1 00:00:04,460 --> 00:00:12,200 Hello and welcome to episode three of Gut Instinct research uptakes, bringing the latest research in gastroenterology and hepatology. 2 00:00:12,200 --> 00:00:21,670 I'm Tamsin Cargill. I'm the gastroenterology registrar in the Thames Valley interested in hepatology, viral hepatitis and vaccine development. 3 00:00:21,670 --> 00:00:27,620 And I'm Michael Fitzpatrick, I'm known as fit to pretty much everyone, as well as being Tamsin sidekick, 4 00:00:27,620 --> 00:00:41,790 I'm a clinical lecturer in Gastroenterology in Oxford with particular interest in GI immunology, coeliac disease and nutrition. 5 00:00:41,790 --> 00:00:46,860 So we started this podcast back at the beginning of last year to kind of bring 6 00:00:46,860 --> 00:00:51,480 you some of the most interesting GI related papers that have come out recently. 7 00:00:51,480 --> 00:00:57,570 Hopefully saving you some time and assuaging your guilt for not reading enough journals. 8 00:00:57,570 --> 00:01:05,250 So each episode we plan to take you through a couple of really interesting primary research papers in a bit of detail. 9 00:01:05,250 --> 00:01:11,430 Generally, one clinical and one translational with a bit of luminal and and hepatology in there, 10 00:01:11,430 --> 00:01:18,600 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. 11 00:01:18,600 --> 00:01:22,920 Unfortunately, life rather got in the way of things last year. 12 00:01:22,920 --> 00:01:30,030 But we are back for our New Year's resolution in 2022 for more regular podcasts. 13 00:01:30,030 --> 00:01:37,230 And possibly not taking ourselves quite so seriously. Clearly, there are lots of great papers coming out every month. 14 00:01:37,230 --> 00:01:42,570 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 15 00:01:42,570 --> 00:01:49,330 five and five section where we'll try and give you the key points of five papers in five minutes. 16 00:01:49,330 --> 00:01:56,620 Now, it shouldn't need to be set, but disclaimer alert. Clearly, nothing on this podcast constitutes medical advice. 17 00:01:56,620 --> 00:02:00,430 If you are a patient, you can consult your medical practitioner. 18 00:02:00,430 --> 00:02:08,440 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. 19 00:02:08,440 --> 00:02:15,040 Please do tell us what you think of this podcast. Write us a lovely review and whatever platform your streaming this through. 20 00:02:15,040 --> 00:02:21,160 Please connect with us via Twitter at Jye Update. We're based on Twitter as well. 21 00:02:21,160 --> 00:02:34,650 Or email us at Gut Instinct Podcast All one word at gmail.com. 22 00:02:34,650 --> 00:02:44,490 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. 23 00:02:44,490 --> 00:02:49,140 And so they're all, maybe not quite as fresh as we normally like them. 24 00:02:49,140 --> 00:03:00,630 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, 25 00:03:00,630 --> 00:03:10,380 comparing low fat and plant based diets like vegan diets compared to low carb animal based kito or carnivore diets. 26 00:03:10,380 --> 00:03:16,380 And this particular area is one of great conflict, particularly on social media, 27 00:03:16,380 --> 00:03:24,390 where the sort of devotees of these different dietary camps take a rather sort of cult like attitude to things, 28 00:03:24,390 --> 00:03:32,190 and it can all get quite quite unpleasant. But I would say this is probably one of the key clinical scientific questions of our 29 00:03:32,190 --> 00:03:38,160 time because obesity is a huge international problem with massive implications. 30 00:03:38,160 --> 00:03:44,730 And while there are exciting drug treatments like Semaglutide that we've discussed before and 31 00:03:44,730 --> 00:03:50,910 a whole range of highly efficacious bariatric surgical options for those with morbid obesity, 32 00:03:50,910 --> 00:03:58,320 understanding how diet can be used to control weight is clearly hugely important. 33 00:03:58,320 --> 00:04:09,660 So this paper was out in Nature Medicine in early 2021. It's published by Kevin Hall's lab and and colleagues, 34 00:04:09,660 --> 00:04:19,440 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. 35 00:04:19,440 --> 00:04:22,260 I always laugh a little bit of Latin in a title. 36 00:04:22,260 --> 00:04:31,470 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. 37 00:04:31,470 --> 00:04:37,050 And this is this is the human equivalent of of of that. 38 00:04:37,050 --> 00:04:46,110 So Kevin Hall is based at the niche in Bethesda, where he's one of the senior investigators studying nutrition and metabolism. 39 00:04:46,110 --> 00:04:50,640 And I didn't notice but the the hospital where they work, 40 00:04:50,640 --> 00:04:56,490 Bethesda is the largest hospital in the world, which is dedicated purely to clinical research. 41 00:04:56,490 --> 00:05:04,710 And it sounds absolutely incredible. They've got a effectively a 200 patient hospital just for residential clinical studies. 42 00:05:04,710 --> 00:05:09,540 So this huge resource and that's where that's where he works. 43 00:05:09,540 --> 00:05:20,730 So the premise of this study is two competing models of obesity and the drivers for sort of excess calorie intake. 44 00:05:20,730 --> 00:05:26,580 And the reason those those models are important are that they suggest that different 45 00:05:26,580 --> 00:05:32,640 diets will be effective really about excluding fat or carbohydrates in them. 46 00:05:32,640 --> 00:05:37,350 So the first is called the carbohydrate insulin model of obesity. 47 00:05:37,350 --> 00:05:47,190 And this says that eating high glycemic carbohydrates results in elevated postprandial insulin that 48 00:05:47,190 --> 00:05:55,050 is then supposed to drive the accumulation of body fat and drive increased hunger and energy intake. 49 00:05:55,050 --> 00:06:02,910 So it's the carbs, what does it that drives insulin and it leads to accumulation of fat and you taking in more calories? 50 00:06:02,910 --> 00:06:10,770 The alternative model is the passive overconsumption model, which is that high energy density foods, 51 00:06:10,770 --> 00:06:20,010 particularly like high fat foods, have a relatively weak effect on satiety in proportion to their energy intake. 52 00:06:20,010 --> 00:06:27,000 And and this is a quote from the paper modifying food hedonic in a way that supports increased intake. 53 00:06:27,000 --> 00:06:38,050 Basically, they taste bloody delicious. So but I do like modifying food head head, which sounds philosophical. 54 00:06:38,050 --> 00:06:47,490 Yeah, it does. It does so. So these are these two, these two models, one of which says that we should exclude carbohydrates. 55 00:06:47,490 --> 00:06:54,450 The other we should exclude energy dense foods, in particular high fat foods. 56 00:06:54,450 --> 00:06:58,410 Now the problem with nutrition science and a lot of nutrition studies is that 57 00:06:58,410 --> 00:07:05,430 they're often flawed in design and execution because they're often retrospective. 58 00:07:05,430 --> 00:07:14,640 They're often based on surveys, and people are very bad at recalling retrospectively what they've actually eaten when they are interventional. 59 00:07:14,640 --> 00:07:20,520 They are often done in a way that sort of often has poured hereabouts to the diet. 60 00:07:20,520 --> 00:07:24,570 There's often a lack of detail in what's what's measured. 61 00:07:24,570 --> 00:07:32,490 And it makes it really challenging to interpret individual trial results and generalise them to the population. 62 00:07:32,490 --> 00:07:38,150 So good. It example is evening on high quality, randomised controlled trials. 63 00:07:38,150 --> 00:07:42,230 We often get confirmed contradictory or unclear results. 64 00:07:42,230 --> 00:07:45,200 So two that I wanted to mention in the past. 65 00:07:45,200 --> 00:07:53,810 One was the direct study, which was published in the New England Journal of Medicine about 13 or 14 years ago now, 66 00:07:53,810 --> 00:08:00,230 and that showed that some low carbohydrates and and Mediterranean diets were more 67 00:08:00,230 --> 00:08:06,950 effective at than low fat diet for weight loss after two years of follow up, 68 00:08:06,950 --> 00:08:13,010 albeit with a pretty small difference of about two kilos after two years follow up. 69 00:08:13,010 --> 00:08:18,500 But then another randomised controlled trial called that Diet Fitz trial again of low fat versus low 70 00:08:18,500 --> 00:08:23,990 carb diet showed no difference at all in weight loss between these two strategies after a year. 71 00:08:23,990 --> 00:08:35,790 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. 