METHODS: Study quality was assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist. Owing to the heterogeneity of the studies, no formal meta-analysis was undertaken. A de novo mathematical model was constructed to estimate the incremental costs and incremental quality-adjusted life-years (QALYs) associated with alternative strategies compared with a biopsy-all strategy. The tests are assessed first as a replacement for liver biopsy, and secondly as an additional test prior to liver biopsy. Thirty-six scenarios were assessed for each non-invasive test strategy, which varied the sensitivity of biopsy, the anxiety associated with biopsy, sensitivity and specificity values and whether or not the biopsy was percutaneous or transjugular. For each scenario, threshold levels were reported where biopsying all patients was more cost-effective than the strategy for two parameters (the decreased level of abstinence associated with the strategy compared with biopsying all and the level of incidental QALY gain associated with biopsy). RESULTS: No studies were identified that specifically assessed the ELF test, although a study was identified that evaluated the diagnostic accuracy of the European Liver Fibrosis Test (essentially, the ELF test with the addition of age to the algorithm) compared with biopsy. Three studies of FibroTest, no relevant studies of FibroMax, and six studies of FibroScan assessing accuracy compared with biopsy in patients with known or suspected alcohol-related liver disease were identified. In all studies, the number of patients with suspected ALD was small, meaning that the estimated sensitivities and specificities were not robust. No conclusive estimate of the cost per QALY of each non-invasive test could be provided. Scenarios exist in which each of the strategies analysed is more cost-effective than biopsying all patients and, in contrast, scenarios exist in which each strategy is less cost-effective than biopsying all patients. LIMITATIONS: Study selection and data analysis were undertaken by one reviewer. CONCLUSIONS: No conclusive result can be provided on the most cost-effective strategy until further data are available. A large number of parameters require data; however, the following are selected as being of most importance: (1) the sensitivity and specificity of each non-invasive liver test (NILT) against biopsy at validated and pre-selected cut-off thresholds; (2) the influence of potential confounding variables such as current drinking behaviour and the degree of hepatic inflammation on the performance of NILTs; and (3) the likelihood, and magnitude, of decreases in abstinence rates associated with a diagnosis of significant ALD by diagnostic modality and the incidental gains in QALYs that may be associated with biopsy. FUNDING: The National Institute for Health Research Technology Assessment programme.

Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence.

The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.

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

BACKGROUND: The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. AIMS: To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. METHODS: A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. RESULTS: It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. CONCLUSIONS: The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.

A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse.

The opioid antagonist, naltrexone, is reported, in single centre studies, to improve the clinical outcome of individuals with alcohol dependence participating in outpatient psychosocial programmes. This is the first multicentre controlled study to evaluate the efficacy and safety of naltrexone as adjunctive treatment for alcohol dependence or abuse. Patients who met criteria for alcohol dependence (n = 169) or alcohol abuse (n = 6) were randomly assigned to receive double-blind oral naltrexone 50 mg daily (n = 90) or placebo (n = 85) for 12 weeks as an adjunct to psychosocial treatment. The primary efficacy variable was time to first episode of heavy drinking; secondary efficacy assessments included time to first drink, alcohol consumption, craving, and changes in the serum biological markers gamma-glutamyl transferase (GGT), and aspartate and alanine aminotransferases. Compliance was assessed by tablet counts and, in the naltrexone-treated group, by measurement of urinary concentrations of 6-ss-naltrexol. Forty-nine (58%) patients randomized to placebo and 53 (59%) randomized to naltrexone did not complete the study. In intention-to-treat analyses, there was no difference between groups on measures of drinking. The median reduction from baseline of serum GGT (P: < 0.05) and the reductions in alcohol craving (Obsessive and Compulsive Drinking Scale: OCDS) were greater in the naltrexone group (P: < 0.05), from approximately half-way through the study. Of 70 patients (35 placebo; 35 naltrexone) who met an a priori definition of compliance (80% tablet consumption, attendance at all follow-up appointments), those allocated to naltrexone reported consuming half the amount of alcohol (P: < 0.05), had greater median reduction in serum GGT activity (P: < 0.05), and greater reduction in alcohol craving (OCDS total score: P: < 0.05; Obsessive subscale score: P: < 0.05), compared to patients in the placebo group. Use of naltrexone raised no safety concerns. Naltrexone is effective in treating alcohol dependence/abuse in conjunction with psychosocial therapy, in patients who comply with treatment.

