Professor John O'Grady, Retired Professor of Hepatology, King's College Hospital, London

AUTHORS:  Dr Sanketh Rampes and Dr Anvarjon Mukhammadaminov 

In this series the Medspire team interviews doctors about their career, their specialty, the choices they have made and their advice for doctors and medical students.

Today, the subject is Professor John O'Grady, who is a recently retired professor of hepatology at King's College Hospital in London. Professor O'Grady is renowned for his research in hepatology, which has shaped the treatment of patients with liver disease.

A podcast of this interview is available here:

 

How did you get to where you are today?

I'm an Irish graduate. I went to a small medical school in Galway, in the West of Ireland. I graduated in 1978, and did my first two years of clinical work there. I was about to go into the second residential year when my professor offered me a job as a clinical researcher, which came out of the blue. 

I was given 12 hours to think about it and I decided to do it - so I deviated away from the normal early pathway of clinical training. I did two years of research in splenic function and coeliac disease. From that, I achieved my MD and my first 12 papers. At the same time, my first consultant as an SHO was a new arrival back from the US, who was very enthusiastic. 

In a short space of time we had cases of an acute Wilson's in a 14-year-old, and an alcoholic hepatitis. This instilled into me at that moment: ‘This is what I want to do. I want to be a hepatologist’. I was told: 'You can't be a hepatologist. You have to be a gastroenterologist’, and then ‘make your mind up’. I completed my general medical training in Ireland, and just as I was about to finish I saw an advert for a registrar in the liver failure unit - a two-bedded ward that Roger Williams had set up to look after patients with acute liver failure. 

I started that job in 1984. In that two-bedded unit, you were the only clinical member of staff - you did everything, which would either be no patient, one patient or two patients. It was a ledger of all the patients who had been through the unit. I was curious about that ledger, and I started to get the notes of all of the patients involved. 

That was quite a bit of detective work - finding old notes - and I extracted a dataset from those notes of the admission details and episodes, the best or worst and then the ultimate, death, and collected over 1,000 patients. When I finished that year, I was given the opportunity of doing clinical work in liver transplantation from 1985 onwards - still staying in the liver unit with Professor Williams. 

All of my courses had been clinical courses. I hadn't done any dedicated research course, but I had built up this database of acute liver failure patients. Roger Williams had appointed a young, ambitious statistician. I had a dataset, she wanted to get a PhD, so that's how we set about working and analysing the dataset that resulted in the criteria that were published in 1989. 

From 1985 onwards, essentially my clinical work was a bit in general hepatology, but mainly liver transplantation. My first consultant post was in Leeds, in 1992. When Roger Williams retired from King's, I was appointed, and I came back to King's in 1996 where I stayed until I retired. 

 

Can you tell us about King's history of liver medicine?

King's has a very long history of liver medicine. It goes back to the 1880s. If you're familiar with the condition called ‘Budd-Chiari Syndrome’, which is blockage of the hepatic veins, the Budd of Budd-Chiari is actually a King's hepatologist. If you look him up, in the 1840s his writings were considered the ultimate insight into liver disease. 

Roger Williams is the most obvious person associated with the reputation of King's and liver. He set up the unit in 1996, and died last year, still working. He brought a vision, set up a unit, and wanted to be on the cutting edge of hepatology. Very quickly, he got to work with Roy Calne. They did the first liver transplant in the UK in 1968. 

Roger’s other big interest was acute liver failure. He was very wise in going to the areas where you could make a lot of impact - where there was a lot of novel work to be done. He also set up a very successful basic science laboratory. Essentially he tried, and succeeded in many ways, to create a liver unit within the hospital. 

There were other big names who contributed to that. John Dawson was a hepatobiliary surgeon. In 1968, when liver transplants started, the liver did not come to the hospital where the patient was - the patient was taken to the hospital where the dying patient - the donor -was. In 1968, one of the first transplants ever to be done was at King's, because the donor was at King's. 

John Dawson was one of the surgeons who took part. He himself went on to have two liver transplants. He died some months after his second liver transplant, but had a normal working life and was very healthy. He was a hepatobiliary surgeon.  Ted Howard was a contemporary and is still alive. He was a paediatric hepatobiliary surgeon. 

His biggest contribution to paediatric hepatology was the operation in young babies, carried out with biliary atresia, so it has to be done within two weeks to be successful.He was the first to bring that concept and practice to the UK. It wasn't original to the UK, but he brought it here. 

They were both very good thinkers, very influential, and phenomenally impactful to us younger people. That's why I mentioned those two names, and that's reflected in their having wards named after them - they contributed to the liver heritage of King's.

