Investigative Pediatric Hepatology with Dean Yimlamai

Transcript

• 00:17Welcome back, this session is
• 00:19being recorded. Thank you.
• 00:23Hello, it's my pleasure now to
• 00:25introduce our next speaker Dean
• 00:27Yumemi who is assistant professor
• 00:28in the Department of Pediatrics and
• 00:31the Director of Pediatric Hepatology
• 00:33Research at Yale School of Medicine
• 00:35and his topic today is going to be
• 00:39investigative pediatric hepatology Dean.
• 00:44Sharing my screen.
• 00:47Thanks a lot Michael for introducing
• 00:49me thanks to the organizing committee.
• 00:52Mario, Michael Nathanson, Dr.
• 00:54Boyer, for just giving me
• 00:56a little bit of time as a,
• 00:59you know, as a pediatrician,
• 01:01as a as a pediatric gastrologist
• 01:04hepatologist I've been asked to talk about
• 01:07investigative pediatric, hepatology,
• 01:08and my subtitle is where we've been
• 01:11where we are and where we're going,
• 01:13and in preparation to talk to you today,
• 01:17I actually pulled a number of
• 01:19my colleagues from around the
• 01:20country just to get an impression.
• 01:22You know, from different places
• 01:24and and different people,
• 01:25both on the West Coast, Midwest,
• 01:27several people here on the East Coast,
• 01:29about, you know what are the
• 01:31the real problems in pediatric
• 01:34hepatology that have been?
• 01:36Assured and the ones that have
• 01:38gotten better and ones that we
• 01:41wish we had better solutions for.
• 01:43And remarkably,
• 01:44you know,
• 01:44although there are some differences
• 01:46between you know those who
• 01:48practice in Los Angeles versus
• 01:49those who practice in Saint Louis.
• 01:51A lot of the problems that they see
• 01:53across the country are the same.
• 01:55The questions that I talked to them about,
• 01:57and I'm going to.
• 01:58We're going to talk about a couple
• 02:01of vignettes about things that
• 02:03came up in our conversation.
• 02:05I asked them in the last five to 10 years.
• 02:07That and scientific improvements
• 02:08have made it a significant impact in
• 02:12your clinical hepatology practice.
• 02:14You know,
• 02:15have there are there conceptual or
• 02:17technical hurdles that you know you
• 02:20wish we could get through that could
• 02:22improve your current practice and
• 02:24you know what diseases are going
• 02:27to still be with us in five years,
• 02:29and what diseases seem to be
• 02:33increasing in prevalence.
• 02:35So we're going to have.
• 02:36I'm going to talk about 3 quick
• 02:38vignettes and each of them start
• 02:39with a a quote from one of the
• 02:41hepatologists that I talked to and
• 02:42then the first one was this that
• 02:44this is the bread and butter of
• 02:46pediatric transplant hepatology,
• 02:47and it still will be a major
• 02:49problem for us in five years.
• 02:51You know, as pediatricians we see.
• 02:55At birth,
• 02:56yellow babies very very commonly and
• 02:59the differential is quite broad.
• 03:02The 1st 2 on this list of differential
• 03:06are the most common and sometimes
• 03:09when you get to more serious
• 03:12hepatology focused diagnosis
• 03:14it it causes a delay in care.
• 03:18But most children who are born
• 03:21in neonates have physiologic
• 03:23jaundice because of the transition.
• 03:25Between going from inside to outside,
• 03:28there is some association with breastfeeding,
• 03:31jaundice and you know if they need
• 03:33a little phototherapy that'll
• 03:34get them through it,
• 03:35but for those who have actually
• 03:38conjugated hyperbilirubinemia,
• 03:39you know there are.
• 03:40There's a list of things,
• 03:42and the most common thing that I'll
• 03:45touch on which that Hepatologist said,
• 03:48is his bread and butter is biliary atresia.
• 03:51If you're not familiar with biliary atresia,
• 03:55it's basically a fibroscan.
• 03:56We're seeing disease of the
• 03:59extra hepatic bile ducts,
• 04:00although it's known that it
• 04:02can actually at times affect
• 04:05the intrahepatic bile ducts,
• 04:07and that there's a variety of causes,
• 04:09it's multifactorial.
• 04:10There's no one specific cause,
• 04:12and you know there are many
• 04:14models that have been developed,
• 04:15both viral models, toxic models.
• 04:19There are known genetic causes,
• 04:21and as a result we actually
• 04:24know quite a bit about things.
• 04:27That that can cause biliary atresia.
• 04:30There can be children who are born at
• 04:33birth with the form of biliary trees
• 04:35with fibrosis and significant jaundice,
• 04:37but the most common causes of biliary
• 04:41atresia seem to happen after birth,
• 04:43and it's not clear you know what
• 04:46exactly is causing these things.
• 04:48It it likely is a combination of of
• 04:51genes as well as viruses and toxins,
• 04:54but what is known is that
• 04:57there's a significant.
