During the event ‘The liver day: New perspectives in clinical hepatology 2017’ on Wednesday 8th November 2017, organised by the Royal Society of Medicine (RSM), the EMJ caught up with one of the presenters, Dr Harry Antoniades, a Reader in Hepatology in the Division of Digestive Diseases, Imperial College London, London, UK, to discuss his work and perspectives in the field. We picked up on a number of the themes in the presentation, entitled ‘Current concepts in the management of liver failure’, in which he spoke about the challenges of managing the rising number of liver failure cases in the UK, including the problems caused by infections in these patients, pathophysiology of the condition, and advances in this area of medicine. In particular, the strategies that could be pursued to improve the management and treatment of liver failure patients was a big element of our discussion.
Postcode Lottery and Care Strategies
HA: The postcode lottery in regard to healthcare was shown in the NCEPOD report,1 which showed marked differences in how patients are cared for when they are admitted to hospital. A very simple way to combat this lottery is to standardise the care. One initiative that has been started by the British Association for the Study of the Liver (BASL), and we have developed further at Imperial, has been the liver care bundles. We have subsequently expanded these bundles and tailored them to our institution. One way is to standardise the acute care, providing care bundles for the acutely admitted patients, which has the potential to harmonise the care if implemented nationally. There would be a number of points to address for the admitting physician, be they a general physician or an ED doctor. It will be applicable to all the acute clinical specialties and they often are encompassed in our acute admitting medical teams. As liver doctors, we try and pick them up after they are admitted. The other is to have what was initially outlined in the national liver plan, which is to have a dedicated hepatology service in every single hospital. That is a major aim to have, and to achieve; whilst there certainly have been improvements in the number of people nationally with an interest in hepatology, it is still a speciality that is largely based in teaching hospitals; however, the landscape is changing. But that is where I think the differences in care lie.
Dedicated Hepatology Services
HA: I think, with the current pressures that are placed on hospitals, it is going to be challenging to bring in dedicated hepatology services. The alternative that other specialities have modelled is the acute care model, for example, the acute hepatology service. We have, for example, acute gastroenterology, oncology, and cardiology services on the front line, which are actually able to triage the patients, prevent unnecessary investigations, or escalate appropriately. I think this care model could be a realistic aim for liver medicine. The problem is that hepatology has evolved out of gastroenterology in a lot of institutions. That is one of the challenges: to get a dedicated hepatology service. It would require a lot of funding, infrastructure, and support to implement nationally, but, if we do the simple things first, then we can consider more expensive novel treatments to actually address this problem, where we are able to promptly identify our patients and treat them in a timely fashion. The experience of the tertiary care centres, including the tertiary liver centres, is that they get patients referred very late and they do not have the infrastructure to take every single patient in their hospital, therefore care has to be implemented locally. Something that has been suggested by Prof Graham Foster, The Royal London Hospital, London, is to develop dedicated centres that will look after these patients. It is a pilot suggestion at the moment, but that will be a strategy, both at a national and regional level, where we could focus infrastructure and expertise to get patients treated by the right person, at the right time.
HA: The first component of a top-down approach is really, again, very similar to the sepsis model; the concept is that the window of opportunity to treat these patients, to prevent them developing established organ failure and requiring intensive care, which is a huge burden on healthcare resources, is to identify organ failure early, enabling treatment to prevent progression, and that is where we can make a difference in their outcome. So, a top-down approach would be an aggressive model of care which intensivists like to use. This model is applicable across various patient groups, such as haematology and oncology patients that present to hospital with infection. Oncologists have been doing it for years; neutropenic sepsis patients have immediately been getting antibiotics and fluids on presentation to hospital given their inherently high risk of infection. The top-down approach will be a very similar model: fluid resuscitation, early antibiotic administration, and understanding that these patients are hugely susceptible to deterioration, with the ability to alert the admitting physician to that fact. Then, once you have treated them in the 24–48-hour window of admission, you can actually determine the severity of their illness and be able to rationalise the medical treatment. Giving timely antibiotics to this patient is challenging because they do not often manifest the signs of infection. As such, it is necessary to alert the relevant individuals and develop appropriate care bundles. A number of medical specialities should be alerted to the patient’s risk of deterioration and the target is to treat them as soon as possible before they can develop complications, which is an approach that has not previously been possible.
Increase in Liver Failure Cases
HA: We are seeing an increasing trend in liver failure cases throughout the UK, in both the north and south. Alcohol consumption is the leading cause of liver disease and hospital admission. The striking aspect from the NCEPOD data1 is that patients who die of liver disease present to hospital with liver failure in the last 2 years of their life and have an increased frequency of hospital admissions. So, the endpoint is that you have an increase in the population developing liver disease, presenting, probably, at a younger age now due to the disease developing earlier in life. They present to hospital with these complications in the 2 years before their death; as such, there are huge issues for us on the wards.
Risk of Infections
HA: This is my major area of research. What my research group have done over the past 2 years is to identify numerous defects in antimicrobial responses of circulating immune cells in these patients. What is very clear is that these patients, when they present to hospital, have marked defects in their ability to clear bacteria and produce effective responses to clear these infections. The reason they develop one infection and then go on to develop more is because the effect of the immune system is temporarily weakened after clearing the primary infection, meaning they are at heightened risk of developing a further one. Understanding this aspect of immunity is what I am focussing on in my work.
