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By 2020, it is estimated that non-alcoholic steatohepatitis (NASH) will be the leading indication for liver transplantation.
During the Sheila Sherlock Lecture, Dr Matthew Armstrong of Queen Elizabeth University Hospital Birmingham, reminded delegates NASH is the most common form of liver disease, especially in the Western world, and that up to 20% of cases progress to cirrhosis
So far, there have been no licensed therapies for NASH; Dr Armstrong’s presentation focused on research into the glucagon-like peptide-1 (GLP-1) analogues and their potential role in the management of the condition.
GLP-1 analogues were developed as treatments for type 2 diabetes, however, Trevaskis et al (2012) provided evidence to suggest that liver fibrosis had regressed on histological assessment and collagen-1 immunostaining (marker of fibrogenesis) with GLP-1.
A study in type 2 diabetes (Armstrong et al 2013) had demonstrated a dose -dependent improvement in liver enzymes. However, as Dr Armstrong pointed out, these findings were retrospective and the study was diabetes-focussed and not powered for liver endpoints.
However, the LEAN double-blinded, randomised, placebo-controlled phase 2 trial assessed the GLP-1 analogue, liraglutide, in overweight patients with clinical evidence of NASH (Armstrong et al 2016). The primary outcome measure was resolution of definite NASH with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed by two independent pathologists.
Nine of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite NASH compared with two of 22 patients in the placebo group (relative risk 4·3). Two of 23 patients in the liraglutide group versus eight of 22 patients in the placebo group had progression of fibrosis. Most adverse events were grade 1 or 2, and were self-limiting in the first 12 weeks with the exception of gastrointestinal disorders in 21 liraglutide patients and 17 placebo patients.
Dr Armstrong summarized that GLP-1 agonists achieve histological clearance of NASH, reduce fibrosis progression and improves key metabolic risk factors with a direct and indirect mechanism of action. And they are well tolerated with an acceptable safety profile.
Binge drinking culture was created deliberately to aid falling profits and public health is picking up the bill.
In a blistering attack on the Government and the drinks industry, Professor Nick Sheron, a consultant hepatologist, traced the current “epidemic of liver disease” to the 1990s, when marketing campaigns targeted a generation that had shunned alcohol in favour of “party drugs”.
“The drinks industry got worried because young people stopped drinking, so they changed their marketing and targeted 18 year olds with a new type of drink: alco-pops.
“At the beginning of the 1990s, children did not drink any spirits at all. By the end, 10 to 15 year olds are drinking at last one double vodka a week.”
Talking at the annual meeting of the British Association for the Study of the Liver in Manchester this week, he used the Government’s own figures to slam the U-turn on introducing a minimum price per unit (MUP) in 2014. In the same year there were 8,697 alcohol-related deaths in the UK.
“If we are going to stop people dying of liver disease we have to stop people drinking alcohol,” he said.
Far from MUP penalising moderate drinkers, as critics of the policy claimed, it would disproportionally impact those drinking at harmful levels, he said.
“Back in the 1980s, a litre of spirits would have cost more than £90. Today, the equivalent price is £28. The mean consumption of one of my patients with cirrhosis is 150 units a week.
“People with cirrhosis spent 30p a unit, others, on average, spend £1 a unit. Patients with cirrhosis on the whole are not drinking frozen mojitos for £7 a go in a rooftop bar.”
Charging 70p a unit, Prof Sheron said, would take the average weekly alcohol bill of his caseload from £23.25 to £105.
There is a direct correlation between the price of alcohol and deaths from liver disease, Prof Sheron said.
In 2008 in the midst of the economic downturn and to the backdrop of rising deaths from liver disease, a 2% tax escalator policy was introduced by the then Chancellor Alistair Darling.
The policy, which saw duty on wine and spirits automatically rise by 2% above inflation each year, was hotly opposed by the drinks lobby, but Prof Sheron said the number of deaths started to level out.
The policy was dropped in 2014 following extensive lobbying from the Wine and Spirits Association.