Energy expenditure in chronic alcohol abuse.

BACKGROUND: In healthy subjects, alcohol decreases lipid oxidation favouring fat deposition. However, individuals who chronically abuse alcohol are not obese. To investigate this paradox, we measured energy expenditure (EE) and fuel utilization in chronic alcohol abusers in relation to their drinking behaviour. METHODS: Resting and postprandial EE and nonprotein respiratory quotient (NPRQ) were measured using indirect calorimetry, in 36 alcohol abusers [mean (+/- SE) age 42 +/- 2 years; weight 67 +/- 2 kg; 21 with steatosis, eight with hepatitis; seven with cirrhosis] and in 36 gender-, age- and weight-matched healthy controls. Alcoholic patients were re-evaluated either after 14 days (n = 14) or on days 2, 4, 6, 8, 14 and 42 (n = 6) after abstinence. RESULTS: When alcoholics were compared to healthy controls, mean energy intake was greater, 15 +/- 1 MJ day-1 (38 +/- 2% from alcohol) cf. 9 +/- 1 MJ day-1 (P < 0.001), resting EE increased, 82 +/- 2 cf. 65 +/- 2 W (P < 0.001) and NPRQ decreased, 0.75 +/- 0.02 cf. 0.82 +/- 0.01 (P < 0.001). The postprandial increases in EE and NPRQ were of similar magnitude in both groups. Abstinence from alcohol for 14 days was accompanied by reduced energy intake, 16 +/- 1 cf. 11 +/- 1 MJ day-1 (P < 0.005) and decreased resting EE, 84 +/- 5 cf. 73 +/- 4 W (P < 0.05). The decrease in resting EE consistently occurred 4 days after abstinence from alcohol. CONCLUSIONS: Chronic alcohol abuse is associated with energy wasting and inhibition of adipose tissue accumulation. This may explain why alcoholics are not obese despite high total energy intakes.

United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol.

A 6-month randomized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK. Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were randomly assigned to treatment with either acamprosate (A) 666 mg three times/day or identical placebo (P). A total of 664 patients were screened; 581 were entered into the treatment phase. One-third were episodic drinkers, 84% were male, 44% were unmarried and 48% were unemployed. Medication was first taken on average 24 days after the start of detoxification; 32% of patients had already relapsed by this time. The 6-month study period was completed by 35% of patients; adverse events led to withdrawal of a further 14% (A) and 9% (P) respectively. Compliance was poor in that, by the end of the second week, only 57% of patients were judged to be taking at least 90% of their tablets. The mean total of abstinent days achieved was 77 (A) and 81 (P). Complete abstinence for 6 months was achieved by 12% (A) and 11% (P); drinking remained within controlled limits in a further 3% (A) and 6% (P). An effect of acamprosate on consumption was not seen when subgroups, including those defined by the Lesch typology, were analysed separately. However, the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate, than placebo, patients at week 2 and week 4 (P<0.001) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients (P = 0.017). In comparison with other published trials of acamprosate, patients started study medication after a longer time following detoxification, had more often recommenced drinking before medication was started and had a higher drop-out rate, and this might have contributed to the lack of a treatment effect in this study.

Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study.