72 00:08:35,790 --> 00:08:45,830 So often the the followers of these particular camps will say that that these are not good trials for testing these, 73 00:08:45,830 --> 00:08:52,580 these questions and these diets because people weren't excluding enough of the problematic macronutrients. 74 00:08:52,580 --> 00:08:53,360 So, for instance, 75 00:08:53,360 --> 00:09:02,180 in these studies of the low carb arms in these studies were generally consuming about 30 percent of their calories from carbohydrates, 76 00:09:02,180 --> 00:09:11,450 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. 77 00:09:11,450 --> 00:09:17,840 And so the question is, is there some kind of nonlinear effect of like excluding something like carbohydrates where, 78 00:09:17,840 --> 00:09:25,610 you know, going from 50 or 60 percent down to 30 percent doesn't do very much, but maybe going further matters. 79 00:09:25,610 --> 00:09:35,160 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 80 00:09:35,160 --> 00:09:45,060 that occur on changing to one of these low carb or low fat diets in some real detail. 81 00:09:45,060 --> 00:09:54,240 And the study design was effectively a random, randomised crossover design between a low carbohydrate and a low fat diet. 82 00:09:54,240 --> 00:10:00,030 But they did it at this facility, the NIH facility in Bethesda. 83 00:10:00,030 --> 00:10:11,520 And effectively, it was a four week long all expenses paid full board holiday, a little bit like Club Med, possibly without the alcohol. 84 00:10:11,520 --> 00:10:16,770 It's kind of like the lockdown dream. It's basically like being on furlough and not having to cook. 85 00:10:16,770 --> 00:10:24,470 So they managed to recruit 20 people to this dance, to this, to this study. 86 00:10:24,470 --> 00:10:30,990 And I think I think we're were a sensible group to look at. These were young, generally healthy people. 87 00:10:30,990 --> 00:10:38,280 They don't have diabetes. And like, like many in Western Europe and America, they were a bit chubby. 88 00:10:38,280 --> 00:10:42,910 Their BMI was 27 and a mix of mix in men and women. 89 00:10:42,910 --> 00:10:49,170 I'm the I think the design of the study sounds really good. 90 00:10:49,170 --> 00:10:54,360 First off, they weren't told what the aims of the study were. They were told that this wasn't a weight loss study. 91 00:10:54,360 --> 00:11:01,800 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. 92 00:11:01,800 --> 00:11:07,260 They deliberately didn't show them any of their results, like their weight or any of their other measurements. 93 00:11:07,260 --> 00:11:10,350 And they even specified that they wore loose fitting clothing. 94 00:11:10,350 --> 00:11:16,260 So I'm imagining these 20 people hanging out in a flat with in scrubs or something like that. 95 00:11:16,260 --> 00:11:21,810 You know, it's so unglamorous clothing, so they don't feel too concerned about their body weight. 96 00:11:21,810 --> 00:11:29,880 And then they were given just like the mice ad Lib Dem food, so they had three meals a day, snacks and water. 97 00:11:29,880 --> 00:11:34,140 And I think I think they were offered something like 4000 calories a day. 98 00:11:34,140 --> 00:11:38,130 So they were they had as much as they could possibly want. 99 00:11:38,130 --> 00:11:40,900 And the low carb bomb was a proper low carb. 100 00:11:40,900 --> 00:11:49,020 So 10 percent carbohydrate, 76 percent fat and 14 percent protein, and 80 percent of that was from animal products. 101 00:11:49,020 --> 00:11:55,470 And the low fat arm was 10 percent fat, 75 percent carb and 14 percent protein. 102 00:11:55,470 --> 00:12:01,680 And that was a vegan or plant based diet. Importantly, both of them. 103 00:12:01,680 --> 00:12:06,810 This was all unprocessed food, and they had loads of access to non-starchy vegetables. 104 00:12:06,810 --> 00:12:13,530 So, you know, salads and lots of like vegetable side dishes and and stuff like that. 105 00:12:13,530 --> 00:12:23,040 So I think the results of this are a lovely triumph of physiology and common sense over all of 106 00:12:23,040 --> 00:12:31,200 the sort of slightly cult like nutritional hype that one gets on one's one's Instagram feed. 107 00:12:31,200 --> 00:12:40,230 So the results are, I think, interesting, and the physiology in this paper is is really cool for those interested in nutrition. 108 00:12:40,230 --> 00:12:46,020 So first off, the intake, so this is the total calorific intake for the two groups. 109 00:12:46,020 --> 00:12:55,770 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. 110 00:12:55,770 --> 00:13:05,700 So a reasonably big difference. Interestingly, in the second week, that difference between low carb and low fat seems to have kind of waned. 111 00:13:05,700 --> 00:13:13,650 And it may be that people sort of acclimatise to the low carb diet and then start reducing their intake over time. 112 00:13:13,650 --> 00:13:22,830 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. 113 00:13:22,830 --> 00:13:28,410 And there was no difference in their ratings as of the palatability of the food. 114 00:13:28,410 --> 00:13:35,700 But interestingly, both groups lost weight. And actually, it's the low carb group that lost the most. 115 00:13:35,700 --> 00:13:42,360 But that was probably fat free mass change as in loss of water and glycogen from 116 00:13:42,360 --> 00:13:47,340 kind of going into a ketosis state and using up their day glycogen in stores. 117 00:13:47,340 --> 00:13:54,810 Also, interestingly, the resting and sleeping energy expenditure of those in the low carb group was higher, 118 00:13:54,810 --> 00:14:01,000 so they were spending more, expending more calories, expending more energy, even though they were taking in more energy as well. 119 00:14:01,000 --> 00:14:12,180 So that sort of balances things out there are they describe the the physiological changes of going onto these diets really nicely, 120 00:14:12,180 --> 00:14:20,100 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. 121 00:14:20,100 --> 00:14:25,170 So in the low carb group, people went into a mild ketogenic state. 122 00:14:25,170 --> 00:14:30,150 They had detectable urinary and capillary ketones. 123 00:14:30,150 --> 00:14:34,200 They had higher urea and creatinine levels, higher ammonia levels. 124 00:14:34,200 --> 00:14:41,400 And in the low fat group, they had higher C-peptide concentrations, higher insulin levels, 125 00:14:41,400 --> 00:14:47,850 higher postprandial glucose and higher continuous interstitial glucose monitoring as well. 126 00:14:47,850 --> 00:14:56,040 So these are, you know, the kind of the physiological changes you'd expect what you can then, 127 00:14:56,040 --> 00:15:02,430 I guess, debate about what the implications of those are and both harms. 128 00:15:02,430 --> 00:15:08,220 You could certainly make a case for for them being good from a from a general 129 00:15:08,220 --> 00:15:12,250 health point of view and make a case that there are some like concerning features. 130 00:15:12,250 --> 00:15:19,110 So in the low low carb group, you've got benefits for in terms of your glucose and insulin controls. 131 00:15:19,110 --> 00:15:26,040 They were those those were better, but they had higher triglycerides and free fatty acids, 132 00:15:26,040 --> 00:15:30,960 and that's associated in some studies with cardiovascular risk. 133 00:15:30,960 --> 00:15:32,880 Whereas in the low fat group, 134 00:15:32,880 --> 00:15:40,590 we've got a higher continuous glucose monitoring levels and that has been associated in some studies with coronary artery disease. 