Ian Gilmore

Molecular Diagnosis of Early Pancreatic Ductal Adenocarcinoma in High-Risk Patients

The prevalence of pancreatic cancer in the general population is too low – even in high-prevalence areas such as Northern Europe and North America (8–12 per 105 population) – relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.

Projections of alcohol deaths--a wake-up call.

According to WHO, morbidity attributable to alcohol in countries with an established market economy (10·3% of disability adjusted life years) comes second only to that of tobacco (11·7%).1 Liver disease is responsible for 70% of the directly recorded mortality from alcohol,2 and perhaps a quarter of the total attributable mortality; the true total is uncertain but is probably between 18?000 and 30?000 per year in England and Wales. Alcohol causes around 80% of deaths from liver disease,2 and trends in liver mortality reflect trends in overall alcohol-related harm; liver death rates are a measure of the damage caused to society by alcohol, and a good measure for the success of alcohol policy. Few can doubt that there is a particular problem in the UK. Compared with the UK, the Netherlands, Sweden, Norway, Australia, and New Zealand have similar cultures, genetic backgrounds and drinking cultures, and in 1986 they had broadly similar liver death rates. The most recent WHO liver death rates for these countries range from 2·6 per 100?000 (New Zealand) to 5·3 (Sweden); whereas in the UK liver death rates more than doubled from 4·9 to 11·4 since 1986.3 A liver death rate of around 4 per 100?000 is therefore a reasonable and achievable aspiration for an outcomes-based alcohol policy. We projected outcomes in terms of liver death rates according to four different policy scenarios (figure).4 With the black scenario, liver deaths increase at a similar rate to that seen in the UK as a whole over the past 10 years. A green scenario would see a reduction in UK death rates with the same gradient as that for France—the country with the most profound reductions in mortality. The intermediate scenarios, amber and red, would see liver deaths reduce along the gradients followed by the rates in Italy or in the European Union as a whole

An evidence-based alcohol policy

In October 2007 the BBC performed a survey of British Society of Gastroenterology members in which they asked a number of questions about the changing patterns of alcohol related disease they were seeing in the UK. Of the 115 responses, only 9 had seen no change in alcohol-related liver disease over the last 10 years; 92% reported a rise, usually large. Recurrent themes were the increase in women presenting with alcoholic liver disease and the younger age of presentation. Nearly three quarters of responders had seen patients of 25 or under with alcoholic hepatitis or cirrhosis, and nearly a quarter had patients in their late teens. These depressing findings are in line with the report by the chief medical officer in 2001: 9In the last 30 years of the 20th Century deaths from liver cirrhosis steadily increased, in people aged 35 to 44 years the death rate went up 8-fold in men and almost 7-fold in women, in 25-34 year-olds a 4-fold increase was seen over the 30 year period9. The UK situation is in stark contrast to the decrease in liver mortality in Mediterranean countries over the same period of time (figure 1).In October 2007 the BBC performed a survey of British Society of Gastroenterology (BSG) members in which a number of questions were asked about the changing patterns of alcohol-related disease the BSG was seeing in the UK. Of the 115 responses, only nine members had seen no change in alcohol-related liver disease over the last 10 years; 92% reported a rise, usually large. Recurrent themes were the increase in women presenting with alcoholic liver disease and the younger age of presentation. Nearly three-quarters of responders had seen patients of 25 years or under with alcoholic hepatitis or cirrhosis, and nearly a quarter had patients in their late teens. These depressing findings are in line with the report by the Chief Medical Officer in 2001: > In the last 30 years of the 20th century deaths from liver cirrhosis steadily increased, in people aged 35 to 44 years the death rate went up 8-fold in men and almost 7-fold in women, in 25–34 year-olds a 4-fold increase was seen over the 30 year period. The UK situation is in stark contrast to the decrease in liver mortality in Mediterranean countries over the same period of time (fig 1). Figure 1 Over the last 30 years standardised cirrhosis mortality rates (cirrhosis deaths/100 000 under the age of 64 years) have increased in the UK, Finland, Denmark and Ireland, countries where traditionally tight controls on alcohol have been relaxed, and decreased in the wine drinking countries of France, Italy and Spain where the traditionally high consumption of cheap wine with meals has reduced. The biggest drop is in France where strict controls ( la loi Evin ) on the promotion of alcohol were also introduced. (Data obtained from the WHO HFA database.31) So why is the UK facing this increase in liver deaths when mortality elsewhere is falling? According to death certification data more than 80% of UK liver deaths are due to alcohol-related cirrhosis.1 Other causes of liver disease are also increasing; for example, steatosis and viral hepatitis, but only 205 out of 6889 reported liver deaths in 2005 were due to viral hepatitis.2 While viruses and, more importantly, steatosis secondary to obesity3 may be co-factors in some cases, the evidence suggests that it is our drinking habits that are the problem. Since 1970 the standardised death rate (SDR) for cirrhosis …