OBJECTIVE: To determine the efficacy, tolerability and safety of oral rifaximin given at three dose levels in patients with cirrhosis and mild to moderate hepatic encephalopathy (HE). DESIGN: Prospective, double-blind, randomized, parallel-group study. SETTING: Multi-centre trial in four university teaching hospitals. PARTICIPANTS: Fifty-four patients with cirrhosis and mild to moderate HE. INTERVENTION: Seven days treatment with rifaximin, 600, 1200 or 2400 mg/day in three divided doses. MAIN OUTCOME MEASURE: Change in the portal-systemic encephalopathy (PSE) index between baseline and day 7, calculated on the basis of mental state, asterixis, number connection test time, EEG mean cycle frequency and blood ammonia concentrations. RESULTS: Treatment with rifaximin was associated with an improvement in the PSE index. There was a trend towards a greater treatment effect of rifaximin with the highest dose of 2400 mg/day. Rifaximin was well tolerated; the few treatment-related adverse events showed no consistent pattern or dose relationship. CONCLUSION: Rifaximin may be useful as alternative or adjuvant therapy for grade I-III hepatic encephalopathy in patients with cirrhosis at a dose of 1200 mg/day.

Resting energy expenditure should be measured in patients with cirrhosis, not predicted.

Measurements of resting energy expenditure (REE) can be used to determine energy requirements. Prediction formulae can be used to estimate REE but have not been validated in cirrhotic patients. REE was measured, by indirect calorimetry, in 100 cirrhotic patients and 41 comparable healthy volunteers, and the results compared with estimates predicted using the Harris-Benedict, Schofield, Mifflin, Cunningham, and Owen formulae, and the disease-specific Müller formula. The mean (+/- 1 SD) measured REE in the healthy volunteers (1,590 +/- 306 kcal/24 h) was significantly greater than the mean Harris-Benedict, Mifflin, Cunningham, and Owen predictions but comparable with the mean Schofield prediction; individual predicted values varied widely from measured values (95% limits of agreement, -460 to +424 kcal). The mean measured REE in the cirrhotic patients was significantly greater than in the healthy volunteers (23.2 +/- 3. 8 cf 21.9 +/- 2.9 kcal/kg/24 h; P <.05). The mean measured REE in the cirrhotic patients (1,660 +/- 337 kcal/24 h) was significantly different from mean predicted values (Harris-Benedict, 1,532 +/- 252 kcal/24 h, P <.0001; Schofield, 1,575 +/- 254 kcal/24 h, P <.0005; Mifflin, 1,460 +/- 254 kcal/24 h, P <.0001; Cunningham, 1,713 +/- 252 kcal/24 h, P <.05; Owen, 1,521 +/- 281 kcal/24 h, P <.0001; Müller, 1,783 +/- 204 kcal/24 h, P <.0001); individual predicted values varied widely from measured values (95% limits of agreement, -632 to +573 kcal). Simple regression analysis showed that fat-free mass (FFM) was the strongest predictor of measured REE in the cirrhotic patients, accounting for 52% of the variation observed. However, a population-specific prediction equation, derived using stepwise regression analysis, which incorporated FFM, age, and Pugh's score, accounted for only 61% of the observed variation in measured REE. REE should, therefore, be measured in cirrhotic patients, not predicted.

Patterns of energy intake in patients with cirrhosis and healthy volunteers.

Fuel utilization and N economy are optimized in patients with cirrhosis by provision of several small meals throughout the day and a late-night snack of complex carbohydrate. Currently, however, only limited information is available on the patterns of energy intake in patients with chronic liver disease. The aims of the present study were to determine the number of days required to undertake such an investigation and to observe the daily distribution of energy intake in this patient population. Eight patients with cirrhosis and eight matched healthy volunteers kept weighed dietary intake records for fifteen separate days over a 6-month period. The records were analysed for energy intake per hour and the number and size of energy intake episodes per 24 h calculated. Intake was verified against resting energy expenditure. Fourteen separate observational days were required to investigate the pattern of energy intake in the cirrhotic patients while 20 d were required for healthy volunteers. Considerable inter- and intrasubject variations in the number and size of energy intake episodes were observed in both the patients and healthy volunteers. However, no significant differences were observed between the mean total number of daily energy intake episodes (6.3 (SD 1.6) v. 7.0 (SD 1.4)) or in the distribution of daily energy intake between the two groups. Most patients and volunteers tended to eat frequent small meals, often including a late-night snack, rather than two or three large meals daily. It should, therefore, be possible to establish optimum patterns of energy intake in these patients in line with recent guidelines.