“Everything was going in the right direction and now we are back to an 8% year-on-year increase in alcohol related deaths,” said Dr Sheron, adding there was a very simple reason the industry had been opposed to MUP.
Just 1.3% of the population, those who are consuming 75+ units a week, are drinking 16% of all alcohol – and accounting for more than 50% of all alcohol-related deaths.
“Quite simply, the drinks industry does not want to lose these customers,” said Prof Sheron.
And it is public health, not to mention the public purse, which is missing out.
In 1980, 4% of the Government’s income came from alcohol taxation, but that has halved – that equates to £3.55billion of lost tax revenue a year since 2013.
“Shall we compare that to the £4billion hole in NHS?,” Prof Sheron asked.
Not everyone who drinks will become dependent, not everyone who becomes dependent will get fibrosis and not everyone who gets fibrosis will progress to cirrhosis and liver disease.
During the BASL annual meeting, Dr Marsha Morgan looked at the genetic predisposition for becoming alcohol dependent "versus being susceptible to cirrhosis".
“Only 40-50% of alcohol misusers are going to develop dependence over time and less than 20% of misusers will develop cirrhosis,” she said.
“It is so complex – there is a genetic susceptibility for alcohol misuse and one for cirrhosis what is unclear is where they overlap.”
PNPLA3 has a confirmed pivotal role, said Dr Morgan: “It has got nothing to do with alcohol dependence but everything to do with alcohol-related cirrhosis.”
It is also a risk factor for HCC: the cancer tends to occur at an earlier age, lead to multiple lesions and a worse outcome.
“It carries a population attributable risk of 27%, meaning it could be giving us 200,00 more cases of alcohol-related cirrhosis,” said Dr Morgan.
In her presentation “Improving outcomes following paediatric liver transplantation”, Professor Deidre Kelly (Birmingham) had stressed the importance of issues involved in the transition to adult services. These themes were expanded on by Dr Alison Darcy, Clinical Research Psychologist at Stanford University, and Dr Marianne Samyn, Consultant Paediatric Hepatologist at King’s College Hospital, in their joint presentation.
Dr Darcy specialises in developing models that specifically target individuals who are difficult to reach. In her presentation, which centred on adolescent neurocognitive development in the context of chronic Illness, she explained that neuroimaging studies have shown how adolescence is a distinct period. Higher-order cognitive functioning matures later than “primary” function regions and the development of subcortical regions is also pronounced at that age.
Adolescence is a turbulent period, with 75% of mental illnesses arising before age 24 and with 8% reporting a suicide attempt in the previous year. However, she noted, most adolescents do not get treated for mental illness problems.
Most adolescents exist on a different space-time continuum and experience danger differently. Most importantly, they value their peer groups very highly (this, she noted, has also been observed in some higher primates). As the quality of the peer group matters, this has implications for clinicians. She suggested that clinicians should not tell adolescents NOT what not to do: negative messages inhibit learning and messages should be framed positively. Clinicians could also adjust expectations around self-management, adherence and adaptability, and adopt a “growth mindset” rather than a “fixed mindset.
Dr Samyn is the Clinical Lead at King’s multidisciplinary liver transition service and, in her presentation “Looking after young people: getting it right”, she told delegates that a study by Sagar et al (2015) had concluded that the outcomes were good for young liver transplant patients who transferred to the adult services.
She reminded delegates that other transitions are occurring at the same time, such as leaving school, leaving home, or starting work or college. Furthermore, IMPARTS had shown that amongst young people attending a liver transition clinic, prevalent anxiety and depression were higher than in the general adolescent population (17.7% versus 4-6%) and were similar across liver transplant, AILD and other liver conditions. And they were likely to interact with treatment adherence.
Based on her experience at King’s, she stressed the importance of the multidisciplinary team. She emphasised the need to foster a positive patient/provider relationship, with collaborative decision-making. Therefore, the multidisciplinary transition team should adopt a proactive individualised and flexible approach and be aware of psychosocial, educational and vocational needs.
Liver transplantation (OLT) in children is now highly successful, with a more than 80% 20-year survival.