• 04:58Response by the immune system where
• 05:01the epithelium and fibroblasts in
• 05:04biliary ducts actually respond pretty
• 05:06significantly and in the last 15 to 20
• 05:10years I made that go away 15 to 20 years.
• 05:13You know,
• 05:13we understand much more about the.
• 05:17The contribution,
• 05:18both of the immune system as well as
• 05:20the fibrotic component that starts it.
• 05:23But you know Despite that.
• 05:26You know and and using immune suppression,
• 05:28we haven't made a significant
• 05:31impact on actually reducing the the
• 05:35need for surgical intervention.
• 05:38A number of studies this is 1 by Georgie
• 05:41Pizzera at Cincinnati Children's.
• 05:42Put everyone on steroids after
• 05:45surgical intervention for BA.
• 05:46They saw minimal if any impact
• 05:49when they put children on steroids.
• 05:52What they did see is that there
• 05:54was increased biliary drainage.
• 05:55What was actually?
• 05:56More important in this study is that
• 05:59when you put children on steroids,
• 06:01a significant proportion in under 30
• 06:03days actually developed a a signal.
• 06:05First,
• 06:06a severe event such as sepsis
• 06:11or other surgical intervention
• 06:13causing the cessation of the this
• 06:17this trial now you know,
• 06:19although we know quite a bit
• 06:23about potential mechanisms.
• 06:26There are delays in identification if
• 06:30we could have a better understanding
• 06:32of what some of the mechanistic
• 06:34understanding using maybe some of the
• 06:37technologies that are out there today.
• 06:39Single cell sequencing is one that's
• 06:41being applied to to this area.
• 06:43We could probably develop better.
• 06:47Targeted therapies for children
• 06:50with with BA but currently whoops.
• 06:53I lost the I lost the the slide
• 06:56about our major therapy today is
• 06:59is surgery and although getting
• 07:02children to a Kasai procedure is
• 07:06the the preferred treatment today,
• 07:08many of the hepatologists I spoke to
• 07:11wish that there were medical therapies
• 07:13that could help people either avoid
• 07:15or at least extend the time that.
• 07:17It would take to get to surgery.
• 07:22Other hepatologists that I spoke to.
• 07:25Saying different things that have really
• 07:28impacted their practice and they stated
• 07:30that this technology has has changed how I
• 07:32diagnosed and practiced hepatology today.
• 07:34Here's a picture of Bob Dylan from the
• 07:371970s and you'll actually notice that a
• 07:39lot of our major categories for needle
• 07:41needle Cholestasis haven't changed.
• 07:43So about 1/4 of the patients that we see
• 07:48who have conjugated hyperbilirubinemia
• 07:50have biliary atresia,
• 07:52about 3 to 5% have a viral infection.
• 07:56Of some kind.
• 07:57But in the 1970s you know more than 2/3 of
• 08:01kids had what we termed neonatal hepatitis,
• 08:04which really is idiopathic, where you know,
• 08:07we just didn't know what the pathology was.
• 08:10Now it's time God has gone on.
• 08:12Obviously Bob Dylan's gotten a little
• 08:14bit older, wiser, more grizzled.
• 08:17We understand much better
• 08:21potential mechanisms.
• 08:22We we now understand.
• 08:25Things such as A1 antitrypsin.
• 08:27Disease, metabolic disease.
• 08:30Various metabolic causes of
• 08:34intrahepatic Cholestasis.
• 08:36There does remain a small
• 08:38proportion instead of 65%.
• 08:39Now about 10 to 15% of our patients,
• 08:43which remain undefined,
• 08:44but the technology that that these
• 08:47have ethologists were talking
• 08:49about have really changed how they
• 08:52practice their clinical hematology.
• 08:54Of course, the the most common.
• 08:58Cause of hyperbilirubinemia.
• 09:02In this age range remains biliary atresia.
• 09:05There was the discovery
• 09:06of A1 antitrypsin disease,
• 09:08and it can be quickly streamed for.
• 09:12You know,
• 09:12and then there are a number of rare
• 09:15diseases which we can go through different
• 09:17kinds of biochemical or imaging modalities,
• 09:20but one which was not really available
• 09:235 to 10 years ago because of cost is
• 09:28genotyping and whole genome sequencing.
• 09:31And you know that that really relates to
• 09:33how much sequencing the genome has had.
• 09:36The cost has followed where you know in
• 09:382001 to to sequence of persons genome.
• 09:40It cost more than $100 million.
• 09:42We're now at about 1000 or maybe under
• 09:44$1000 to sequence a person's genome,
• 09:46so you know it's now become cost
• 09:50competitive to to quickly go and sequence,
• 09:52and it's actually the the the roadblock
• 09:54now is on the bioinformatic side.