Preservation of macronutrient preferences in cancer anorexia.

Indirect evidence suggests that cancer anorexia is associated with specific aversions to macronutrients. To investigate this, patients with cancer anorexia and hospitalized control subjects devised 3-day menus comprising foods that they wished to eat. These foods were then provided for 3 days and the intakes of each food carefully measured. As expected, patients with cancer anorexia consumed substantially less energy than hospitalized control subjects (6.0 +/- 0.9 MJ vs 9.5 +/- 0.5 MJ, P < 0.001). However, macronutrient composition was consistently maintained in the patients with cancer anorexia. These data argue against cancer anorexia representing a state of macronutrient aversion.

Cerebral magnetic resonance imaging in patients with chronic liver disease.

Bilateral, symmetrical hyperintensity of the globus pallidus is observed in T1-weighted cerebral magnetic resonance images in from 52 to 100% of patients with chronic liver disease. No significant relationship exists between the presence of these cerebral changes in image signal intensity and the patients' neuropsychiatric status. However, their presence significantly relates to both the severity of the liver disease and the presence and degree of portal-systemic shunting of blood. This shortening of the T1-relaxation time is associated with pallidal deposition of manganese most likely reflecting the presence of an adaptive process designed to improve the efficacy of ammonia detoxification by astrocytes. Future studies employing magnetic resonance imaging techniques to obtain information on cerebral function or combined with magnetic resonance spectroscopy to obtain localized biochemical information might further our understanding of the pathogenesis of hepatic encephalopathy in cirrhotic patients.

Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences.

Impairment of gustatory acuity may influence nutrient intake and hence nutritional status. The aim of this study was to evaluate gustatory acuity in patients with cirrhosis and its relationship to circulating concentrations of micronutrients, and food preferences. Gustatory evaluation was undertaken, using a rinsing technique, in 75 cirrhotic patients and 75 comparable healthy volunteers. Circulating concentrations of magnesium, zinc, vitamin A, and alpha- and beta-carotene were measured, and food preferences were assessed by questionnaire. The cirrhotic patients showed impaired gustatory function with significantly higher (less sensitive) median thresholds for detection of salt, sweet, and sour and for recognition of bitter, salt, sweet, and sour, together with a higher overall median gustatory score (P < .0001). Mean circulating concentrations of magnesium, zinc, vitamin A, and alpha- and beta-carotene were significantly lower in the patient population. Serum magnesium was significantly negatively associated with detection of salt (P = .02) and gustatory score (P = .02). Patients' subjective assessment of taste acuity did not correspond with objective measurements. Overall, no differences were observed in food preferences between the two groups, nor was any association found between food preferences and gustatory acuity. Patients with cirrhosis have impaired gustatory acuity that is associated with hypomagnesemia but apparently does not affect food selection.

The potential role of dual-energy X-ray absorptiometry in the assessment of body composition in cirrhotic patients.

Very little information is available on body composition in patients with cirrhosis. Difficulties arise in studying these patients because they tend to retain fluid and this results in changes in tissue density and in the hydration fraction of fat-free mass. As the classic body composition techniques rely on the assumption that these variables remain constant, use of these methods will result in either under- or overestimates of body composition variables. Use of multicomponent models, employing two or more measurement techniques, will obviate the need for some of the assumptions inherent in the use of single techniques, thereby increasing the accuracy of the assessments without loss of precision. Dual-energy x-ray absorptiometry can be used to measure total body bone mineral, fat, and fat-free soft tissue mass. In healthy individuals excellent agreement is observed between data obtained using this technique and data obtained from the more established reference methods. However, the degree to which the absorptiometry measurements of soft tissue are sensitive to the hydration is not known. Thus, in order to assess this method of body composition analysis in patients with chronic liver disease, a multicomponent model must be devised which incorporates the absorptiometry technique and allows cross-validation of the individual component measures.