Hello and welcome to episode three of Gut Instinct research uptakes, bringing the latest research in gastroenterology and hepatology.
I'm Tamsin Cargill. I'm the gastroenterology registrar in the Thames Valley interested in hepatology, viral hepatitis and vaccine development.
And I'm Michael Fitzpatrick, I'm known as fit to pretty much everyone, as well as being Tamsin sidekick,
I'm a clinical lecturer in Gastroenterology in Oxford with particular interest in GI immunology, coeliac disease and nutrition.
So we started this podcast back at the beginning of last year to kind of bring
you some of the most interesting GI related papers that have come out recently.
Hopefully saving you some time and assuaging your guilt for not reading enough journals.
So each episode we plan to take you through a couple of really interesting primary research papers in a bit of detail.
Generally, one clinical and one translational with a bit of luminal and and hepatology in there,
and we'll give you our take on the research and what we think about is this been a bit of a hiatus since our last episode.
Unfortunately, life rather got in the way of things last year.
But we are back for our New Year's resolution in 2022 for more regular podcasts.
And possibly not taking ourselves quite so seriously. Clearly, there are lots of great papers coming out every month.
So in addition, we're going to give you a rapid fire rundown of what else is out there in the western world in our
five and five section where we'll try and give you the key points of five papers in five minutes.
Now, it shouldn't need to be set, but disclaimer alert. Clearly, nothing on this podcast constitutes medical advice.
If you are a patient, you can consult your medical practitioner.
For doctors, I'm sure you wouldn't base everything that you do in clinical practise based on what some guys told you on the internet.
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Right. I think it's my turn to start this week, so these are these are papers, I think all of these papers, the ones from early 2021.
And so they're all, maybe not quite as fresh as we normally like them.
But this one, I think, is a cracker and is tackling a really tricky and contentious issue about diets for weight loss and in particular,
comparing low fat and plant based diets like vegan diets compared to low carb animal based kito or carnivore diets.
And this particular area is one of great conflict, particularly on social media,
where the sort of devotees of these different dietary camps take a rather sort of cult like attitude to things,
and it can all get quite quite unpleasant. But I would say this is probably one of the key clinical scientific questions of our
time because obesity is a huge international problem with massive implications.
And while there are exciting drug treatments like Semaglutide that we've discussed before and
a whole range of highly efficacious bariatric surgical options for those with morbid obesity,
understanding how diet can be used to control weight is clearly hugely important.
So this paper was out in Nature Medicine in early 2021. It's published by Kevin Hall's lab and and colleagues,
and it's entitled to the the effects of a plant based low fat diet versus an animal based ketogenic diet on ad libitum energy intake.
I always laugh a little bit of Latin in a title.
I'm more used to hearing the phrase ad Lib Dem in a in a mouse experiments where it means that you give give the mouse as much chow as they like.
And this is this is the human equivalent of of of that.
So Kevin Hall is based at the niche in Bethesda, where he's one of the senior investigators studying nutrition and metabolism.
And I didn't notice but the the hospital where they work,
Bethesda is the largest hospital in the world, which is dedicated purely to clinical research.
And it sounds absolutely incredible. They've got a effectively a 200 patient hospital just for residential clinical studies.
So this huge resource and that's where that's where he works.
So the premise of this study is two competing models of obesity and the drivers for sort of excess calorie intake.
And the reason those those models are important are that they suggest that different
diets will be effective really about excluding fat or carbohydrates in them.
So the first is called the carbohydrate insulin model of obesity.
And this says that eating high glycemic carbohydrates results in elevated postprandial insulin that
is then supposed to drive the accumulation of body fat and drive increased hunger and energy intake.
So it's the carbs, what does it that drives insulin and it leads to accumulation of fat and you taking in more calories?
The alternative model is the passive overconsumption model, which is that high energy density foods,
particularly like high fat foods, have a relatively weak effect on satiety in proportion to their energy intake.
And and this is a quote from the paper modifying food hedonic in a way that supports increased intake.
Basically, they taste bloody delicious. So but I do like modifying food head head, which sounds philosophical.
Yeah, it does. It does so. So these are these two, these two models, one of which says that we should exclude carbohydrates.
The other we should exclude energy dense foods, in particular high fat foods.
Now the problem with nutrition science and a lot of nutrition studies is that
they're often flawed in design and execution because they're often retrospective.
They're often based on surveys, and people are very bad at recalling retrospectively what they've actually eaten when they are interventional.
They are often done in a way that sort of often has poured hereabouts to the diet.
There's often a lack of detail in what's what's measured.
And it makes it really challenging to interpret individual trial results and generalise them to the population.
So good. It example is evening on high quality, randomised controlled trials.
We often get confirmed contradictory or unclear results.
So two that I wanted to mention in the past.
One was the direct study, which was published in the New England Journal of Medicine about 13 or 14 years ago now,
and that showed that some low carbohydrates and and Mediterranean diets were more
effective at than low fat diet for weight loss after two years of follow up,
albeit with a pretty small difference of about two kilos after two years follow up.