When is pancreatitis considered to be of biliary origin and what are the implications for management

Acute pancreatitis is a disease caused by gallstones in 40–60% of patients. Identification of these patients is extremely important, since there are specific therapeutic interventions by endoscopic sphincterotomy and/or cholecystectomy. The combination of trans-abdominal ultrasound (stones in the gallbladder and/or main bile duct) and elevated serum alanine transaminase (circa >60 IU/l within 48 h of presentation) indicates gallstones as the cause in the majority of patients with acute pancreatitis. In the presence of a severe attack this is a strong indication for intervention by endoscopic sphincterotomy. The presence of a significant main bile duct dilatation is also strongly indicative of gallstones and should prompt the use of endoluminal ultrasonography: >8 mm diameter with gallbladder in situ, or >10 mm following cholecystectomy if aged <70 years and >12 mm, respectively, if ≧70 years. In mild pancreatitis surgically fit patients should be treated by cholecystectomy, and intra-operative cholangiography, as pre-operative biliary imaging is not efficient in this setting. Patients who are not fit for cholecystectomy should undergo prophylactic endoscopic sphincterotomy to prevent further attacks. In the post-acute-phase, pancreatitis patients in whom the aetiology is uncertain should undergo endoluminal ultrasonography. Thisis the most sensitive method for the detection of cholelithiasis and choledocholithiasis and may reveal alternative aetiological factors such as a small ampullary or pancreatic cancer. A number of recent studies have shown that bile crystal analysis, a marker for microlithiasis, increases the yield of positive results over and above endoluminal ultrasonography, and should be considered as part of the modern investigative algorithm.

Brief interventions in dependent drinkers: a comparative prospective analysis in two hospitals.

AIMS To investigate whether brief interventions (BIs) delivered by a dedicated Alcohol Specialist Nurse (ASN) to non-treatment-seeking alcohol-dependent patients in an acute hospital setting are effective in reducing alcohol consumption and dependence. METHODS A prospective cohort control study in two acute NHS Hospital Trusts in the North West England, one of which provided BI (university teaching hospital-test site) while the other did not (district general hospital-control site), including follow-up BIs. Subjects were alcohol-dependent patients aged ≥18 years. RESULTS A total of 100 patients were recruited at each site. No differences were found between the groups in the baseline demographic parameters or medical co-morbidities. At the test site, further sessions were sometimes offered, and 46 patients received more than one intervention (median 4, mean 6.3 and maximum 20). At 6 months, alcohol consumption (P < 0.0001), Alcohol Use Disorders Identification Tool (AUDIT) score (P < 0.0001) and Severity of Alcohol Dependence Questionnaire score (P = 0.0001) were significantly lower at the test site than the control site. Outcomes were found to be independent of both the baseline level of dependence and medical co-morbidity. CONCLUSION BI delivered by a dedicated ASN for non-treatment-seeking alcohol-dependent individuals, who often have significant medical co-morbidities, seem to be effective in an acute hospital setting. This study provides a framework to inform the design of a future randomized controlled trial.