Deidre Kelly, Professor of Paediatric Hepatology at Birmingham Children’s Hospital NHS Trust, explained that most paediatric liver diseases are potentially curable with OLT and that long-term (i.e. over 10 years) histological outcome of liver allografts is evolving. Innovative surgery has allowed the extension of transplantation to under one year and under 10kg and include split liver and living related transplantation.
These techniques have been matched by improved specialised medical and nursing care, pre-operative nutritional therapy and post-operative immunosuppression. There have been many advances in therapy including anti-oxidant cocktail and iron chelation, exchange transfusions and IV immunogloblulin, primary bile salt therapy and nitisinone.
An example of a major advance has been the centralization, at Birmingham, Leeds and London, of the diagnosis and management of biliary atresia, Kasai portoenterostomy and liver transplantation. From 15 centres (1993-1995) to the three centres (2009-2013), changes in the clearance of jaundice have been 55% to 64%, five-year native liver survival, 27% to 56%, and five-year overall survival, 84% to 93%, respectively.
Prof Kelly believes that current challenges in paediatric liver transplantation include long term outcomes, indeterminate graft hepatitis and fibrosis, the detection and prevention of adverse cognitive or psychological functioning, and adherence and transition to adult care. She stressed that future pre-plant initiatives should include the optimization of nutrition and the time of transplant to prevent neurocognitive damage. And further research was needed on the aetiology of graft hepatitis/fibrosis.
Prof Kelly emphasized the crucial role of managing the transition to adult care. Young people’s anxiety about transition to adult care related to difficulties forming new relationships once in adult care and a lack of continuity of care. A BSPGHAN research project had found that young people with a liver transplant diagnosis felt different from their peers. They adopt different coping strategies in order to manage and cope with their condition. And they identify building relationships with healthcare professionals and having continuity of care as being important for their transitional care.
Three stalwarts of hepatology were presented with lifetime achievement awards at the BASL Conference Annual Dinner.
Dr Roger Chapman, consultant at the Oxford University Hospital, Dr James Dooley, consultant at the Royal Free Hospital, and Dr Alex Gimson, consultant at Cambridge University Hospital Trust, were presented with their awards at the Manchester Football Museum.
Dr Chapman, a founding member of the International Autoimmune Hepatitis Group and the International PSC Study Group, and a Fellow of the American Association for the Study of Liver Diseases, said: “It is a great honour and a great privilege.”
Congratulating BASL president, Dr Greame Alexander, and treasurer Dr David Patch, he said: “When I was secretary of BASL we got 90 people in 1991, and the meeting has grown into what it is today. It is a fantastic meeting and I am very grateful to Greame and David for taking it even further.”
Of Dr Dooley, who co-authored three editions of ‘Diseases of the Liver’ with Dame Sheila Sherlock, Dr Patch joked: “He is loved by all his patients and it’s very hard to see patients after they have seen James because they look crestfallen.”
Dr Dooley said he was moved by the award and the kind words.
“I have had hell of a career with a tremendous number of colleagues and friends in a wonderful speciality,” he said, adding that he had witnessed amazing progress.
“To witness the discovery to the cure of HCV in one career in stunning.”
Dr Alex Gimson, director of medicine at Cambridge from 2003 to 2013, and char of the NHS BT Liver Advisory Group from 2008 to 2013 was also recognised.
Accepting the accolade, he said: “This is a considerable surprise!
“It has been an honour and a privilege to work with these people who are far brighter and cleverer than me. They have taught me an incredible amount.”
Nutrition is key to managing non-alcoholic fatty liver disease (NAFLD) and even a small amount of weight loss can help reverse steatosis and fibrosis.
Jill Johnson, a specialist dietitian in liver disease and hepatobiliary disease spoke about the rising prevalence of NAFLD during the BASL Nurse Forum meeting at conference today.
“We are getting a lot of patients coming through with cirrhosis and it is probably going to become the most frequent indication for transplant,”’ she said, citing a nationwide shift towards higher calorie intake and lower activity levels as the reason.