But then another randomised controlled trial called that Diet Fitz trial again of low fat versus low
carb diet showed no difference at all in weight loss between these two strategies after a year.
Both of them did lose weight. And so one of the one of the criticisms of these those particular studies is that the diets weren't strict enough.
So often the the followers of these particular camps will say that that these are not good trials for testing these,
these questions and these diets because people weren't excluding enough of the problematic macronutrients.
So, for instance,
in these studies of the low carb arms in these studies were generally consuming about 30 percent of their calories from carbohydrates,
which sounds like a lot. But the average American diet is around 50 to 60 percent carbohydrates, so they were cutting their carbs quite a lot.
And so the question is, is there some kind of nonlinear effect of like excluding something like carbohydrates where,
you know, going from 50 or 60 percent down to 30 percent doesn't do very much, but maybe going further matters.
So that's kind of the background for this study. So this study sought to look at the physiology that occurs and the metabolic changes
that occur on changing to one of these low carb or low fat diets in some real detail.
And the study design was effectively a random, randomised crossover design between a low carbohydrate and a low fat diet.
But they did it at this facility, the NIH facility in Bethesda.
And effectively, it was a four week long all expenses paid full board holiday, a little bit like Club Med, possibly without the alcohol.
It's kind of like the lockdown dream. It's basically like being on furlough and not having to cook.
So they managed to recruit 20 people to this dance, to this, to this study.
And I think I think we're were a sensible group to look at. These were young, generally healthy people.
They don't have diabetes. And like, like many in Western Europe and America, they were a bit chubby.
Their BMI was 27 and a mix of mix in men and women.
I'm the I think the design of the study sounds really good.
First off, they weren't told what the aims of the study were. They were told that this wasn't a weight loss study.
They were told not to try and change their weight. They were just told we're studying the effect of carbohydrates and fats on the body.
They deliberately didn't show them any of their results, like their weight or any of their other measurements.
And they even specified that they wore loose fitting clothing.
So I'm imagining these 20 people hanging out in a flat with in scrubs or something like that.
You know, it's so unglamorous clothing, so they don't feel too concerned about their body weight.
And then they were given just like the mice ad Lib Dem food, so they had three meals a day, snacks and water.
And I think I think they were offered something like 4000 calories a day.
So they were they had as much as they could possibly want.
And the low carb bomb was a proper low carb.
So 10 percent carbohydrate, 76 percent fat and 14 percent protein, and 80 percent of that was from animal products.
And the low fat arm was 10 percent fat, 75 percent carb and 14 percent protein.
And that was a vegan or plant based diet. Importantly, both of them.
This was all unprocessed food, and they had loads of access to non-starchy vegetables.
So, you know, salads and lots of like vegetable side dishes and and stuff like that.
So I think the results of this are a lovely triumph of physiology and common sense over all of
the sort of slightly cult like nutritional hype that one gets on one's one's Instagram feed.
So the results are, I think, interesting, and the physiology in this paper is is really cool for those interested in nutrition.
So first off, the intake, so this is the total calorific intake for the two groups.
The low fat group took in less calories, quite a lot less calories over this study, so about 700 calories a day lower in the low fat group.
So a reasonably big difference. Interestingly, in the second week, that difference between low carb and low fat seems to have kind of waned.
And it may be that people sort of acclimatise to the low carb diet and then start reducing their intake over time.
But every single participant, all 20 of them had less intake in their in the low fat arm than they did in the low carb diet.
And there was no difference in their ratings as of the palatability of the food.
But interestingly, both groups lost weight. And actually, it's the low carb group that lost the most.
But that was probably fat free mass change as in loss of water and glycogen from
kind of going into a ketosis state and using up their day glycogen in stores.
Also, interestingly, the resting and sleeping energy expenditure of those in the low carb group was higher,
so they were spending more, expending more calories, expending more energy, even though they were taking in more energy as well.
So that sort of balances things out there are they describe the the physiological changes of going onto these diets really nicely,
and they are exactly what you'd predict from physiology and common sense, but it's really nice to have them demonstrated in this in this way.
So in the low carb group, people went into a mild ketogenic state.
They had detectable urinary and capillary ketones.
They had higher urea and creatinine levels, higher ammonia levels.
And in the low fat group, they had higher C-peptide concentrations, higher insulin levels,
higher postprandial glucose and higher continuous interstitial glucose monitoring as well.
So these are, you know, the kind of the physiological changes you'd expect what you can then,
I guess, debate about what the implications of those are and both harms.
You could certainly make a case for for them being good from a from a general
health point of view and make a case that there are some like concerning features.
So in the low low carb group, you've got benefits for in terms of your glucose and insulin controls.
They were those those were better, but they had higher triglycerides and free fatty acids,
and that's associated in some studies with cardiovascular risk.
Whereas in the low fat group,
we've got a higher continuous glucose monitoring levels and that has been associated in some studies with coronary artery disease.
So it may be that these two dietary strategies can both be effective,
but potentially we should tailor this a little bit based on things like the presence or absence of diabetes and so on.