135 00:15:40,590 --> 00:15:47,910 So it may be that these two dietary strategies can both be effective, 136 00:15:47,910 --> 00:15:55,890 but potentially we should tailor this a little bit based on things like the presence or absence of diabetes and so on. 137 00:15:55,890 --> 00:16:02,970 One thing that strikes me is, in reality, a lot of people don't stick to either of these diets, 138 00:16:02,970 --> 00:16:10,380 and it would have been really interesting to have an arm where the diet was mixed to see what effect that had, 139 00:16:10,380 --> 00:16:14,850 but what sort of alternate alternating between the dietary strategies or well, 140 00:16:14,850 --> 00:16:24,150 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. 141 00:16:24,150 --> 00:16:33,720 What if a real diet is so slightly American diet? The American diet, slightly higher levels of carbohydrates and slightly higher levels of fat? 142 00:16:33,720 --> 00:16:42,930 Spot on. You know, I think that would have been really interesting, and I'll I'll I'll mention why in a sec, 143 00:16:42,930 --> 00:16:54,480 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. 144 00:16:54,480 --> 00:17:03,720 So if you remember at the beginning, there were two stresses, i.e. the two to two systems, two sort of theories of obesity. 145 00:17:03,720 --> 00:17:12,220 So one model was the passive overconsumption model. So those high and these high energy density foods, which resulted. 146 00:17:12,220 --> 00:17:22,060 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. 147 00:17:22,060 --> 00:17:29,560 In fact, they lost weight overall and they lost some body fat. So that challenges that passive overconsumption model. 148 00:17:29,560 --> 00:17:34,720 Similarly, the carbohydrate insulin model would present in these people who were eating, you know, 149 00:17:34,720 --> 00:17:44,980 80 percent carbs and who had increased postprandial insulin and postprandial sugars, which gained weight. 150 00:17:44,980 --> 00:17:48,880 But they didn't. They lost weight and they lost body fat. 151 00:17:48,880 --> 00:17:54,520 So despite that, and they didn't gain weight. 152 00:17:54,520 --> 00:18:03,490 So neither of these models or in a short term study supported by this and this, I think, just shows that, 153 00:18:03,490 --> 00:18:10,330 you know that the devotees of these simplistic diets are kind of missing a trick here 154 00:18:10,330 --> 00:18:16,360 because the regulation of energy intake is more complex than these straightforward, 155 00:18:16,360 --> 00:18:18,760 these straightforward models would suggest. 156 00:18:18,760 --> 00:18:26,840 So much more complex and probably changes over time as well over the long term, maybe the body adapts and that kind of thing. 157 00:18:26,840 --> 00:18:34,060 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? 158 00:18:34,060 --> 00:18:39,790 Yeah, yeah. And what happens at different times, you know, different different times of life. 159 00:18:39,790 --> 00:18:46,600 And you know, the effects, the effects that age and activity and so on do here. 160 00:18:46,600 --> 00:18:49,840 But I think what was really interesting is these people are allowed to eat whatever they like. 161 00:18:49,840 --> 00:18:55,000 They were probably sitting around pretty bored, and I would have predicted that both of them would have gained weight. 162 00:18:55,000 --> 00:19:00,310 Yeah. If you describe that being locked in a facility with as much food as you like. 163 00:19:00,310 --> 00:19:04,450 Yeah, I mean, I'm pretty sure I'm pretty sure I'll gain weight. 164 00:19:04,450 --> 00:19:08,590 But yeah, but they didn't. So what was the difference? 165 00:19:08,590 --> 00:19:18,840 And I think this was actually this is a point that was made by Rowan Francis, who's on on YouTube as midlife crisis. 166 00:19:18,840 --> 00:19:24,970 He did a video about this, this paper as well, and he made the point that that they would. 167 00:19:24,970 --> 00:19:30,100 This was all, you know, freshly prepared food with loads of leafy greens. 168 00:19:30,100 --> 00:19:39,310 There was no processed food in it at all. And maybe the real outcome of this is that actually having a diet, 169 00:19:39,310 --> 00:19:45,340 whether you choose one extreme or the other of the kind of vegan versus keto arguments 170 00:19:45,340 --> 00:19:52,330 that's full of unprocessed food and actually results in short term weight loss? 171 00:19:52,330 --> 00:19:56,660 And those that's the that's maybe that's maybe the takeaway from this. 172 00:19:56,660 --> 00:20:02,770 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, 173 00:20:02,770 --> 00:20:06,560 he'd go crazy, they didn't just have to have, you know, McDonalds all day long. 174 00:20:06,560 --> 00:20:18,190 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. 175 00:20:18,190 --> 00:20:21,910 It would be interesting to compare that to these to these diets. 176 00:20:21,910 --> 00:20:25,930 No, would be. And it's actually just such an interesting paper because it makes you think about 177 00:20:25,930 --> 00:20:33,190 these things and how much we don't know still about the things we all do every day, 178 00:20:33,190 --> 00:20:39,400 which is eating. Yeah, no, we really don't. And I think it's I think it's a really interesting area to study. 179 00:20:39,400 --> 00:20:45,490 And, you know, just massive kudos to the the authors of this, this study, because, you know, 180 00:20:45,490 --> 00:20:53,260 if you look at the paper, the detail of all of the stuff that they measured and they recorded is is is fantastic. 181 00:20:53,260 --> 00:21:02,550 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. 182 00:21:02,550 --> 00:21:07,990 Uh, aside from that, there's really very little to criticise in this in this paper. 183 00:21:07,990 --> 00:21:08,410 It's, you know, 184 00:21:08,410 --> 00:21:27,730 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. 185 00:21:27,730 --> 00:21:36,300 OK, so I've got to hepatology papers this time voters in the from March 2021 as well. 186 00:21:36,300 --> 00:21:39,970 And they both link together in terms of the topic. 187 00:21:39,970 --> 00:21:42,970 So I thought that I presented both at the same time. 188 00:21:42,970 --> 00:21:50,350 So there were two hepatology trials, and they were both published in the March edition of the New England Journal of Medicine last year. 189 00:21:50,350 --> 00:21:59,260 And the first trial is entitled a randomised trial of albumin infusions in hospitalised patients with psoriasis, otherwise known as the entire trial. 190 00:21:59,260 --> 00:22:08,410 And this was led from the Royal Free Hospital UCL in London by Louise China and Alistair O'Brien. 191 00:22:08,410 --> 00:22:13,990 So the aim of this trial was to assess whether the regular administration of human albumin 192 00:22:13,990 --> 00:22:22,300 solution intravenously was associated with a reduction in three outcomes nosocomial infection, 193 00:22:22,300 --> 00:22:31,750 kidney dysfunction or death in patients with decompensated liver cirrhosis that were hospitalised with a low serum albumin. 194 00:22:31,750 --> 00:22:43,930 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. 195 00:22:43,930 --> 00:22:54,580 Preclinical studies in which albumin administration has been associated with a reduction in systemic inflammation and albumin is already good. 196 00:22:54,580 --> 00:23:00,100 An evidence base for the treatment of spontaneous bacterial peritonitis, 197 00:23:00,100 --> 00:23:04,690 where it is associated with a reduced incidence of kidney dysfunction and death, 198 00:23:04,690 --> 00:23:10,840 and it is also being trialled in outpatients previously with cirrhosis and uncomplicated decisoes. 199 00:23:10,840 --> 00:23:15,700 But these trials have had conflicting results. 200 00:23:15,700 --> 00:23:25,930 So one randomised trial, which was an open label trial called Anser, which is published in The Lancet in 2018, 201 00:23:25,930 --> 00:23:34,540 and that randomised 440 patients to once weekly albumin versus standard care and that found an 202 00:23:34,540 --> 00:23:42,340 association between the administration of albumin and a reduction in mortality at 18 months follow up. 203 00:23:42,340 --> 00:23:45,310 However, another smaller, randomised trial, 204 00:23:45,310 --> 00:23:55,870 but this one was blinded of albumin and in addition to an alpha agonist drug every two weeks versus a placebo, 205 00:23:55,870 --> 00:24:03,700 found no difference in mortality after one year. And these are all in outpatients with decompensated cirrhosis. 