Politicians must heed health effects of climate change

The UCL Lancet Commission on climate change and health (May 16, p 1693) concludes: “Climate change is the biggest global health threat of the 21st century”. In this report, the authors emphasise not only the immediacy and gravity of this threat, but also the directness: while the poorest in the world will be the fi rst aff ected, none will be spared. The escalating carbon footprint of the developed world has led to the present situation, but the rapid impact on developing countries such as the encroaching deserts in Africa is the immediate price. This is one reason why doctors must take a lead in speaking out. Another is that there are important co-benefi ts of tackling climate change for those with long-term conditions in the developed world, such as those that come from more exercise with less use of cars and dietary change with reduced meat consumption. In December of this year, world governments meet in Copenhagen, Denmark, to negotiate a new UN Framework Convention on Climate Change. There is a real danger that politicians will be indecisive, especially in such turbulent economic times as these. Should their response be weak, the results for interna tional health could be catastrophic. Doctors are still seen as respected and independent, largely trusted by their patients and the societies in which they practise. As leaders of physicians across many countries, we call on doctors to demand that their politicians listen to the clear facts that have been identifi ed in relation to climate change and act now to implement strategies that will benefi t the health of communities worldwide.

Projections of alcohol-related deaths in England and Wales—tragic toll or potential prize?

The latest alcohol-related harm statistics from the UKs Office of National Statistics (ONS) were released on Jan 26, 2012,1 and provide an opportunity to re-evaluate the projections of alcohol-related liver deaths that we previously reported in this journal with 2008 data.2 Using the standard ONS definition,3 alcohol-related liver deaths in England and Wales fell from 6470 in 2008 to 6230 in 2009, but then increased again to 6317 in 2010.4 These data do not include the wider spectrum of alcohol attributable mortality, which would also include acute deaths from accidents, violence, and suicide or from chronic diseases, such as hypertension, stroke, cardiovascular disease, and cancers of the breast and gastrointestinal tract. Alcohol-related liver deaths thus account for around a quarter of total alcohol-related deaths.

Alcohol imagery and branding, and age classification of films popular in the UK

Background Exposure to alcohol products in feature films is a risk factor for use of alcohol by young people. This study was designed to document the extent to which alcohol imagery and brand appearances occur in popular UK films, and in relation to British Board of Film Classification (BBFC) age ratings intended to protect children and young people from harmful imagery. Methods Alcohol appearances (classified as ‘alcohol use, inferred alcohol use, other alcohol reference and alcohol brand appearances’) were measured using 5-min interval coding of 300 films, comprising the 15 highest grossing films at the UK Box Office each year over a period of 20 years from 1989 to 2008. Results At least one alcohol appearance occurred in 86% of films, at least one episode of alcohol branding in 35% and nearly a quarter (23%) of all intervals analysed contained at least one appearance of alcohol. The occurrence of ‘alcohol use and branded alcohol appearances’ was particularly high in 1989, but the frequency of these and all other appearance categories changed little in subsequent years. Most films containing alcohol appearances, including 90% of those including ‘alcohol brand appearances’, were rated as suitable for viewing by children and young people. The most frequently shown brands were American beers: Budweiser, Miller and Coors. Alcohol appearances were similarly frequent in films originating from the UK, as from the USA. Conclusion Alcohol imagery is extremely common in all films popular in the UK, irrespective of BBFC age classification. Given the relationship between exposure to alcohol imagery in films and use of alcohol by young people, we suggest that alcohol imagery should be afforded greater consideration in determining the suitability of films for viewing by children and young people.

Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Governments soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.

Alcohol: taking a population perspective

Alcohol consumption is a global phenomenon, as is the resultant health, social and economic harm. The nature of these harms varies with different drinking patterns and with the societal and political responses to the burden of harm; nevertheless, alcohol-related chronic diseases have a major effect on health. Strong evidence exists for the effectiveness of different strategies to minimize this damage and those policies that target price, availability and marketing of alcohol come out best, whereas those using education and information are much less effective. However, these policies can be portrayed as anti-libertarian and so viewing them in the context of alcohol-related harm to those other than the drinker, such as the most vulnerable in society, is important. When this strategy is successful, as in Scotland, it has been possible to pass strong and effective legislation, such as for a minimum unit price for alcohol.