 

What are the biggest changes you have witnessed?

My career in hepatology lasted less than 40 years, but in that time I've seen monumental change. I think more has changed in hepatology probably than most other specialities combined. Transplantation was revolutionary. 

It's now considered standard treatment, but it went through a very difficult, formative phase. Now it's normal. The condition of acute liver failure had an 85% mortality when Roger Williams opened his specialist unit for it. Now, over 80% of people will survive without a transplant. 

Your expectations are that you will survive acute liver failure.  Globally, the biggest impact has been hepatitis B and hepatitis C. Hepatitis C is the more recent. It is an incredibly difficult virus to manage. It became one that was difficult to treat, but treatable, and then, very quickly, became one that is easy to treat. 

The final hurdle for hepatitis C is to create the vaccine, which is still alluding us. With Hepatitis B, the vaccine came early on and then the drugs came. The drugs for hepatitis B, in terms of managing it, are akin to the HIV story. 

It's very similar in that now, with hepatitis B you should be able to live a normal life - albeit taking drugs - and also the drugs that will eradicate the infection have yet to be developed.  There are new conditions. In the 1980s, nobody knew what NAFLD was. Now NAFLD is the new disease, the new challenge. 

It has risen to the top of the list of causes of liver disease that are triggering transplant or are leading to death. That's the situation in terms of numbers. There are many other things that have changed in terms of management of disease, but there are also diseases whose treatment hasn't changed at all. 

For example, autoimmune hepatitis is still treated in exactly the same way as in the 1980s. There has been no progress whatsoever. So there is still a lot of work to be done, but it's been a very dynamic situation. 

It's incredible when you're working in a situation where you have a ‘get-out clause’ of a transplant if things don't work. With that disease, it’s an amazing extension beyond when a patient would be expected to die.

 

How did you develop the criteria which help determine which patients are suitable for liver transplantation?

In terms of what was going through my mind, at the very first step it was really a combination of boredom and curiosity. I had time on my hands. I had this registrar of names of patients sitting there beside my desk, and I just started going through that, and wanted to find out more. 

As I was putting it together and writing things down - this was before you had electronic databases - patterns started to emerge. Those patterns were contrary to what was considered the norm, and correct at the time. 

As it evolved, my original thinking was to work around better profiling of the causes of acute liver failure. But because I had the opportunity to work with a very good statistician, she took things to a much higher level of definition of a prognosis. 

It was published as early prognostic indicators, because what we were trying to do was to pick up signs early on in the disease course - influenced by the fact that that may identify certain patients to take to transplantation and others to manage medically. The thinking behind it was to develop early indicators of prognosis.  

In the climate, they became quite quickly identified as prognostic indicators in the context of transplantation and were used either as in the original form, or modified around the world, in terms of bringing this basic fundamental understanding to an individual patient or their likely outcome.

 

What research area or project are you most proud of, and why?

The clinical trial I am most proud of  is the trial in immunosuppression, the comparison of tacrolimus and cyclosporin after liver transplantation. It's notable, because it asked a very simple question, which at the beginning I thought was a mistake, but it proved to be the strength. 

It brought together all of the centres in the UK who performed the TMC study, and it was published in The Lancet. It is considered to be one of the best immunosuppression trials ever done, even though it's quite simple in its construct. 

Proving that the British community could come together and very quickly - it was done in a couple of years - to undertake a trial of this size to the highest standards on a relatively small budget was phenomenally powerful and satisfying. 

My favourite achievement was recognising and describing a condition called ‘fibrosing cholestatic hepatitis’. This was a new manifestation of liver injury in liver transplant patients with hepatitis B originally. I recognised it in clinical practice as a recurring entity. 

It took me quite some time to convince Roger Williams and Bernard Portman,a pathologist, that it was real. They accepted it. After describing it, we spent time working out the novel mechanisms of injury to the liver in this condition. 

This is now in the normal, fibrosing cholestatic hepatitis - the normal vernacular of hepatologists. So that's another area that has given me a lot of satisfaction. The third area that I've always been interested in has been alcohol-related liver disease. There is some progress there. It's not as emphatic as in some of the other areas I've mentioned, but it also illustrates what can be achieved in the UK when people come together. 

The study that was published a few years ago in the New England Journal of Medicine is a fantastic salute to British hepatology's ability - again on a relatively low budget - to come together and execute a trial to a high standard, very effectively. 

 

Can you tell us about the TMC trial in immunosuppression? 