One thing that strikes me is, in reality, a lot of people don't stick to either of these diets,
and it would have been really interesting to have an arm where the diet was mixed to see what effect that had,
but what sort of alternate alternating between the dietary strategies or well,
so you've obviously got a very low carb and then a very low fat, whereas you could have had another arm where it was more like a real diet.
What if a real diet is so slightly American diet? The American diet, slightly higher levels of carbohydrates and slightly higher levels of fat?
Spot on. You know, I think that would have been really interesting, and I'll I'll I'll mention why in a sec,
because I think it's relevant to the fact that about these two models of obesity and the fact that this study kind of doesn't support either of them.
So if you remember at the beginning, there were two stresses, i.e. the two to two systems, two sort of theories of obesity.
So one model was the passive overconsumption model. So those high and these high energy density foods, which resulted.
Excess energy intake and weight gain. So we'd predict, you know, that low carb diet was 76 per cent fat, but they didn't gain body fat.
In fact, they lost weight overall and they lost some body fat. So that challenges that passive overconsumption model.
Similarly, the carbohydrate insulin model would present in these people who were eating, you know,
80 percent carbs and who had increased postprandial insulin and postprandial sugars, which gained weight.
But they didn't. They lost weight and they lost body fat.
So despite that, and they didn't gain weight.
So neither of these models or in a short term study supported by this and this, I think, just shows that,
you know that the devotees of these simplistic diets are kind of missing a trick here
because the regulation of energy intake is more complex than these straightforward,
these straightforward models would suggest.
So much more complex and probably changes over time as well over the long term, maybe the body adapts and that kind of thing.
Yeah, I think that's a really good point because we don't know what you know, what actually happens after six months or a year or five years?
Yeah, yeah. And what happens at different times, you know, different different times of life.
And you know, the effects, the effects that age and activity and so on do here.
But I think what was really interesting is these people are allowed to eat whatever they like.
They were probably sitting around pretty bored, and I would have predicted that both of them would have gained weight.
Yeah. If you describe that being locked in a facility with as much food as you like.
Yeah, I mean, I'm pretty sure I'm pretty sure I'll gain weight.
But yeah, but they didn't. So what was the difference?
And I think this was actually this is a point that was made by Rowan Francis, who's on on YouTube as midlife crisis.
He did a video about this, this paper as well, and he made the point that that they would.
This was all, you know, freshly prepared food with loads of leafy greens.
There was no processed food in it at all. And maybe the real outcome of this is that actually having a diet,
whether you choose one extreme or the other of the kind of vegan versus keto arguments
that's full of unprocessed food and actually results in short term weight loss?
And those that's the that's maybe that's maybe the takeaway from this.
Yeah, yeah. And that's the bit where I totally agree with you that if you had a third of the people who you know,
he'd go crazy, they didn't just have to have, you know, McDonalds all day long.
But you know, you had a diet that, let's be honest, most of most of the UK and America have that contains a significant amount of processed food.
It would be interesting to compare that to these to these diets.
No, would be. And it's actually just such an interesting paper because it makes you think about
these things and how much we don't know still about the things we all do every day,
which is eating. Yeah, no, we really don't. And I think it's I think it's a really interesting area to study.
And, you know, just massive kudos to the the authors of this, this study, because, you know,
if you look at the paper, the detail of all of the stuff that they measured and they recorded is is is fantastic.
And aside from the fact that it was only four weeks long, which to be fair, it's about as long as you could probably lock anyone in Bethesda for yes.
Uh, aside from that, there's really very little to criticise in this in this paper.
It's, you know,
it's just it's really beautifully done and is is a really fascinating insight into these metabolic implications of of of a popular Instagram diet.
OK, so I've got to hepatology papers this time voters in the from March 2021 as well.
And they both link together in terms of the topic.
So I thought that I presented both at the same time.
So there were two hepatology trials, and they were both published in the March edition of the New England Journal of Medicine last year.
And the first trial is entitled a randomised trial of albumin infusions in hospitalised patients with psoriasis, otherwise known as the entire trial.
And this was led from the Royal Free Hospital UCL in London by Louise China and Alistair O'Brien.
So the aim of this trial was to assess whether the regular administration of human albumin
solution intravenously was associated with a reduction in three outcomes nosocomial infection,
kidney dysfunction or death in patients with decompensated liver cirrhosis that were hospitalised with a low serum albumin.
So the background to this is that for a long time, it has been hypothesised that album might be beneficial in patients with decompensated cirrhosis.
Preclinical studies in which albumin administration has been associated with a reduction in systemic inflammation and albumin is already good.
An evidence base for the treatment of spontaneous bacterial peritonitis,
where it is associated with a reduced incidence of kidney dysfunction and death,
and it is also being trialled in outpatients previously with cirrhosis and uncomplicated decisoes.
But these trials have had conflicting results.
So one randomised trial, which was an open label trial called Anser, which is published in The Lancet in 2018,
and that randomised 440 patients to once weekly albumin versus standard care and that found an
association between the administration of albumin and a reduction in mortality at 18 months follow up.
However, another smaller, randomised trial,
but this one was blinded of albumin and in addition to an alpha agonist drug every two weeks versus a placebo,
found no difference in mortality after one year. And these are all in outpatients with decompensated cirrhosis.