Moving on to what treatments we should give, I think efforts should be focussed on trying to boost these patient’s antimicrobial responses in order to enhance their infection clearing capability by giving them targeted pharmacological interventions. So, I think that is one key factor. Infection is the number one killer, cause for hospitalisation, organ failure, resource utilisation, for these patients. Currently, we do not have any emerging effective therapies to combat infections apart from antibiotics. As such, the concept is that we should give them something to prime their immune responses. This is really topical at the moment, given the problems that we have with antimicrobial resistance, and the fact that these patients are getting multiple courses of antibiotics over a number of months or years presenting with multi-drug resistant infections; we are only going to propagate this by continuing the same style of medicine: just giving them antibiotics and hoping they recover. We have to approach this differently and innovatively in terms of treating their infection.
My main research theme is to develop effective strategies to facilitate immune responses to finding and clearing infections in these patients. One approach is a trial we have now initiated, the R-RID trial,2 which studies the use of rifaximin as part of a multicentre study in the UK and is approaching the issue in a slightly different way. We know that circulating immune cells are not very good at clearing the bacteria, so why don’t we try and reduce the bacterial load these patients are exposed to, which we know then seed into tissues? That is giving rifaximin, because we know bacteria translocate across the gut and are not effectively cleared by the liver. Therefore, if you give rifaximin, you reduce the number of bacteria and potentially their seeding in other tissues.2 The trial started this year so we hope to be reporting the results in a couple of years. Another approach is to acknowledge that the infections are common; we have got quickly circulating bacteria, and will give the immune cells a chance to clear them by giving them something to stimulate their infection fighting capabilities.
Dealing with Infections
HA: Common advice, like having the flu vaccine, is absolutely fine, but you do not see a lot of viral infections; you see bacterial infections, you see the type of infections that you cannot really prevent. We see chest infections, we see urinary tract infections, and it is not a particular type of infection we see that we can prevent. People have tried previous strategies to prevent infections by giving prophylactic antibiotics. That strategy has not worked, and in fact in this current era, that would only enhance antimicrobial resistance. Perhaps, again, strategies to find the immune response to prevent these infections from happening in the first place might be a better approach. However, directed advice to these patients is difficult because you don’t get the same type or a predicted pattern of infections. I may get a similar infection, but I am able to clear it, whereas liver disease patients are unable to clear it because their immune system isn’t working. The environmental factors are the same between people with and without liver disease, but the liver disease puts them at higher risk. This is the difficulty: once they have got that advanced disease, it is very difficult to predict and actually treat it.
HA: The general theme is that we should invest. The focus of the government has been on primary prevention, which is a completely valid target, with alcohol cessation programmes and similar programmes to prevent the disease from developing in the first place. The problem with this approach is that there has been no emphasis on secondary care. Another general theme is that liver disease is also quite stigmatised, especially in regards to alcohol behaviour patterns. The problem is that until recently there has been little interest within the pharmaceutical industry. The fact is that these patients are a significant problem in the hospital. Most gastroenterology wards are full of liver patients, not gastroenterology patients; most of the problems that we face are these types of patients. It is a huge burden of any gastroenterologist or hepatologist in patient practice. Unfortunately, this trend is only increasing.
Stigmatism of the Condition
HA: Stigmatism of liver disease patients, because of the perceived self-induced nature of the condition, is something I feel very strongly about. I have had a number of conversations with people and charitable bodies who give me funding for my research who say: “Why on earth are we going to give you money to treat a self-inflicted disease?”. I would argue that many diseases, such as smoking and obesity-related malignancies for example, are associated with lifestyle, but why prejudice one particular disorder compared to another? There are a number of lifestyle-associated diseases that we treat in this population without the associated stigma, and I think that needs to be readdressed, it is a problem in the UK. Instead of saying we are not particularly interested because it is a self-inflicted disease, actually, it is a burning problem for the UK population and is becoming more prevalent. Unless we face it and try and improve treatments, not only primary but secondary prevention, then, unfortunately, we are not going to make any progress in the management of these patients.
HA: I think that a number of the strategies that I am proposing and are in evolution, may well come through. My research programme looks at ways to prime immune responses and, I hope, over the next 3–4 years we will be putting some of these into clinical trials. With other groups there is the granulocyte colony stimulating factor (G-CSF), or immune priming, immune strategies to prime infection against treating infection. I think that would be one target. However, I think big emphasis in the EASL-Clif Consortium, which is a European-wide initiative for challenging and treating this condition, is really looking at the immune suppression and trying to find strategies to restore antimicrobial responses. They have tried a number of things, including plasma exchange which works in acute liver failure. We have some data in patients with acute liver failure; these are patients that do not have an underlying pre-existing liver disease where you treat to improve the outcome. It may well be that you can repurpose and establish safe medical treatment for that in acute and chronic liver failure. So that is another possibility, and the third possibility is that which Dr Alistair O’Brien is doing at University College London. He is a hepatologist who is looking at the use of albumin to reduce infections and the use of immune priming strategies to put it together, which is what I am approaching.
HA: In order to take this forward, we have to really understand what drives the disease. That is the bit that goes back to the basic science of understanding the mechanisms that drive this process in order to get good therapies going through.
- NCEPOD. Alcohol Related Liver Disease: Measuring the Units. 2013. Available at: http://www.ncepod.org.uk/2013arld.html. Last accessed: 13 November 2017.
- Imperial College London. A multi-centre, double-blind, randomised, controlled clinical trial of Rifaximin to reduce infection in patients admitted to hospital with decompensated cirrhosis. 2016-002628-96. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-002628-96.