The design, the execution, everything was done in the UK. At the outset, I thought it lacked ambition in asking the simple question: ‘What was the better of the two calcineurin inhibitors, ciclosporin or tacrolimus?’, but it makes a very important point. 

It proved  that one of those was more efficient and more effective than the other. Although it confirmed what a lot of people thought, the fact that it was established at a later stage became quite important. It was a randomised control trial, adequately powered, and all of the boxes that needed to be ticked in terms of evaluating the strength of a trial actually were ticked. 

I've heard it in meetings being referred to as the ‘gold standard’ of how a trial should be done, in an area where very few good trials have subsequently been done. This is because they are often asking too complex, or too multifaceted a question at the outset, and end up failing to deliver a clear, specific answer.

 

What does it take to excel in research?

The first thing is an innate curiosity - an ability to ask the question ‘why?’ or ‘ what?’ in a way that isn't overinfluenced by what other people think, and what the literature says. A fundamental curiosity is important.  

Serendipity is incredibly useful - if you're in the right place at the right time, with the right people, asking the right question. The third thing, in terms of the ability to be successful, is if you're able to ‘see the wood from the trees’. 

People who are able to have the clarity to be able to identify the important things and put other issues aside, often communicate with a clarity that makes them very welcome researchers.

 

How did you go about identifying a research question?

With my first research experience, the research questions were already formulated by my supervisor, and I conducted the research to that thinking. With liver, all of the questions evolved from some activity, be it clinical activity, audit activity or looking at groups of patients. 

In the early days of liver transplantation, a lot of publications came about by simply bringing together a group of patients who were similar for some reason or other, working through and defining them in detail. 

So because we were in new practice, in a new clinical activity, there was a lot of opportunity to start with that fact-finding approach in groups of patients. Then, typically that would generate secondary and tertiary questions and areas of research. 

 

What advice would you give to budding clinical academics?

Clinical academics are actually two different populations. I was incredibly lucky in that I could be free-thinking, and free-behaving in a new, evolving area. There weren't that many fixed rules. There was a fantastic opportunity to ‘think outside the box’. 

The opportunities in clinical medicine to do that are relatively small. People who want to be academics, at a fairly early stage of their training, have to go down a pathway that differentiates them from people who want to be life-long clinicians. 

The modern academic pathways are quite specific, and quite competitive. They're dependent on your ability to generate grants but it does lead you, if you are successful, to an academic career where you know everything about very little. You become a specialist in a relatively small area. 

Obviously, the cream of that population go on to stellar careers, but most of us would never achieve that. The hybrid, when I was in training, was the requirement to demonstrate an ability to have some level of academic thought, and the number of publications that you had was very influential in the kind of position that you would be competitive for.  That is something that has largely fallen by the wayside. 

To start writing some papers was the entry pathway for most people as young, practising clinicians. That then seeded activities that took you through to higher levels of achievements. Which is quite a different career development pathway to the one of applying for, and being successful in getting a grant working in a very specific area. 

Nowadays, the pathway that I had, that I was able to take advantage of, is not a very obvious one for young clinicians, but the fundamentals are there. You can still write some basic papers, and audit projects can often be developed from the end of the original intended audit. 

There are opportunities out there to demonstrate your ability to think, to analyse, to interpret. Seize the opportunities you get, to differentiate yourself, to make yourself look different to your peers. Do this  in a way that you will become associated with something that, in itself, will then mould, promote, and encourage that academic behaviour as part of your working life.

 

How can clinical academics maintain diversity?

Sadly, while the pathways to academic clinicians are fairly visible, with the type of career that I've had, you really do need to develop it yourself. There isn't any recognised training pathway to take you there. However, I've spoken earlier about the kind of seeding activities that may start you off. 

The second level is you may undertake some degree of formal training in a clinical science, which you don't intend to be part of your career structure. For example, you may spend two or three years in an institution in an area of your interest, to get to know research in that area well. 

But you may reach a point where you decide that instead of going down the grant-generation academic pathway with a relatively low level of clinical commitment, you want a balanced post. You want to function in real time as a clinician, but bring the lessons you've learned from academia to it. It needs to be an individualised approach, or an individualised approach supported and encouraged by a network.  

Liver is a good example of a network that is still quite small that young people can come through, have some academic activity - in the broadest sense - whilst still in clinical training, and create their own persona for reasons that they will be able to identify yourselves, based on what interests them, and what has been successful for them.

 

Can you tell us about your interest in alcoholic liver disease?

As a profession - and I'll make this statement provocatively, but intentionally - we probably do a significant disservice to the third of the population who choose to drink alcohol regularly. An understanding and an empathy for these patients is not the basis of how we generally treat them. 