206 00:24:03,700 --> 00:24:08,470 So as well as these conflicting results in human clinical trials, 207 00:24:08,470 --> 00:24:15,460 no previous trials have assessed the effect of albumin on infection rates, renal function or mortality in hospitalised patients. 208 00:24:15,460 --> 00:24:27,160 So that was what this trial set out to address. So they recruited patients admitted to hospital in the United Kingdom with an acute 209 00:24:27,160 --> 00:24:33,370 decompensation of liver cirrhosis under serum albumin of under 30 grams per litre, 210 00:24:33,370 --> 00:24:40,840 and they enrolled them within 72 hours of their admission, and they were randomised with stratification of several factors. 211 00:24:40,840 --> 00:24:47,830 So things like the severity of their liver disease and their baseline creatinine to receiving 212 00:24:47,830 --> 00:24:54,130 a daily infusion of 20 percent human albumin solution or standard care and albumin was 213 00:24:54,130 --> 00:24:58,810 administered from the day of enrolment into the trial until the serum albumin level was above 214 00:24:58,810 --> 00:25:05,470 30 grams per litre and the volume of solution administered was calculated on individual basis. 215 00:25:05,470 --> 00:25:12,820 So they calculated this using their current serum albumin level and their weight. 216 00:25:12,820 --> 00:25:17,770 I believe patients who were randomised to standard care were prescribed albumin as per usual 217 00:25:17,770 --> 00:25:25,060 clinical practise if it was indicated for the treatment of hepatic renal syndrome or SBP. 218 00:25:25,060 --> 00:25:31,060 The clinicians and the trial investigators were not blinded to the intervention received, 219 00:25:31,060 --> 00:25:35,170 and the primary composite endpoint was the development of infection, 220 00:25:35,170 --> 00:25:40,300 the development of kidney dysfunction or death in these patients between day 221 00:25:40,300 --> 00:25:46,690 three and day 15 of the trial or the date of the discharge of the patient, 222 00:25:46,690 --> 00:25:55,510 whichever was first. So I always get a bit worried with composite end points. 223 00:25:55,510 --> 00:26:02,740 So what was the sort of the reasoning behind choosing a composite primary end points rather than just picking, 224 00:26:02,740 --> 00:26:11,770 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? 225 00:26:11,770 --> 00:26:20,980 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. 226 00:26:20,980 --> 00:26:26,170 But the academic rationale, I guess, and why this is maybe an okay. 227 00:26:26,170 --> 00:26:31,510 Thing to do to lump them all together is that obviously and death is the worst outcome, 228 00:26:31,510 --> 00:26:40,420 but a new infection or kidney dysfunction carry a very high mortality risk if they develop in cirrhotic patients. 229 00:26:40,420 --> 00:26:44,260 So that's why they decided to put all three together. 230 00:26:44,260 --> 00:26:50,240 But that's what the authors claimed in the study. Fair enough. 231 00:26:50,240 --> 00:26:52,720 And I suppose with all trials, 232 00:26:52,720 --> 00:27:00,190 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. 233 00:27:00,190 --> 00:27:05,130 Yeah, these are tricky. These are tricky patients to to run trials on trial. 234 00:27:05,130 --> 00:27:13,950 Exactly. Exactly right. Exactly right. And and presumably that explains why they didn't blind clinicians and investigators to the intervention. 235 00:27:13,950 --> 00:27:20,710 Yeah. Exactly. I presume a that's exactly the case. 236 00:27:20,710 --> 00:27:28,510 So the other thing about the end point was they did choose a short timescale in which to assess the primary outcome. 237 00:27:28,510 --> 00:27:35,530 And the reasoning for this was initially after recruitment and starting the albumin. 238 00:27:35,530 --> 00:27:42,580 If the patient was randomised to that arm, they reasoned that the administration would not have an effect within the first day of treatment, 239 00:27:42,580 --> 00:27:52,660 essentially until the serum albumin had actually improved. So they gave it time to work and they followed up to 15 days. 240 00:27:52,660 --> 00:27:57,220 So day 15 of admission or discharge, whichever came first because, you know, 241 00:27:57,220 --> 00:28:03,190 they were aiming to just see what effect albumin had on the composite end. 242 00:28:03,190 --> 00:28:06,580 In the short term, rather than in the longer term. 243 00:28:06,580 --> 00:28:11,800 And they did define infection in quite a reasonable way because obviously that's slightly subjective, 244 00:28:11,800 --> 00:28:18,520 but it was defined by the patients attending clinician and then confirmed by a blinded physician panel, 245 00:28:18,520 --> 00:28:24,940 which I think is completely fair enough and in practical sense and makes it a bit more applicable to the real world. 246 00:28:24,940 --> 00:28:32,320 And kidney dysfunction was defined by an increase in testing of over 50 percent of baseline, 247 00:28:32,320 --> 00:28:39,070 or an increase by twenty six point two miles per litre and or 0.3 milligrams per decilitre in 48 hours. 248 00:28:39,070 --> 00:28:44,440 So did it work, Tamsin? In short, no, but it was a great trial. 249 00:28:44,440 --> 00:28:50,020 So seven hundred and seventy seven patients were randomised, which I think is a brilliant effort for, 250 00:28:50,020 --> 00:28:58,060 as we said, a very difficult patient group to run a trial on in the hospitalised setting. 251 00:28:58,060 --> 00:29:05,050 So the baseline characteristics were similar across both groups, which indicates that the randomisation was was good. 252 00:29:05,050 --> 00:29:12,730 And it's worth saying that in this group of patients, alcohol was the aetiology of liver disease in the majority, 253 00:29:12,730 --> 00:29:19,780 which reflects the local aetiology of liver disease in the United Kingdom, 254 00:29:19,780 --> 00:29:25,450 and approximately two thirds in each group were admitted to hospital due to worsening of their cities. 255 00:29:25,450 --> 00:29:31,600 And the remainder were admitted due to either worsening or new encephalopathy or of our total bleed. 256 00:29:31,600 --> 00:29:39,130 So there was no difference between the album and group and the standard care group in meeting the primary outcome, 257 00:29:39,130 --> 00:29:44,800 which was the composite outcome of the development of infection. 258 00:29:44,800 --> 00:29:52,270 Kidney dysfunction or death between three and 15 days after enrolment in each group, 259 00:29:52,270 --> 00:30:03,280 approximately 30 percent of patients developed one of those outcomes at the time to event analysis and the subgroup analyses 260 00:30:03,280 --> 00:30:11,920 that were run on the individual components of the composite outcome also showed no significant differences between groups. 261 00:30:11,920 --> 00:30:21,460 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. 262 00:30:21,460 --> 00:30:29,680 So a day 28, three months and six months after enrolment, there were no differences in death between the groups. 263 00:30:29,680 --> 00:30:35,710 Now, the next part of their findings is probably the most interesting, 264 00:30:35,710 --> 00:30:42,280 so they found that pulmonary oedema or fluid overload was significantly increased in the albumin group. 265 00:30:42,280 --> 00:30:52,510 So in 380 patients randomised to albumin, there were 23 events of pulmonary oedema or fluid overload compared to the Standard Care Group, 266 00:30:52,510 --> 00:30:56,470 where there were eight patients in 397 patients who developed this. 267 00:30:56,470 --> 00:31:03,670 So although it wasn't common, it was more more common in the group that received albumin in the discussion. 268 00:31:03,670 --> 00:31:12,850 They didn't feel that their findings and of no difference between the groups were due to suboptimal dosing because they found that firstly, 269 00:31:12,850 --> 00:31:20,050 the patients that were randomised to albumin received significantly more albumin with the standard care group. 270 00:31:20,050 --> 00:31:26,070 So 200 grams versus 20 grams. And the mean serum albumin level achieved in the patients. 