So as well as these conflicting results in human clinical trials,
no previous trials have assessed the effect of albumin on infection rates, renal function or mortality in hospitalised patients.
So that was what this trial set out to address. So they recruited patients admitted to hospital in the United Kingdom with an acute
decompensation of liver cirrhosis under serum albumin of under 30 grams per litre,
and they enrolled them within 72 hours of their admission, and they were randomised with stratification of several factors.
So things like the severity of their liver disease and their baseline creatinine to receiving
a daily infusion of 20 percent human albumin solution or standard care and albumin was
administered from the day of enrolment into the trial until the serum albumin level was above
30 grams per litre and the volume of solution administered was calculated on individual basis.
So they calculated this using their current serum albumin level and their weight.
I believe patients who were randomised to standard care were prescribed albumin as per usual
clinical practise if it was indicated for the treatment of hepatic renal syndrome or SBP.
The clinicians and the trial investigators were not blinded to the intervention received,
and the primary composite endpoint was the development of infection,
the development of kidney dysfunction or death in these patients between day
three and day 15 of the trial or the date of the discharge of the patient,
whichever was first. So I always get a bit worried with composite end points.
So what was the sort of the reasoning behind choosing a composite primary end points rather than just picking,
you know, one of these particular units in the night, something like death? What's the what's the rationale between sort of lumping them together?
So I suspect the rationale for lumping them together was to pile the study adequately in terms of funding and time and things like that.
But the academic rationale, I guess, and why this is maybe an okay.
Thing to do to lump them all together is that obviously and death is the worst outcome,
but a new infection or kidney dysfunction carry a very high mortality risk if they develop in cirrhotic patients.
So that's why they decided to put all three together.
But that's what the authors claimed in the study. Fair enough.
And I suppose with all trials,
there's always an ideal way in which we would like to conduct and then a real world way in which it is practical to do so.
Yeah, these are tricky. These are tricky patients to to run trials on trial.
Exactly. Exactly right. Exactly right. And and presumably that explains why they didn't blind clinicians and investigators to the intervention.
Yeah. Exactly. I presume a that's exactly the case.
So the other thing about the end point was they did choose a short timescale in which to assess the primary outcome.
And the reasoning for this was initially after recruitment and starting the albumin.
If the patient was randomised to that arm, they reasoned that the administration would not have an effect within the first day of treatment,
essentially until the serum albumin had actually improved. So they gave it time to work and they followed up to 15 days.
So day 15 of admission or discharge, whichever came first because, you know,
they were aiming to just see what effect albumin had on the composite end.
In the short term, rather than in the longer term.
And they did define infection in quite a reasonable way because obviously that's slightly subjective,
but it was defined by the patients attending clinician and then confirmed by a blinded physician panel,
which I think is completely fair enough and in practical sense and makes it a bit more applicable to the real world.
And kidney dysfunction was defined by an increase in testing of over 50 percent of baseline,
or an increase by twenty six point two miles per litre and or 0.3 milligrams per decilitre in 48 hours.
So did it work, Tamsin? In short, no, but it was a great trial.
So seven hundred and seventy seven patients were randomised, which I think is a brilliant effort for,
as we said, a very difficult patient group to run a trial on in the hospitalised setting.
So the baseline characteristics were similar across both groups, which indicates that the randomisation was was good.
And it's worth saying that in this group of patients, alcohol was the aetiology of liver disease in the majority,
which reflects the local aetiology of liver disease in the United Kingdom,
and approximately two thirds in each group were admitted to hospital due to worsening of their cities.
And the remainder were admitted due to either worsening or new encephalopathy or of our total bleed.
So there was no difference between the album and group and the standard care group in meeting the primary outcome,
which was the composite outcome of the development of infection.
Kidney dysfunction or death between three and 15 days after enrolment in each group,
approximately 30 percent of patients developed one of those outcomes at the time to event analysis and the subgroup analyses
that were run on the individual components of the composite outcome also showed no significant differences between groups.
And although I don't remember whether that was powered adequately to do those subgroup analyses, and they did follow up to a later stage.
So a day 28, three months and six months after enrolment, there were no differences in death between the groups.
Now, the next part of their findings is probably the most interesting,
so they found that pulmonary oedema or fluid overload was significantly increased in the albumin group.
So in 380 patients randomised to albumin, there were 23 events of pulmonary oedema or fluid overload compared to the Standard Care Group,
where there were eight patients in 397 patients who developed this.
So although it wasn't common, it was more more common in the group that received albumin in the discussion.
They didn't feel that their findings and of no difference between the groups were due to suboptimal dosing because they found that firstly,
the patients that were randomised to albumin received significantly more albumin with the standard care group.
So 200 grams versus 20 grams. And the mean serum albumin level achieved in the patients.
Receiving album was an on target, so it increased to their target of 30 grams per litre between day three and five,
so they felt that they were giving them enough albumen for it to have had an effect if it did have an effect.
So in summary,
the takeaway from this study is that daily albumin infusions do not improve outcomes in hospitalised patients with decompensated cirrhosis.