If you are a heavy drinker, you are at the point - and a lot of the ones that I am talking about I will have met in clinics or in hospitals - where you are getting towards the end of your clinical liver disease inflicted by alcohol. If you can get these patients to stop drinking, it amazes me, time and again, the degree to which the liver could improve. 

With these patients, you need to get them in the right environment, at the right time, when they are minded to do what they have to do, which is to abstain from alcohol. I have a very old teaching slide which has the heading: 'The five most important things in treating alcohol’, and it says: 'Abstinence, abstinence, abstinence, abstinence and abstinence’. 

So anything you can do to bring the patient to the point where they choose to abstain and maintain that abstinence means you've truly saved a life. You have to understand the complexity of getting that patient in the right mood. As a professional, you have to recognise when they are in the right mood. 

Once they wake up on a Monday morning and decide that they want to change their lives, then the rest of the support services have to recognise that and fall into place. So they can't make it difficult for them to find the support networks they need to help them. It has to be easy. 

At the lower level of alcohol injury, my criticism of the medical process is that we tend to be judgemental, and a lot of patients do not feel comfortable having that discussion with us right from the beginning in an open way. We need to ask why we are listening to this response from a large section of the population who are uncomfortable having that conversation with us. 

It's only when we understand their perspective that we can, as individuals, change the way in which we approach them, ask the right questions, and encourage them along that pathway of discussing how they drink alcohol, and how we can work that, so they do it in a way that is less harmful to themselves.

 

Have you seen the documentary Drinking to Oblivion by Louis Theroux, which shows you in a consultation?

I have seen it. It's uncomfortable looking at yourself on television. Most of us don't realise just exactly how we come across. Once you get beyond that interaction with Aurelie [the patient] in the consultation, I think it speaks a lot to the things that I was talking about after that consultation. 

Aurelie stayed in my clinic and was still there when I retired. Obviously, confidentiality has to be protected, but the very fact that our professional pathway and relationship with our patient  was ongoing, speaks to what you can achieve, even with people who seem to be coming across as the most challenging of patients to change.

 

Are you concerned about the impact of the pandemic on people’s alcohol usage?

COVID is presenting young guys and girls with an unbelievable opportunity to be curious and ask questions. There are so many questions to be asked and answered. COVID is creating a fantastic opportunity to start your thinking, writing, and the academic part of your career. 

COVID is an infection that affects almost every organ in the body, although the liver has yet to be a prominent one. It is a condition with a very acute defined phase, but also a protracted phase. That creates wonderful opportunities for observation and intervention. In terms of COVID and alcohol, it's very interesting. 

Talking to my patients, what I'm getting is, COVID is leading some people to drink more, but others to drink much less. So it's going both ways. Regarding the population of alcohol users for whom alcohol drinking is about going out to socialise, going out to the pub, or for a meal, a lot of them are reporting that they're actually drinking much less or not at all during COVID.  

However, others are using alcohol to deal with some of the boredom and stresses of COVID, and there has been a significant percentage of regular drinkers whose alcohol consumption has increased. Although this is happening en masse, the issues aren't any different to an individual patient who's on the pathway to understanding what the stressors are in terms of alcohol use. 

Now, there's just an awful lot more of them. The conversation I would typically have with somebody who's a regular drinker of alcohol, who is drinking more than what the government would like - which I've issues with - but who otherwise is functioning reasonably well, is to look at the total quantities - what they are and where they should be. I would also look at abstinence. 

For example, having two or three days consecutive days of abstinence every week, and doing Sober October or Dry January.  Having regular periods, both brief and more prolonged, where you actually don't drink anything at all, is very important. 

There are issues about general health, and exercise that are also relevant. But all COVID is doing is magnifying well-known pathways and responses to alcohol, and how it can be modified.

 

What issues do you have with the government guidelines?

The government guidelines are not evidence-based. It was taken to an extreme with a previous chief medical officer, who came out with the statement that no consumption of alcohol can be considered ‘safe’. 

That statement came from the perspective of, if you're a scientist and you're looking for evidence of drinking that is either safe or beneficial, you won't get that level of evidence in the community. So we can never look somebody in the eye who doesn't drink at all, and say: 'With your condition, actually there's evidence that some alcohol is good, I suggest you start drinking’. 

We can't go there - that will never happen. One of the most common mistakes we make as a profession is to ask people the number of units that they drink and make judgements on whether that is 12, 16 or 30. That judgement then influences the way we deal with that individual. What we should be saying is, if you are going to use units, its value is as an agreed language that you as a doctor and the patient will understand. 