271 00:31:26,070 --> 00:31:34,110 Receiving album was an on target, so it increased to their target of 30 grams per litre between day three and five, 272 00:31:34,110 --> 00:31:42,720 so they felt that they were giving them enough albumen for it to have had an effect if it did have an effect. 273 00:31:42,720 --> 00:31:43,410 So in summary, 274 00:31:43,410 --> 00:31:51,390 the takeaway from this study is that daily albumin infusions do not improve outcomes in hospitalised patients with decompensated cirrhosis. 275 00:31:51,390 --> 00:31:59,760 If the albumin is low and we need to be careful because there's an increased risk of pulmonary oedema in these patients, 276 00:31:59,760 --> 00:32:04,260 although no difference in mortality. Wow. 277 00:32:04,260 --> 00:32:10,440 So I think, as you said, this is a really well conducted trial. 278 00:32:10,440 --> 00:32:18,600 I think it shows that shows the benefit of high quality, large, randomised controlled trials, even when they're negative. 279 00:32:18,600 --> 00:32:28,620 Indeed, especially when they're negative too late. Because a little bit like the whole trial for GI bleeding, which showed, you know, 280 00:32:28,620 --> 00:32:39,090 really definitive evidence that tranexamic acid is is not effective in in that in the setting of GI bleeding this. 281 00:32:39,090 --> 00:32:48,390 This says pretty clearly that outside of these specific indications of HRT or or spontaneous bacterial peritonitis, 282 00:32:48,390 --> 00:32:51,240 we should not be giving our opinion. 283 00:32:51,240 --> 00:33:05,460 Do you think are there any subgroups or other and other indications within this population who who you think should, 284 00:33:05,460 --> 00:33:13,740 should ever have albumin, or whether there's, I guess, any kind of doubt based on the results of this trial. 285 00:33:13,740 --> 00:33:23,370 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, 286 00:33:23,370 --> 00:33:32,670 they deplete because in in this trial, the albumin was given and calculated based on their serum albumin, 287 00:33:32,670 --> 00:33:37,170 not whether they needed intravascular volume or not. 288 00:33:37,170 --> 00:33:46,470 And so in a patient where the intravascular deplete, I'm in clinical practise, Krista Lloyd. 289 00:33:46,470 --> 00:33:49,730 But some people do get five percent albumin, 290 00:33:49,730 --> 00:34:01,470 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. 291 00:34:01,470 --> 00:34:05,790 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, 292 00:34:05,790 --> 00:34:14,250 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. 293 00:34:14,250 --> 00:34:24,420 So those intravascular depletes or and or have an acute kidney injury, which doesn't meet the criteria for HRC. 294 00:34:24,420 --> 00:34:32,730 And I think they're still the patients in whom I think we worry about flooding them with Crestor Lloyd and that maybe, 295 00:34:32,730 --> 00:34:38,970 maybe some aspects of the colloidal effective and albumin would be good. 296 00:34:38,970 --> 00:34:49,020 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, 297 00:34:49,020 --> 00:34:56,670 for these patients. So the second trial is entitled TelePresence Plus Albumin for the treatment of 298 00:34:56,670 --> 00:35:03,150 type one hepatic renal syndrome and otherwise known as the confirmed trial. 299 00:35:03,150 --> 00:35:09,030 And this was conducted in 60 centres in the United States and Canada. 300 00:35:09,030 --> 00:35:18,720 So this is a slightly different situation. So type one hepatic renal syndrome just to give a bit of background or say chi 301 00:35:18,720 --> 00:35:23,520 and is acute kidney dysfunction within seven days associated with cirrhosis, 302 00:35:23,520 --> 00:35:30,510 where the serum creatinine increases by an approximately 26 micro moles per litre, 303 00:35:30,510 --> 00:35:38,970 or 9.3 milligrams per decilitre, within 48 hours for an increase of 1.5 times from the baseline level. 304 00:35:38,970 --> 00:35:42,870 So it's it's a diagnosis of exclusion, really. 305 00:35:42,870 --> 00:35:52,530 So initially, when you assess a patient with acute kidney dysfunction in the context of cirrhosis, you need to assess whether they're intravascular, 306 00:35:52,530 --> 00:35:59,100 deplete or not and attempt to expand the intravascular volume and also withdraw diuretic 307 00:35:59,100 --> 00:36:06,240 treatment and assess over the next 48 hours or so whether that improves the renal function. 308 00:36:06,240 --> 00:36:11,280 And if that doesn't, then haphazard renal syndrome is more likely, 309 00:36:11,280 --> 00:36:16,110 and the pathophysiology is thought to be due to the combination of systemic inflammation 310 00:36:16,110 --> 00:36:21,540 and renal micro circulatory dysfunction due to splenic arterial phase the dilation. 311 00:36:21,540 --> 00:36:25,960 So even if somebody is rehydrated despite that, the. 312 00:36:25,960 --> 00:36:30,340 We have a persistently high. 313 00:36:30,340 --> 00:36:41,290 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. 314 00:36:41,290 --> 00:36:43,870 But in the United States, 315 00:36:43,870 --> 00:36:52,450 10 percent is yet to be incorporated into the clinical practise guidelines because the previous randomised trials were small. 316 00:36:52,450 --> 00:36:59,350 So this study aimed to assess the efficacy and safety of a person with albumin for the treatment of Horus in a larger, 317 00:36:59,350 --> 00:37:07,090 randomised trial to inform a clinical practise in North America. 318 00:37:07,090 --> 00:37:15,850 So the inclusion population were hospitalised patients with psoriasis as cities and as renal syndrome, 319 00:37:15,850 --> 00:37:24,790 with the sérum question that was two times higher than baseline and at least one hundred ninety nine millimetres per litre. 320 00:37:24,790 --> 00:37:34,690 And patients were randomly stratified by creatinine two to one to receive six hourly telepresence kids plus albumin or placebo, 321 00:37:34,690 --> 00:37:46,750 plus albumin for 14 days or until they had two measurements of the creatinine under one three three minute miles per litre. 322 00:37:46,750 --> 00:37:52,210 And the primary outcome they measured was reversal of HRC or clinical failure, 323 00:37:52,210 --> 00:38:00,880 and success was defined by a patient having to create an index of under 1.5 milligrams per decilitre, 324 00:38:00,880 --> 00:38:11,500 or 133 mike moles per litre less than two hours apart, and survival without renal replacement therapy for a further 10 days. 325 00:38:11,500 --> 00:38:16,900 So a slightly complicated but importantly fastidious definition. 326 00:38:16,900 --> 00:38:25,990 So what did this study find? So this randomised 300 patients and the baseline characteristics were similar between the two groups. 327 00:38:25,990 --> 00:38:36,400 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. 328 00:38:36,400 --> 00:38:41,770 So clinical success, it's a reversal of HRC was achieved in a significantly higher proportion of 329 00:38:41,770 --> 00:38:46,630 patients that were randomised to tell a person plus us than placebo plus us. 330 00:38:46,630 --> 00:38:59,620 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. 331 00:38:59,620 --> 00:39:01,850 Clinical failure rates were still high. 332 00:39:01,850 --> 00:39:12,620 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. 333 00:39:12,620 --> 00:39:17,410 There was no significant difference in those that achieved and sustained hepatic renal syndrome. 334 00:39:17,410 --> 00:39:26,710 Mortality was similar in both groups at day 30, but during the on treatment period at nine patients in the telecasting groups 335 00:39:26,710 --> 00:39:31,420 of four percent and one patient in the placebo groups of one percent died. 336 00:39:31,420 --> 00:39:38,440 The 12 person group were more likely to have respiratory failure and die from a respiratory cause within 90 days. 337 00:39:38,440 --> 00:39:49,240 So while it's clear that those who received her depressant had a double double that 338 00:39:49,240 --> 00:39:56,470 that sort of the the chance of accuracy reversal and not needing replacement therapy, 339 00:39:56,470 --> 00:40:05,080 those short term gains weren't really carried on until two kind of medium term outcomes. 