Cirrhosis and Portal Hypertension

Cirrhosis and Portal Hypertension

– It’s great to be back and talk to you about my favorite topic. So what my plan is to review some of the most eye-catching
abstracts from the liver meeting that are pertinent to
patients with cirrhosis and portal hypertension, and I’ve got a ton of
slides for you to review, but I think my key
interest here is to look at the clinical background
for each of these studies, pull out the most important
tidbits that would apply for you in the clinic when
you’re seeing patients in terms of conflict of
interest on an advisory board for one of the drugs
that we’ll be discussing. So the first few abstracts
are pertinent to patients with hepatic encephalopathy, and the coolest one comes from the group in Virginia, Commonwealth University. This is Dr. Jas Bajaj, whose name is synonymous with hepatic encephalopathy research, and what he is trying
to champion is the idea that our microbiome is
playing a critical role in the development and progression of hepatic encephalopathy. As we’ll see throughout
these abstracts, obviously, ammonia plays a key
role in the development of hepatic encephalopathy, but one of the things
that causes that ammonia to be particularly neurotoxic
and one of the reasons why ammonia levels don’t
correlate with symptoms is because inflammatory burden
in your patient’s blood is what determines how toxic that ammonia is. So he explored the role
of periodontal therapy in the burden of inflammation
in patients with cirrhosis. So cirrhosis is a systemic
inflammatory condition vis-a-vis translocation of bacteria and bacterial wall products from the gut. Portal hypertension causes
gut barrier disruption and, therefore, translocation of
the contents of our small and large intestine systemically through portal hypertension. So obviously, the bugs are
coming from the GI tract, but there’s more to the GI
tract than just your intestine, and what he hypothesized
is that the microbiome of our mouths may be contributing, and you may recall the teeth
of many of your patients with cirrhosis. Dentition is an underlooked
problem for this population, and we also have a way of
fixing that by referring them to a dentist. So what he did is he enrolled
20 cirrhotic patients and age matched healthy
controls, each of whom had mild to moderate generalized
chronic periodontitis. If it was so severe that they
needed to have teeth pulled, they were excluded from the study, and what he did is he
collected baseline information about their inflammatory
burden and their MELD scores, and what we see in this poster, the key points here are
that, before therapy, there was an elevated inflammatory burden in patients with cirrhosis, and after therapy, not only did you see
a significant decrease in the white blood count, an obvious indicator of inflammation, but also endotoxin, that
is cell wall products from bacteria, and TNF. So the actual inflammatory
cascade triggered by bacteria has been
decreased significantly, statistically significantly
for patients with cirrhosis. That was also true for
patients without cirrhosis, implying that they were doing something that is generalizable, but obviously, for people without
cirrhosis, the overall impact on inflammatory burden vis-a-vis white blood count
endotoxin wasn’t changed. So does this change one’s risk
for hepatic encephalopathy? Obviously, that’s something
that he’ll explore beyond these preliminary data, but it is something to consider, that this may potentially
benefit our patients. So moving forward, Dr. Bajaj
also had a pretty cool study. This is a picture of somebody meditating, and it brings up a couple of things about the broader syndrome
of hepatic encephalopathy. Obviously, if they’re
showing up in a coma, meditation is not going to help, but for people with
grade one encephalopathy, to some degree, it’s how
we cope with those deficits that influences whether
it will change our impact on our daily lives or our family members, and when you have a rapidly
fluctuating condition like hepatic encephalopathy, not only does it stress you out, it stresses out your caregivers. So taking care of, living with a patient with hepatic encephalopathy
creates a profound burden. How are we going to treat that? There might be pills that help
for that, but beyond pills, it’s worth thinking outside the box, and so what this group did
is they enrolled people in a prospective trial of mindfulness meditation
or qi gong meditation, and essentially, this is what
the Dalai Lama advocates, a process of sitting in
a quiet room and thinking about the conflicts that you have in life, internalizing those conflicts, and viewing everyone through