“Right up to cirrhosis, everything else is reversible. One of the things I do with patients is talk them through their place on the scale and explain they can reverse it.”
Studies have shown losing a relatively small amount of weight, around to 3-5% of body weight, lead to a loss of fat from the liver – though the optimum level was 7-10%.
“We aim for 5-10% of weight loss, but it’s important to break that down and show patients what that means,” said Jill, adding that a 5% reduction in BMI equates to a 28% reduction in liver fat.
Supporting people to lose weight was about motivation and individualisation, she told delegates.
She said: “It's not just trying to lose weight but about what's going on inside. It's motivating for patients to see their LFTs returning to normal.”
She recommended talking to patients about their daily lives and using that information to help them make one easy change at a time.
Jill used the example of a man who had two sugars in his coffee and 20 coffees a day – by losing the sugar, he cut 800 calories from his daily intake.
“Individualise your advice: it might just be parking the car a bit further away from the supermarket or getting off the bus a stop earlier: even exercise without losing weight can cut liver fat,” she said.
Around 10% of adolescents in the UK have a chronic illness, but they have all the same problems and worries as their peers.
Monica Smith asked delegates at the BASL Nurse Forum meeting to remember their duty of care to young people with liver conditions.
“It’s our job to give them all the information they need to be able to live a healthy and fulfilled life within the confines of the chronic illness they are living with,” she said.
Monica, clinical nurse specialist for liver transition at Birmingham Children’s Hospital, recommended all those in the audience get trained on using the HEADSS (Home Education/Employment Activities Drugs Sexuality Suicide) assessment.
“It’s a very good tool and gives you guidance on what questions to ask and how to go forward,” said Monica.
Young people with long-term conditions engage in all the same risk-taking behaviours as other teenagers, such as smoking, drinking, taking drugs and having sex, but might need a little more support.
Monica suggested asking the parents to leave, for at least a part of the consultation, to allow for a more open conversation. Confidentiality is extremely important, she added.
“We have a golden opportunity to utilise the HEADSS survey tool,” said Monica.
“Even if you can’t talk about all the topics, pick two or three that are particularly important to the young person.
“Young people often engage in risky behaviour so helping them to be safe while they assert their independence is our duty of care.”
Pregnancy is a window of opportunity to help expectant mothers deal with substance and alcohol misuse.
Debbie Reid is a specialist substance misuse midwife and said she acted as a conduit between women and the various services they needed to access.
“Most women have never even considered trying to stop before they became pregnant, so it's an opportunity to get them thinking about making positive changes,” she said.
“We have to be optimistic that they can change.”
Of all the drugs she came across in pregnancy, Debbie said, alcohol was the biggest worry as the damage to babies could be irreversible.
“We try to get them through as much detox during the pregnancy as we can,” she said.
Reducing vertical transmission of HCV is a priority in her service and all women referred to her are screened with those testing positive being offered treatment after the birth.
Working with people written off by the system not only helps them get their lives back on track, but saves the NHS hundreds of thousands of pounds.
Mark Holmes, team leader of the Long Term Condition nurses in Nottingham, told the BASL nurses that he and his colleagues had saved the NHS £360,000 in just one year by acting as a “life raft” for people who had “fallen through the cracks”.
“We work with people who have long-term conditions related to alcohol. People who have been written off by the doctors, and in many cases, themselves,” said Mark.
The team identifies “people in trouble” and works proactively with them in a way they are comfortable with.
One such service user shared his story of how Mark’s team had helped him after he had fallen into a spiral of depression and alcoholism following his wife’s death.
“I didn't care if I died, it didn't matter to me,” he said, adding he had tried to commit suicide a number of times.
He was drinking at least a bottle of vodka a day and was homeless by the time he started working with Mark’s team, which helped him access the care he needed.
Despite multiple relapses and hospital admissions, Mark never gave up on him, he said, and one day “it just clicked”.
Mark encouraged nurses in the audience to look into setting up similar services, adding it wasn't hard to find the people who would benefit.
“We know who these people are – they are the ones in our hospitals, they are the ones calling 999,” he said.