340 00:40:05,080 --> 00:40:16,300 That's right. And the second thing that draws my eyes, you know, just how ineffective our treatment is of individuals with a. 341 00:40:16,300 --> 00:40:17,760 Yeah, it's pretty dismal. 342 00:40:17,760 --> 00:40:27,760 We really we have very little in our therapeutic armamentarium other than, you know, good, you know, good kind of basic care. 343 00:40:27,760 --> 00:40:35,690 Yeah. Yeah, absolutely. In terms of generalisability. 344 00:40:35,690 --> 00:40:44,230 So they did exclude some patients with large who had had a large volume person and teases within 48 hours 345 00:40:44,230 --> 00:40:56,170 before enrolment or sepsis or uncontrolled bacterial infection within 24 hours of antibiotic treatment. 346 00:40:56,170 --> 00:41:02,710 So I thought that might be difficult in terms of infection is often quite difficult 347 00:41:02,710 --> 00:41:07,780 to diagnose accurately in patients with cirrhosis and decompensated cirrhosis, 348 00:41:07,780 --> 00:41:15,130 particularly in the initial stages where it's unclear what might have precipitated the decompensation. 349 00:41:15,130 --> 00:41:25,840 And patients can often have clinically silent infection with negative blood cultures and and certainly in the UK antibody. 350 00:41:25,840 --> 00:41:32,200 Treatments often given even when there's no positive culture. 351 00:41:32,200 --> 00:41:40,540 And that might have excluded many patients from participation if this was and if this trial had been done in the UK. 352 00:41:40,540 --> 00:41:52,510 And the other thing that I thought was noticeable was and in the European definition of acute and acute kidney injury associated with cirrhosis, 353 00:41:52,510 --> 00:42:02,350 the minimum serum creatinine of one nine nine micrograms per litre is higher than the accepted European DNA definition. 354 00:42:02,350 --> 00:42:15,280 So they the enrolled patients with a higher serum creatinine than we would define as having a race in Europe. 355 00:42:15,280 --> 00:42:20,320 And furthermore, that benefit may have been found if they included these patients as well. 356 00:42:20,320 --> 00:42:33,340 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. 357 00:42:33,340 --> 00:42:41,320 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? 358 00:42:41,320 --> 00:42:46,600 I don't know. Actually, I should look that up and see when the guidelines have changed or being rewritten since. 359 00:42:46,600 --> 00:42:53,260 Yeah, but certainly the authors were supporting its use in North America. 360 00:42:53,260 --> 00:43:02,710 So these are two really interesting, although I'd argue, pretty depressing, randomised controlled trials in liver disease. 361 00:43:02,710 --> 00:43:11,320 And, you know, I think it's a reflection of all kind of our usual inpatient practise that I experience, 362 00:43:11,320 --> 00:43:18,970 that this is a group of patients who who it's we don't have a lot to offer them. 363 00:43:18,970 --> 00:43:22,060 I, aside from a being supportive care, 364 00:43:22,060 --> 00:43:32,710 really good supportive care and that and there's a real lack of effective therapeutic treatments for for the conditions that we've got. 365 00:43:32,710 --> 00:43:35,560 And even the ones that we do have, 366 00:43:35,560 --> 00:43:47,580 like telepresence are actually the evidence base suggests they probably don't by themselves lead to kind of medium term or long term gains. 367 00:43:47,580 --> 00:43:52,390 And they only work and it's fantastic to see the proportion of patients. 368 00:43:52,390 --> 00:44:01,840 Yeah, great to see like two really good trials answering like really clinically relevant questions. 369 00:44:01,840 --> 00:44:16,790 Awesome. So there are two papers that we've sort of kind of done in in possibly excessive detail. 370 00:44:16,790 --> 00:44:21,830 And then we've got a few more that we'll pretend to do quickly, but probably not actually do it. 371 00:44:21,830 --> 00:44:26,920 I will try my best. So these quickly? Yeah. 372 00:44:26,920 --> 00:44:30,430 What do you want to do? You want to start with one or two? Yeah. 373 00:44:30,430 --> 00:44:40,880 OK, I'll take over. So my number one is got a long title towards personalised medicine in autoimmune hepatitis measurement of thought peri 374 00:44:40,880 --> 00:44:47,240 metabolites results in higher biochemical response rates compared to standard weight based dosing of stock here in therapy. 375 00:44:47,240 --> 00:44:58,700 And the first author was Leena Candles, and the senior author was Michael Hennigan, both based at Kings College Hospital in London. 376 00:44:58,700 --> 00:45:04,100 OK, maybe, maybe just assume, maybe assume that we are all. 377 00:45:04,100 --> 00:45:14,600 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. 378 00:45:14,600 --> 00:45:19,220 So it was a retrospective single centre case control study, 379 00:45:19,220 --> 00:45:28,700 and the population was patients with autoimmune hepatitis treated with AIDS fibrin between 1999 and 2019 at King's College Hospital. 380 00:45:28,700 --> 00:45:33,650 So 94 percent received either therapy and six percent received microfinance. 381 00:45:33,650 --> 00:45:41,690 Mike Finley alone or in combination with other therapies, and the intervention was metabolic and metabolite monitoring of aces high. 382 00:45:41,690 --> 00:45:46,430 So these were people that the clinician had decided to do a stop monitoring, 383 00:45:46,430 --> 00:45:55,130 and the control was weight based dosing phase of Typekit and that there was approximately just over 100 in each group. 384 00:45:55,130 --> 00:45:59,150 And the outcome that was measured was the maintenance of biochemical response. 385 00:45:59,150 --> 00:46:06,470 In this case, normalisation of ECG and transmit disease at six or 12 months after the metabolites were tested. 386 00:46:06,470 --> 00:46:12,350 And the main finding was that the patients in the group were metabolites were measured were significantly more 387 00:46:12,350 --> 00:46:20,000 likely to maintain biochemical response at six months follow up compared to those without metabolite measurement. 388 00:46:20,000 --> 00:46:22,700 So that was 77 percent versus 60 percent. 389 00:46:22,700 --> 00:46:32,210 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. 390 00:46:32,210 --> 00:46:43,310 And this is an interesting study that we might want to use more of metabolite testing in in the autoimmune hepatitis cohort. 391 00:46:43,310 --> 00:46:49,520 Yeah, it's interesting that I find it interesting that for different conditions, even within the same speciality, 392 00:46:49,520 --> 00:46:58,430 we have different like different approaches for how we like not just dose, but how we how we monitor and so on. 393 00:46:58,430 --> 00:47:07,730 It's a bit like for biologics, where gastroenterologists have, particularly from the days when Infliximab was the only thing, you know, 394 00:47:07,730 --> 00:47:16,580 therapeutic therapeutic toolbox for the sort of severe IBD we, you know, really look carefully at, 395 00:47:16,580 --> 00:47:21,080 you know, the levels and how we optimise them and how we protect response and so on. 396 00:47:21,080 --> 00:47:29,060 And that's just not been part of the culture in rheumatology, where probably due to their increased number of options. 397 00:47:29,060 --> 00:47:32,030 There have been, you know, much, much happier to switch. 398 00:47:32,030 --> 00:47:41,750 Just one question on this were there like with the sort of the target levels there for the ace of thyroid metabolites the same? 399 00:47:41,750 --> 00:47:50,810 Yeah, I think so. So and so basically it well, it was yes, they they used a range, 400 00:47:50,810 --> 00:47:59,480 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. 401 00:47:59,480 --> 00:48:04,700 And then they applied that to this group retrospectively. 402 00:48:04,700 --> 00:48:11,270 Yes. Is the answer you were looking for. I think yes, but I don't know what the individual. 