If the albumin is low and we need to be careful because there's an increased risk of pulmonary oedema in these patients,
although no difference in mortality. Wow.
So I think, as you said, this is a really well conducted trial.
I think it shows that shows the benefit of high quality, large, randomised controlled trials, even when they're negative.
Indeed, especially when they're negative too late. Because a little bit like the whole trial for GI bleeding, which showed, you know,
really definitive evidence that tranexamic acid is is not effective in in that in the setting of GI bleeding this.
This says pretty clearly that outside of these specific indications of HRT or or spontaneous bacterial peritonitis,
we should not be giving our opinion.
Do you think are there any subgroups or other and other indications within this population who who you think should,
should ever have albumin, or whether there's, I guess, any kind of doubt based on the results of this trial.
So I think what isn't clear, certainly in my head and whether there's evidence for this or not, I don't know, is when a patient is intravascular,
they deplete because in in this trial, the albumin was given and calculated based on their serum albumin,
not whether they needed intravascular volume or not.
And so in a patient where the intravascular deplete, I'm in clinical practise, Krista Lloyd.
But some people do get five percent albumin,
and I don't know what the evidence behind that or indeed whether there is any evidence to recommend one over the other in that situation.
Yeah, I don't. I don't. I don't know. I can't think off the top of my head of any trials about that,
but I was going to say that I think that's the only specific indication or subgroups that I think there's still some doubt of.
So those intravascular depletes or and or have an acute kidney injury, which doesn't meet the criteria for HRC.
And I think they're still the patients in whom I think we worry about flooding them with Crestor Lloyd and that maybe,
maybe some aspects of the colloidal effective and albumin would be good.
But it's really helpful to know that you know that this puts it puts it draws a line under the kind of any kind of routine administration for these,
for these patients. So the second trial is entitled TelePresence Plus Albumin for the treatment of
type one hepatic renal syndrome and otherwise known as the confirmed trial.
And this was conducted in 60 centres in the United States and Canada.
So this is a slightly different situation. So type one hepatic renal syndrome just to give a bit of background or say chi
and is acute kidney dysfunction within seven days associated with cirrhosis,
where the serum creatinine increases by an approximately 26 micro moles per litre,
or 9.3 milligrams per decilitre, within 48 hours for an increase of 1.5 times from the baseline level.
So it's it's a diagnosis of exclusion, really.
So initially, when you assess a patient with acute kidney dysfunction in the context of cirrhosis, you need to assess whether they're intravascular,
deplete or not and attempt to expand the intravascular volume and also withdraw diuretic
treatment and assess over the next 48 hours or so whether that improves the renal function.
And if that doesn't, then haphazard renal syndrome is more likely,
and the pathophysiology is thought to be due to the combination of systemic inflammation
and renal micro circulatory dysfunction due to splenic arterial phase the dilation.
So even if somebody is rehydrated despite that, the.
We have a persistently high.
So for a long time in the U.K., well, we're very used to using albumen and tell a person in combination for the treatment of renal syndrome.
But in the United States,
10 percent is yet to be incorporated into the clinical practise guidelines because the previous randomised trials were small.
So this study aimed to assess the efficacy and safety of a person with albumin for the treatment of Horus in a larger,
randomised trial to inform a clinical practise in North America.
So the inclusion population were hospitalised patients with psoriasis as cities and as renal syndrome,
with the sérum question that was two times higher than baseline and at least one hundred ninety nine millimetres per litre.
And patients were randomly stratified by creatinine two to one to receive six hourly telepresence kids plus albumin or placebo,
plus albumin for 14 days or until they had two measurements of the creatinine under one three three minute miles per litre.
And the primary outcome they measured was reversal of HRC or clinical failure,
and success was defined by a patient having to create an index of under 1.5 milligrams per decilitre,
or 133 mike moles per litre less than two hours apart, and survival without renal replacement therapy for a further 10 days.
So a slightly complicated but importantly fastidious definition.
So what did this study find? So this randomised 300 patients and the baseline characteristics were similar between the two groups.
And alcohol was aetiology of cirrhosis in the majority of patients at two thirds and in 25 percent of patients and metabolic associated liver disease.
So clinical success, it's a reversal of HRC was achieved in a significantly higher proportion of
patients that were randomised to tell a person plus us than placebo plus us.
So in the Taylor Person Plus and albumin group, 32 percent had reversal of HRC, and that was only 17 percent in the placebo plus out in the group.
Clinical failure rates were still high.
So 60 percent of the total person group didn't get better, and 80 percent of the CEBA group didn't have reversal of HRC by 30 days.
There was no significant difference in those that achieved and sustained hepatic renal syndrome.
Mortality was similar in both groups at day 30, but during the on treatment period at nine patients in the telecasting groups
of four percent and one patient in the placebo groups of one percent died.
The 12 person group were more likely to have respiratory failure and die from a respiratory cause within 90 days.
So while it's clear that those who received her depressant had a double double that
that sort of the the chance of accuracy reversal and not needing replacement therapy,
those short term gains weren't really carried on until two kind of medium term outcomes.
That's right. And the second thing that draws my eyes, you know, just how ineffective our treatment is of individuals with a.