• 09:56How quickly can we get the information
• 09:59back once we send persons DNA and
• 10:02it's really changed for a lot of
• 10:05hepatologists you know where we put
• 10:07genotyping or whole exome sequencing
• 10:10in the in the diagnostic criteria?
• 10:13Now the this is one of the.
• 10:15This is a neonatal Cholestasis panel.
• 10:17Actually this can be used on
• 10:19both children and and adults,
• 10:21and you can see I think there's 30
• 10:24something genes on this on this panel.
• 10:26If one quickly looks at the panel though,
• 10:29you know there's very few.
• 10:30I think.
• 10:31I'm sure I have missed a few,
• 10:32but the ones I've marked in red are genes
• 10:36that actually have a therapy for CFTR.
• 10:40We may have a a therapy.
• 10:43For the liver disease we're waiting on.
• 10:48If the the current medications
• 10:50that treat lung liver disease
• 10:52treat liver liver disease,
• 10:53but you can see that leaves,
• 10:55you know a significant number
• 10:57of genes where we actually
• 10:59know the the the genetic defect but
• 11:01don't have an effective therapy.
• 11:03And as one hepatologist told me,
• 11:05you know it's it's nice to be able
• 11:07to tell people that you know their
• 11:09child has a has a disease name,
• 11:12even if there isn't current.
• 11:13Therapy, but on the other hand,
• 11:16you know it feels a little bit
• 11:18that you know our job is just to
• 11:21keep them as healthy as possible so
• 11:23that they can get to a transplant.
• 11:25Whether that means that they get
• 11:27to the size of the transplant
• 11:29or that they don't get too sick
• 11:32before needing the transplant. Umm?
• 11:36In my research though for this talk,
• 11:38I saw that you know there are there.
• 11:41There was actually a very recent
• 11:43paper that came out where a group
• 11:45at Beth Israel actually came up
• 11:47with the synthetic form of ABC
• 11:50before they treated actually a mouse
• 11:52model of this deficiency.
• 11:55But what I found you've actually
• 11:57more interesting is actually the
• 11:59company that that funded this therapy,
• 12:01and obviously it's a company that
• 12:03we're all familiar with in in 2022 now.
• 12:06That's provided a number of, you know,
• 12:10vaccines. So this company Maderna.
• 12:14Is providing M RNA that can be
• 12:17synthesized and targeted to that
• 12:19aside so you know there is at
• 12:21least a hope that we will be able
• 12:24to develop therapies for a lot
• 12:26of these monoallelic diseases,
• 12:27but it obviously you know how do we
• 12:29translate that to each of our patients
• 12:32and and make it cost effective?
• 12:34I think are still barriers.
• 12:35And how do we get that through
• 12:37regulatory approval?
• 12:39We're going to need to wrap up in
• 12:41about a minute or so if you can,
• 12:42that's fine, so I'm just going
• 12:44to run through this. Which is.
• 12:45This is the biggest problem that
• 12:47people see in the hepatology practice,
• 12:49and the pun is really about mash.
• 12:53It's clearly a growing problem,
• 12:55you know, the question is,
• 12:57what do we tell our patients?
• 13:00We have very little data for for children.
• 13:05Most of our insights come from adults.
• 13:08I'm just going to show you.
• 13:09Some data that we have
• 13:11actually just worked on.
• 13:12We looked at both adults as well
• 13:14as a pediatric ward for adults.
• 13:16When you look at the Histology,
• 13:17you actually can predict
• 13:19very well their fibrosis,
• 13:20but that correlation does not hold up
• 13:23in children and you know we need to
• 13:25really build much larger cohorts and sample.
• 13:28We think that the genes that are
• 13:31some genes that are preserved in.
• 13:34In both pediatric and adult
• 13:36national preserve,
• 13:37but there are many other genes which
• 13:39just really have no correlation.
• 13:40So you know,
• 13:42just to summarize my work
• 13:44and that of my colleagues.
• 13:46You know,
• 13:47for a lot of pediatric diseases
• 13:48are our current modalities just
• 13:50don't reflect the heterogeneous
• 13:52causes and we don't have.
• 13:54Because we don't know what
• 13:56the specific causes are,
• 13:57we have a hard time targeting therapy.
• 14:01We know many monogenetic diseases,
• 14:05but we don't have an effective strategy.
• 14:09And finally,
• 14:10a pediatric Nash is rapidly growing.
• 14:14It may be we think,
• 14:16at least in the pediatric community,
• 14:17that the pace of fibrosis
• 14:19actually may be the most severe,
• 14:21because they're presenting
• 14:23so early and you know,
• 14:25one of my colleagues suggested that
• 14:27we include some of the older adults,
• 14:30older adolescents I should say,
• 14:32and the adult Nash studies so
• 14:33that we can translate some
• 14:35of these therapies to our our
• 14:37patients a little bit quicker.
• 14:39So thanks to all the people
• 14:41who who gave me input so.
• 14:46That's not sure how. Thank you.