403 00:48:11,270 --> 00:48:21,470 So at the time, obviously, when the clinicians were making the decision about the ACS offering to alter the levels, 404 00:48:21,470 --> 00:48:25,190 I don't know whether they knew what they were saying was the normal range, 405 00:48:25,190 --> 00:48:32,840 but they retrospectively applied a range that we normally used for the IBD 406 00:48:32,840 --> 00:48:38,030 population on the study cohort to see how many had some therapeutic TGA levels, 407 00:48:38,030 --> 00:48:44,900 too. Okay, so the second one potential effects of minimum unit pricing at local authority level on alcohol. 408 00:48:44,900 --> 00:48:53,450 It attributed harms in North West and North East England. A modelling study this was published by Brennan et al. 409 00:48:53,450 --> 00:48:59,930 From Sheffield. So the aim of this study was to estimate the potential effects on mortality, 410 00:48:59,930 --> 00:49:07,010 hospitalisations and crime of the implementation of minimum unit pricing for alcohol at a local authority level in England, 411 00:49:07,010 --> 00:49:15,220 which, as we all know, has been done in. Scotland and they used a computer modelling strategy to do this. 412 00:49:15,220 --> 00:49:23,320 The data they fit into their model was obtained from a look at the local level about the consumption of alcohol, 413 00:49:23,320 --> 00:49:27,670 local prices and various other things. 414 00:49:27,670 --> 00:49:39,010 So 23 upper tier local authorities in North West England and 12 in northeast England and nine government office regions. 415 00:49:39,010 --> 00:49:49,420 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. 416 00:49:49,420 --> 00:49:57,550 And this 50p minimum unit price for alcohol when it run through the model and was estimated to reduce annual alcohol 417 00:49:57,550 --> 00:50:04,790 related deaths in the North West region and by 205 and hospitalisations by five thousand nine hundred fifty six. 418 00:50:04,790 --> 00:50:14,170 So that's a five point five percent reduction and a reduction in crime by 2.5 percent, which suggests that as in Scotland, 419 00:50:14,170 --> 00:50:16,780 a minimum unit alcohol price in England, 420 00:50:16,780 --> 00:50:25,270 particularly in areas of the country where there's a high burden of alcoholic liver disease, might be very useful. 421 00:50:25,270 --> 00:50:35,920 So haven't they recently published the outcomes of the minimum minimum unit pricing structure in Scotland? 422 00:50:35,920 --> 00:50:39,700 Sure, I saw something on the news. I think we should have read a paper. 423 00:50:39,700 --> 00:50:45,760 We should have a look and talk about it. Yeah, I think I think they did, and I think it was sometime last year. 424 00:50:45,760 --> 00:50:48,560 We should definitely have at least to definitely have a look at a look at that. 425 00:50:48,560 --> 00:50:54,880 I think it's a really it's a really interesting policy and I think it raises. 426 00:50:54,880 --> 00:51:03,970 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. 427 00:51:03,970 --> 00:51:11,440 But you know, the short answer is that if it works, then you know, that's that's hugely, 428 00:51:11,440 --> 00:51:18,970 hugely important as as as as one of the tools for tackling alcohol abuse. 429 00:51:18,970 --> 00:51:28,900 And it's great to see people looking outside of just direct alcohol harms and just looking at, for instance, 430 00:51:28,900 --> 00:51:38,050 like liver disease or that, you know, violent crime or other crime, other other conditions, you know, the wider impacts. 431 00:51:38,050 --> 00:51:44,680 You know, it's really important to consider. Yeah. No, absolutely. Do you want to do a couple? 432 00:51:44,680 --> 00:51:51,970 Yeah, sure. I'll do. I'll do one. And now for something completely different in a Monty Python esque way. 433 00:51:51,970 --> 00:52:01,390 So this is this is more of what it's it's a sort of it's a meuron study, something a bit different. 434 00:52:01,390 --> 00:52:09,010 So it's entitled an organoid based organ repurposing approach for the treatment of short bowel syndrome, 435 00:52:09,010 --> 00:52:15,370 and it's by researchers from Tokyo lead author Shinya Shuggie Muto. 436 00:52:15,370 --> 00:52:26,260 So I thought, this is a really cool, cool paper and some really interesting science, albeit somewhat far from clinical practise. 437 00:52:26,260 --> 00:52:35,380 So as with backgrounds, a significant proportion of the patients who have intestinal failure due to either a short length 438 00:52:35,380 --> 00:52:42,760 of a small bowel bowel out of continuity or lack intrinsic bowel disease like Crohn's disease, 439 00:52:42,760 --> 00:52:50,140 those patients often require long term parenteral intravenous nutrition, also at home nutrition. 440 00:52:50,140 --> 00:52:56,410 But that comes with significant risks, inconvenience and and pretty huge costs. 441 00:52:56,410 --> 00:53:07,120 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. 442 00:53:07,120 --> 00:53:13,540 So this is an expensive, inconvenient and risky intervention, but it's all we have. 443 00:53:13,540 --> 00:53:25,360 The only alternative is an intestinal transplant, which can be highly effective but is relatively relatively high risk transplant still, 444 00:53:25,360 --> 00:53:30,070 and we certainly got some way to go to get better outcomes for those patients. 445 00:53:30,070 --> 00:53:39,580 But there's a big chunk of patients with intestinal failure who intestinal transplant is not appropriate for. 446 00:53:39,580 --> 00:53:50,890 So in short, this paper is about developing a method to which they call developing a small intestine sized colon, 447 00:53:50,890 --> 00:53:57,070 basically turning the colon into an absorber of tissue a bit like a small intestine 448 00:53:57,070 --> 00:54:04,510 as a therapy for intestinal failure and doing this in a couple of mouse models. 449 00:54:04,510 --> 00:54:08,950 So what they did is they they they grew up human or. 450 00:54:08,950 --> 00:54:14,680 Organoids from small bowel, so for those unfamiliar with organoids. 451 00:54:14,680 --> 00:54:24,970 This is where you get some. In this case, epithelial cells from an ideal biopsy, you strip off the epithelium. 452 00:54:24,970 --> 00:54:28,930 So you've just got the epithelial cells and there'll be some stem cells in there. 453 00:54:28,930 --> 00:54:34,480 And if you grow them in the right, the right sort of magic potion in the lab, 454 00:54:34,480 --> 00:54:41,230 they will develop into these little sort of these sort of steroids kind of structures. 455 00:54:41,230 --> 00:54:48,190 And they will often develop some of the characteristics of the epithelium from from where they've where they've come. 456 00:54:48,190 --> 00:54:50,800 They form these, these these structures. 457 00:54:50,800 --> 00:55:01,270 So that's what the researchers did is they got this human ideal organoids and they transplanted them into immunodeficient mice into their colon. 458 00:55:01,270 --> 00:55:09,730 So basically, they just instilled them into the colon after they stripped away the colonists, the colon epithelium. 459 00:55:09,730 --> 00:55:13,030 And what happened is kind of fascinatingly these. 460 00:55:13,030 --> 00:55:21,700 These organoids basically just attach themselves to the kind of denuded mouse colon wall and took up residence there, 461 00:55:21,700 --> 00:55:29,470 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. 462 00:55:29,470 --> 00:55:40,420 It looked quite a lot like small bowel. So those epithelial cells, which in now in this mouse colon, had microvilli for absorption. 463 00:55:40,420 --> 00:55:43,420 They started to form what looks a little bit like villi. 464 00:55:43,420 --> 00:55:55,480 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. 465 00:55:55,480 --> 00:56:03,580 So they expressed the sucrose ICER Maltese enzyme and also the sodium bile acid transporter Ibat. 466 00:56:03,580 --> 00:56:09,040 And then they showed this. This really cool thing, which I which I thought was was really interesting, 467 00:56:09,040 --> 00:56:20,680 was that the the colon kind of sub mucosa altered in response to these human ileal aethereal cells taking up residence there. 468 00:56:20,680 --> 00:56:23,890 So within these kind of pseudo village structures, 469 00:56:23,890 --> 00:56:31,240 we got what they saw was the development of lymphatic like you would see in the small bowel going up into the village structure. 