Yeah, it's pretty dismal.
We really we have very little in our therapeutic armamentarium other than, you know, good, you know, good kind of basic care.
Yeah. Yeah, absolutely. In terms of generalisability.
So they did exclude some patients with large who had had a large volume person and teases within 48 hours
before enrolment or sepsis or uncontrolled bacterial infection within 24 hours of antibiotic treatment.
So I thought that might be difficult in terms of infection is often quite difficult
to diagnose accurately in patients with cirrhosis and decompensated cirrhosis,
particularly in the initial stages where it's unclear what might have precipitated the decompensation.
And patients can often have clinically silent infection with negative blood cultures and and certainly in the UK antibody.
Treatments often given even when there's no positive culture.
And that might have excluded many patients from participation if this was and if this trial had been done in the UK.
And the other thing that I thought was noticeable was and in the European definition of acute and acute kidney injury associated with cirrhosis,
the minimum serum creatinine of one nine nine micrograms per litre is higher than the accepted European DNA definition.
So they the enrolled patients with a higher serum creatinine than we would define as having a race in Europe.
And furthermore, that benefit may have been found if they included these patients as well.
But I think overall, it supports the use of telepresence alongside albumin in HRT and, as is usual, practise at the moment in the United Kingdom.
So do you know if this has changed practise in the in the US and in other countries that haven't traditionally used to repress it in this setting?
I don't know. Actually, I should look that up and see when the guidelines have changed or being rewritten since.
Yeah, but certainly the authors were supporting its use in North America.
So these are two really interesting, although I'd argue, pretty depressing, randomised controlled trials in liver disease.
And, you know, I think it's a reflection of all kind of our usual inpatient practise that I experience,
that this is a group of patients who who it's we don't have a lot to offer them.
I, aside from a being supportive care,
really good supportive care and that and there's a real lack of effective therapeutic treatments for for the conditions that we've got.
And even the ones that we do have,
like telepresence are actually the evidence base suggests they probably don't by themselves lead to kind of medium term or long term gains.
And they only work and it's fantastic to see the proportion of patients.
Yeah, great to see like two really good trials answering like really clinically relevant questions.
Awesome. So there are two papers that we've sort of kind of done in in possibly excessive detail.
And then we've got a few more that we'll pretend to do quickly, but probably not actually do it.
I will try my best. So these quickly? Yeah.
What do you want to do? You want to start with one or two? Yeah.
OK, I'll take over. So my number one is got a long title towards personalised medicine in autoimmune hepatitis measurement of thought peri
metabolites results in higher biochemical response rates compared to standard weight based dosing of stock here in therapy.
And the first author was Leena Candles, and the senior author was Michael Hennigan, both based at Kings College Hospital in London.
OK, maybe, maybe just assume, maybe assume that we are all.
I'm not going. I'm not going to go into the detail. But the metaphor exactly of which I'm sure we all is, we use it all and obviously lots.
So it was a retrospective single centre case control study,
and the population was patients with autoimmune hepatitis treated with AIDS fibrin between 1999 and 2019 at King's College Hospital.
So 94 percent received either therapy and six percent received microfinance.
Mike Finley alone or in combination with other therapies, and the intervention was metabolic and metabolite monitoring of aces high.
So these were people that the clinician had decided to do a stop monitoring,
and the control was weight based dosing phase of Typekit and that there was approximately just over 100 in each group.
And the outcome that was measured was the maintenance of biochemical response.
In this case, normalisation of ECG and transmit disease at six or 12 months after the metabolites were tested.
And the main finding was that the patients in the group were metabolites were measured were significantly more
likely to maintain biochemical response at six months follow up compared to those without metabolite measurement.
So that was 77 percent versus 60 percent.
And although this is a case control study, we're all probably used to measuring and isotopic metabolites in IBD, and it's quite useful.
And this is an interesting study that we might want to use more of metabolite testing in in the autoimmune hepatitis cohort.
Yeah, it's interesting that I find it interesting that for different conditions, even within the same speciality,
we have different like different approaches for how we like not just dose, but how we how we monitor and so on.
It's a bit like for biologics, where gastroenterologists have, particularly from the days when Infliximab was the only thing, you know,
therapeutic therapeutic toolbox for the sort of severe IBD we, you know, really look carefully at,
you know, the levels and how we optimise them and how we protect response and so on.
And that's just not been part of the culture in rheumatology, where probably due to their increased number of options.
There have been, you know, much, much happier to switch.
Just one question on this were there like with the sort of the target levels there for the ace of thyroid metabolites the same?
Yeah, I think so. So and so basically it well, it was yes, they they used a range,
a normal range of the TGA and as the TGA and therapeutic range between two, five and 450 and that was derived from an IBD population.
And then they applied that to this group retrospectively.
Yes. Is the answer you were looking for. I think yes, but I don't know what the individual.
So at the time, obviously, when the clinicians were making the decision about the ACS offering to alter the levels,
I don't know whether they knew what they were saying was the normal range,
but they retrospectively applied a range that we normally used for the IBD
population on the study cohort to see how many had some therapeutic TGA levels,
too. Okay, so the second one potential effects of minimum unit pricing at local authority level on alcohol.