In a sense, it's a currency that you use in your negotiation with them. You can extrapolate that from the starting point to: 'Actually we need to reduce that by X, X or Y, or whatever’. That is an acceptable use of units. But as a binary categorisation of individuals' behaviour, it is unwise and unhelpful.

 

Why isn't liver screening routinely done, and what are some of the barriers?

In the past I have talked about how gamma GT should be in our professional and public vernacular, in the same way as cholesterol is. Cholesterol has been hugely successful for cardiology, to get into people's psyche. 

Everybody knows the importance of cholesterol, and everybody wants to know, or knows what their cholesterol is. If we could get that same level for gamma GT in our population, then the first thing it would do is to allow a conversation to take place on a factual, helpful, non-judgemental basis. 

It would be a fantastic tool to have a population of patients who wanted to know what their gamma GT is and who are prepared to respond to that. I don't know why screening, even simple screening, even screening the questionnaire, runs into a lot of barriers in clinical practice.

Regarding other populations of patients who are presenting for screening, gamma GT would probably be replaced now, or at least supplemented, by fibre scanning, which is non-invasive - tests that can be done in general practice. It's a machine which tells you exactly how much fat is in your liver and how much fibrosis, or stiffness and scarring is involved in the liver.  

There are so many broader health messages to be gained from understanding a fatty liver - it's in harmony with any other health strategy that is looking at diabetes, cardiovascular disease, strokes, or hypertension in a population. There's a synergy there. 

The powerful thing about screening that is numerical, or factual, is that it's an ongoing tool that helps intervention and modification of what you see or find.  I'm a huge fan of facilitating widespread screening at any level in the population in a language that is part of the vernacular of non-medical people. 

 

Is this screening for everyone, or just for patients at higher risk of developing liver disease?

Screening, by definition, is most successful the broader it is, and the broader entry into the screening process is. It's justified, for example, with fatty liver, because non-alcohol-related fatty liver disease also carries with it broader health connotations to identifying a process that's identical to what people who drink alcohol get. 

In populations who are non-alcohol consumers, those populations tend to have significantly higher levels of metabolic disease, hypercholesterolemia, and diabetes. So there is an application and a usefulness, way beyond just picking up and assessing alcohol, but in determining, and getting insight into what the future might hold for individual patients on a broader health criteria. 

The more open screening is, the broader the net is cast, the more helpful it is. But screening must also  be embraced by the population. They must want to be screened. They must want to know the information that you're going to provide them. Screening should never be mandatory, enforced, obligatory. None of those things are compatible with the spirit of population screening for healthcare delivery.

 

What are some of the most memorable moments of your career?

There's so many things. Getting your first publication. Getting your first publication in a great journal. Achieving the prescriptive milestones you have to achieve to progress your career. Getting your first consultant job. 

The things that give me the greatest pleasure, and this may sound quite corny, are based around individual patients, and roles I've played in the pathway of individuals. A lot of that is through transplantation or other issues I’ve taught. The things that make me smile and feel good about having been a doctor for 40-plus years are essentially patient-based.

 

What important lessons have you learned during your career?

Be curious. No question is dumb. A cliché, but it's true. It's only considered a dumb question by people who don't understand.  Humility, particularly in clinical practice. Always make your patient very comfortable to be with you. Not having humility is a blinding process. People of that mindset tend not to see the world that's going on around them and the detail that they might.  

Do good and see good in everybody and enjoy it. Enjoy your career. It's a wonderful career. It can give you great opportunities to feel very good as a person. It will challenge you as you go through that process. There will be lows. There have to be if you are sensitive to the stresses that are around you. But it's a great career. I love it.

 

What's your favourite book?

I'm not going to give you a book. I'm going to give you an author - Sebastian Barry. He's an Irish author and obviously that resonates with me. His pathway through his writings has evolved in a way that there were times, about ten years ago, when this relatively straightforward novel set in the West of Ireland ticked a lot of my boxes, and gave me insights into that particular life. 

More recently, he's taken his writing skills out of his comfort zone. The most recent novel I read by him was based in the US after the civil war, and a lot of the language used is actually the language of a native Indian girl. That pathway of evolution to his books has really intrigued me. He’s my favourite author.

 

Medspire podcasts are produced by Dr Sanketh Rampes and Dr Anvarjon Mukhammadaminov, both full-time junior doctors. They aim to inspire the next generation of doctors and scientists by exploring the career journeys of leading clinicians and researchers.