470 00:56:31,240 --> 00:56:40,450 And they seem to be functional in that they could measure cholesterol absorption, see cholesterol and track cholesterol going into those lymphatic. 471 00:56:40,450 --> 00:56:46,900 And they did some interesting work to try and show how these how these organoids 472 00:56:46,900 --> 00:56:51,910 kind of took up residence and developed these these sort of phyllis protrusions. 473 00:56:51,910 --> 00:57:01,690 And and and so on. And so this was their first bit of work in in mice, kind of as a proof of principle. 474 00:57:01,690 --> 00:57:14,380 And then they said, Well, could these small intestine mice, colon colon be used as a treatment for short bowel syndrome? 475 00:57:14,380 --> 00:57:18,970 And so they went into rats and did some pretty crazy surgery, 476 00:57:18,970 --> 00:57:25,480 which I think is well worth briefly running through because it involves aside other things and into dental. 477 00:57:25,480 --> 00:57:32,050 Panasonic toothbrush, toothbrush really something that you read about in in nature. 478 00:57:32,050 --> 00:57:41,560 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, 479 00:57:41,560 --> 00:57:46,690 to remove the whole colon. So what they did is they went to the rats. 480 00:57:46,690 --> 00:57:52,810 They dissected out four centimetres of colon, but they left its vasculature there. 481 00:57:52,810 --> 00:57:55,540 So effectively, they've just got a tube of colon. 482 00:57:55,540 --> 00:58:05,320 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. 483 00:58:05,320 --> 00:58:13,330 They then scrubbed the inside of the colon with a Panasonic incidental toothbrush. 484 00:58:13,330 --> 00:58:16,210 And then they instilled in these human organoids. 485 00:58:16,210 --> 00:58:22,960 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. 486 00:58:22,960 --> 00:58:28,600 So effectively you've just got a loop of colon. And that enabled them. 487 00:58:28,600 --> 00:58:38,560 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. 488 00:58:38,560 --> 00:58:43,330 So that was just Operation Number one Operation No. Two was. 489 00:58:43,330 --> 00:58:46,450 They effectively just removed the whole small bowel of the rat. 490 00:58:46,450 --> 00:58:53,710 They did a Chechnya ideal reception, and then they put back in that small intestine sized colon, 491 00:58:53,710 --> 00:58:58,210 and they compared it to just putting back the normal mouse colon. 492 00:58:58,210 --> 00:59:06,650 Sorry, the normal rat colon. But but not, but not not with this, nor with the treatment with the organoids. 493 00:59:06,650 --> 00:59:14,370 And again. They demonstrate that, you know, that the the epithelial cells take up shop, they express the right enzymes, 494 00:59:14,370 --> 00:59:21,960 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. 495 00:59:21,960 --> 00:59:29,340 So basically, all the rats that just had their small bag removed in their cone or left or died within 10 days. 496 00:59:29,340 --> 00:59:33,060 The ones who had this small intestine lies colon put in. 497 00:59:33,060 --> 00:59:38,670 Some of them lost weight and died. Some of them lost weight, and then they started gaining weight again. 498 00:59:38,670 --> 00:59:46,080 And they survived, and they were long term survivors. Well, as long term as a rat study ever is. 499 00:59:46,080 --> 00:59:53,970 And they found that those days long time survivors were the ones who had the best engraftment of these organoids. 500 00:59:53,970 --> 01:00:04,800 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. 501 01:00:04,800 --> 01:00:09,180 And you can basically by just switching out to the epithelial cells, 502 01:00:09,180 --> 01:00:15,870 you can turn it into an absorber tive bit of guts like the small bowel that can 503 01:00:15,870 --> 01:00:21,570 function and keep keep at least some rats alive till the end of the experiments. 504 01:00:21,570 --> 01:00:31,830 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. 505 01:00:31,830 --> 01:00:39,900 A very cool idea that you could manipulate tissues to function in different ways to solve, like real world. 506 01:00:39,900 --> 01:00:49,560 Really interesting. So will love. Yeah, super. We'll wait for that to translate into humans with the toothbrush. 507 01:00:49,560 --> 01:00:58,470 Yeah, we're going to need a big. So the last one we're going to do in a you for insights today. 508 01:00:58,470 --> 01:01:04,110 So a massive yoga running is one that is actually not really about gastroenterology at all. 509 01:01:04,110 --> 01:01:12,630 But I think it's a really cool little article, which I think everybody should have a quick glance at. 510 01:01:12,630 --> 01:01:19,440 It's in clinical medicine, which is the Royal College of Physicians in House Journal, and it was, it's called. 511 01:01:19,440 --> 01:01:28,140 I can assure you that there is nothing wrong with your kidney. This is an article from a GP called Tamara Keith, 512 01:01:28,140 --> 01:01:36,660 and this is an article about her experience as a patient when she was a medical student and junior doctor with an, 513 01:01:36,660 --> 01:01:40,860 at that point, undiagnosed abdominal pain syndrome. 514 01:01:40,860 --> 01:01:50,850 So she was diagnosed with recurrent culture, negative pyelonephritis and after six years, finally was given a diagnosis. 515 01:01:50,850 --> 01:01:55,350 The diagnosis was found to be Nutcracker. syndrome, which was a new one to me, 516 01:01:55,350 --> 01:02:01,260 which is where the left renal vein is compressed, sandwiched between the aorta and SMA. 517 01:02:01,260 --> 01:02:08,850 And effectively, that the kidney has periods of ischaemia an intense, intense, long pain. 518 01:02:08,850 --> 01:02:18,750 But I but often these these these patients are not diagnosed at all, labelled as as patients who have a functional disorder. 519 01:02:18,750 --> 01:02:22,890 And so I'm just going to. She describes really, 520 01:02:22,890 --> 01:02:30,420 really well the challenges of having having this functional disorder about the journey to the final 521 01:02:30,420 --> 01:02:38,880 diagnosis and and her kind of observations and thoughts of of how it's relevant to kind of all doctors. 522 01:02:38,880 --> 01:02:47,970 I just wanted to read out one paragraph from from this for six years, my pain had been discredited. 523 01:02:47,970 --> 01:02:53,160 My agenda questions my honesty, mistrusted by many in the renal team. 524 01:02:53,160 --> 01:02:58,290 Yet they continue to treat me as suffering from a recurrence pyelonephritis. 525 01:02:58,290 --> 01:03:06,960 Fortunately, I had a renal physician and a radiologist who believed that my symptoms were real and were keen to find out the cause. 526 01:03:06,960 --> 01:03:12,750 However, there was disagreement within the team thwarting progress. I had been labelled. 527 01:03:12,750 --> 01:03:18,930 I was functional. I was the attention seeking medick, the annoying expert patient. 528 01:03:18,930 --> 01:03:28,710 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. 529 01:03:28,710 --> 01:03:36,130 I knew more about this condition than any of them, but consultants do not take kindly to being taught by medical students. 530 01:03:36,130 --> 01:03:44,560 And it was in it really good, actually edition of clinical medicine, all about functional disorders in different organ systems. 531 01:03:44,560 --> 01:03:54,010 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, 532 01:03:54,010 --> 01:03:57,490 you know, complex functional pain syndromes. 533 01:03:57,490 --> 01:04:06,880 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. 534 01:04:06,880 --> 01:04:12,310 Thank you. That's that's really interesting. I'll need to go back to clinical medicine and read the article. 535 01:04:12,310 --> 01:04:26,330 Thank you. That's. So that concludes our episode three of Gut Instinct. 536 01:04:26,330 --> 01:04:36,560 We hope you enjoyed it. Please get in touch with us on Twitter or via email if you have any comments or any reflections 537 01:04:36,560 --> 01:04:57,938 on anything that we've discussed and hopefully will be back soon for another episode.