It attributed harms in North West and North East England. A modelling study this was published by Brennan et al.
From Sheffield. So the aim of this study was to estimate the potential effects on mortality,
hospitalisations and crime of the implementation of minimum unit pricing for alcohol at a local authority level in England,
which, as we all know, has been done in. Scotland and they used a computer modelling strategy to do this.
The data they fit into their model was obtained from a look at the local level about the consumption of alcohol,
local prices and various other things.
So 23 upper tier local authorities in North West England and 12 in northeast England and nine government office regions.
The model was tested on and the intervention was setting a local minimum unit price and the best case being 50 pence per unit of alcohol.
And this 50p minimum unit price for alcohol when it run through the model and was estimated to reduce annual alcohol
related deaths in the North West region and by 205 and hospitalisations by five thousand nine hundred fifty six.
So that's a five point five percent reduction and a reduction in crime by 2.5 percent, which suggests that as in Scotland,
a minimum unit alcohol price in England,
particularly in areas of the country where there's a high burden of alcoholic liver disease, might be very useful.
So haven't they recently published the outcomes of the minimum minimum unit pricing structure in Scotland?
Sure, I saw something on the news. I think we should have read a paper.
We should have a look and talk about it. Yeah, I think I think they did, and I think it was sometime last year.
We should definitely have at least to definitely have a look at a look at that.
I think it's a really it's a really interesting policy and I think it raises.
I mean, it raises a number of interesting kind of, you know, moral and ethical issues as well as as as well as anything else.
But you know, the short answer is that if it works, then you know, that's that's hugely,
hugely important as as as as one of the tools for tackling alcohol abuse.
And it's great to see people looking outside of just direct alcohol harms and just looking at, for instance,
like liver disease or that, you know, violent crime or other crime, other other conditions, you know, the wider impacts.
You know, it's really important to consider. Yeah. No, absolutely. Do you want to do a couple?
Yeah, sure. I'll do. I'll do one. And now for something completely different in a Monty Python esque way.
So this is this is more of what it's it's a sort of it's a meuron study, something a bit different.
So it's entitled an organoid based organ repurposing approach for the treatment of short bowel syndrome,
and it's by researchers from Tokyo lead author Shinya Shuggie Muto.
So I thought, this is a really cool, cool paper and some really interesting science, albeit somewhat far from clinical practise.
So as with backgrounds, a significant proportion of the patients who have intestinal failure due to either a short length
of a small bowel bowel out of continuity or lack intrinsic bowel disease like Crohn's disease,
those patients often require long term parenteral intravenous nutrition, also at home nutrition.
But that comes with significant risks, inconvenience and and pretty huge costs.
Sort of in the region of £30000 a year to supply parenteral nutrition to someone if they require nursing care tens of thousands of pounds more.
So this is an expensive, inconvenient and risky intervention, but it's all we have.
The only alternative is an intestinal transplant, which can be highly effective but is relatively relatively high risk transplant still,
and we certainly got some way to go to get better outcomes for those patients.
But there's a big chunk of patients with intestinal failure who intestinal transplant is not appropriate for.
So in short, this paper is about developing a method to which they call developing a small intestine sized colon,
basically turning the colon into an absorber of tissue a bit like a small intestine
as a therapy for intestinal failure and doing this in a couple of mouse models.
So what they did is they they they grew up human or.
Organoids from small bowel, so for those unfamiliar with organoids.
This is where you get some. In this case, epithelial cells from an ideal biopsy, you strip off the epithelium.
So you've just got the epithelial cells and there'll be some stem cells in there.
And if you grow them in the right, the right sort of magic potion in the lab,
they will develop into these little sort of these sort of steroids kind of structures.
And they will often develop some of the characteristics of the epithelium from from where they've where they've come.
They form these, these these structures.
So that's what the researchers did is they got this human ideal organoids and they transplanted them into immunodeficient mice into their colon.
So basically, they just instilled them into the colon after they stripped away the colonists, the colon epithelium.
And what happened is kind of fascinatingly these.
These organoids basically just attach themselves to the kind of denuded mouse colon wall and took up residence there,
and they formed an epithelial layer. But not only did they form an epithelial layer, it was a layer that didn't look like colon.
It looked quite a lot like small bowel. So those epithelial cells, which in now in this mouse colon, had microvilli for absorption.
They started to form what looks a little bit like villi.
So these kind of pseudo village structures, the cells expressed the the surface enzymes and transporters we we'd we'd expect of the small bowel.
So they expressed the sucrose ICER Maltese enzyme and also the sodium bile acid transporter Ibat.
And then they showed this. This really cool thing, which I which I thought was was really interesting,
was that the the colon kind of sub mucosa altered in response to these human ileal aethereal cells taking up residence there.
So within these kind of pseudo village structures,
we got what they saw was the development of lymphatic like you would see in the small bowel going up into the village structure.
And they seem to be functional in that they could measure cholesterol absorption, see cholesterol and track cholesterol going into those lymphatic.
And they did some interesting work to try and show how these how these organoids
kind of took up residence and developed these these sort of phyllis protrusions.
And and and so on. And so this was their first bit of work in in mice, kind of as a proof of principle.
And then they said, Well, could these small intestine mice, colon colon be used as a treatment for short bowel syndrome?
And so they went into rats and did some pretty crazy surgery,
which I think is well worth briefly running through because it involves aside other things and into dental.
Panasonic toothbrush, toothbrush really something that you read about in in nature.
So they went into rats as far as I can work out because rats are bigger and easier to do the surgery in particular to do the surgery,
to remove the whole colon. So what they did is they went to the rats.
They dissected out four centimetres of colon, but they left its vasculature there.
So effectively, they've just got a tube of colon.
They then basically wash out the colon with with kind of warmed EDTA, which is, you know, sort of strips off the epithelium of the colon.
They then scrubbed the inside of the colon with a Panasonic incidental toothbrush.
And then they instilled in these human organoids.
And then what they did is they and that's the mouse, the two ends of this colon to the skin, it's effectively a stoma at each end.
So effectively you've just got a loop of colon. And that enabled them.
And then they left it for a couple of weeks for those organoids to take up, you know, set up shop and form their small intestine, mice, colon cord.
So that was just Operation Number one Operation No. Two was.
They effectively just removed the whole small bowel of the rat.
They did a Chechnya ideal reception, and then they put back in that small intestine sized colon,
and they compared it to just putting back the normal mouse colon.
Sorry, the normal rat colon. But but not, but not not with this, nor with the treatment with the organoids.
And again. They demonstrate that, you know, that the the epithelial cells take up shop, they express the right enzymes,
they're doing doing the right things, but they also show that actually it seems to work at least for some of these poor rats.
So basically, all the rats that just had their small bag removed in their cone or left or died within 10 days.
The ones who had this small intestine lies colon put in.
Some of them lost weight and died. Some of them lost weight, and then they started gaining weight again.
And they survived, and they were long term survivors. Well, as long term as a rat study ever is.
And they found that those days long time survivors were the ones who had the best engraftment of these organoids.
So they kind of proved the principle that you can turn a colon that really just absorbs electrolytes and water and some short chain fatty acids.
And you can basically by just switching out to the epithelial cells,
you can turn it into an absorber tive bit of guts like the small bowel that can
function and keep keep at least some rats alive till the end of the experiments.
So I think this is a really, really cool idea, albeit a little a little way away from it, from being applied in clinical practise.
A very cool idea that you could manipulate tissues to function in different ways to solve, like real world.
Really interesting. So will love. Yeah, super. We'll wait for that to translate into humans with the toothbrush.
Yeah, we're going to need a big. So the last one we're going to do in a you for insights today.
So a massive yoga running is one that is actually not really about gastroenterology at all.
But I think it's a really cool little article, which I think everybody should have a quick glance at.
It's in clinical medicine, which is the Royal College of Physicians in House Journal, and it was, it's called.
I can assure you that there is nothing wrong with your kidney. This is an article from a GP called Tamara Keith,
and this is an article about her experience as a patient when she was a medical student and junior doctor with an,
at that point, undiagnosed abdominal pain syndrome.
So she was diagnosed with recurrent culture, negative pyelonephritis and after six years, finally was given a diagnosis.
The diagnosis was found to be Nutcracker. syndrome, which was a new one to me,
which is where the left renal vein is compressed, sandwiched between the aorta and SMA.
And effectively, that the kidney has periods of ischaemia an intense, intense, long pain.
But I but often these these these patients are not diagnosed at all, labelled as as patients who have a functional disorder.
And so I'm just going to. She describes really,
really well the challenges of having having this functional disorder about the journey to the final
diagnosis and and her kind of observations and thoughts of of how it's relevant to kind of all doctors.
I just wanted to read out one paragraph from from this for six years, my pain had been discredited.
My agenda questions my honesty, mistrusted by many in the renal team.
Yet they continue to treat me as suffering from a recurrence pyelonephritis.
Fortunately, I had a renal physician and a radiologist who believed that my symptoms were real and were keen to find out the cause.
However, there was disagreement within the team thwarting progress. I had been labelled.
I was functional. I was the attention seeking medick, the annoying expert patient.
This was a real and general genuine problem. I had concluded the diagnosis was Nutcracker. syndrome long before many of them had even heard of it.
I knew more about this condition than any of them, but consultants do not take kindly to being taught by medical students.
And it was in it really good, actually edition of clinical medicine, all about functional disorders in different organ systems.
But I think I think there's definitely some things that it made me think about about the cohort of patients that we have in gastroenterology who have,
you know, complex functional pain syndromes.
And you know, some thoughts about how we kind of manage, manage their care and how we, you know, best, best kind of understand them and and help them.
Thank you. That's that's really interesting. I'll need to go back to clinical medicine and read the article.
Thank you. That's. So that concludes our episode three of Gut Instinct.
We hope you enjoyed it. Please get in touch with us on Twitter or via email if you have any comments or any reflections
on anything that we've discussed and hopefully will be back soon for another episode.