a lens of loving kindness, trying to see the best in people and work towards conflict resolution. So he enrolled people who
are surrounding outpatients who had, at baseline,
defined by questionnaires, mild depression and an adult caregiver, and there was no pre-specified limits on who that caregiver was, and what they did is they
assessed patient-reported outcomes for both the patients and the caregivers, and they assessed cognitive function in the patients with cirrhosis. So the trial looked like this. They enrolled everybody, and then they had four hour-long
sessions, week two, three, four, five, where they
were trained by someone in the art of meditation, told to go home and practice this, and they had to do their homework
and to turn it in to, say, in a logbook that they had
been doing meditation and home, and at the end of the study like at the beginning of the study, we assess all their
patient-reported outcomes, and what we found is, of course, meditation doesn’t change MELD score. Meditation does not change the prevalence of cognitive dysfunction or
these PHES scores at the bottom, but what it does do is it
reduces the burden of depression, inducing remission in a
substantial proportion of people with diagnoses of depression. It improves their overall
health related quality of life. The questionnaire is the SIP. It improves their sleep overall, too. This is also true for the caregivers who had a substantial decrease or a statistically significant decrease in their self-reported
burden of being a caregiver and improved sleep. So meditation does not improve
encephalopathy, of course, but it improves a host of
patient-reported outcomes, i.e., things that matter to
our patients get better, and in conclusion, why not? The only cost is time. So the standard of care for the management of hepatic encephalopathy
is, at a minimum, lactulose, particularly when they’ve had an episode of overt encephalopathy,
rifaximin, and a high-protein diet, but there are other ways to
think about the management of acute encephalopathy, which get at the pathogenesis
of hepatic encephalopathy, and I’ll talk about this trial of OCR-002, ornithine phenylacetate, in this context. So this is a little cartoon
I once drew that gets at where ammonia comes from and how it leads to encephalopathy. One, ammonia is the product
of protein metabolism, and the number one contributor of ammonia in the blood is the metabolism
of the amino acid glutamine, and like I said before, inflammation influences the
symptoms from hyperammonemia. So there’s this new drug,
ornithine phenylacetate, and it has two components. One, ornithine will combine with glutamate and ammonia to form glutamine. So it’s taking the ammonia
out of the equation by forming glutamine, but before any part of your
body like the kidney can take that glutamine and make more ammonia, which is one of the main problems
with excesses of glutamine in patients with cirrhosis, phenylacetate comes into
the mix and turns it into a water-soluble
molecule called pagan, which the kidney then excretes. This is a way of scavenging
ammonia and glutamine, two hits on the pathogenesis
of encephalopathy. So they enrolled in
this multicenter trial, patients with grade two
encephalopathy or greater. Because their mechanism
of action is excretion through the kidney, you
can’t be on dialysis, and they wanted to have people with a life expectancy greater than 12, and what they did is they
chose to enroll people and then give them the
study drug after 12 hours. So in my experience,
probably in your experience, when you come in with acute
hepatic encephalopathy, you get lactulose. You get better, and then if the trigger for your encephalopathy was infection, you stay in the hospital
for a couple of days, but if you’re only
trigger is noncompliance, you can turn that person
around pretty quickly. So all of a sudden, you start
to see in the study design that this is a relatively
unique population, a population which is
not responding perhaps to the standard of care, or perhaps they did, and they’re still
somewhat encephalopathic. As I’ll show you, they
were enrolling people with grade two encephalopathy. So they randomized people to
placebo plus standard of care, lactulose and rifaximin, your choice, for a five-day infusion. They titrated the infusion dose to how severe the injury was, and they were looking for a
clinically meaningful decrease, i.e., coma to grade two
or grade two to grade one. So everyone had to have at least asterixis and clinically
significant improvement, no more asterixis, no more
disorientation, and of course, if they got them all the
way better, fantastic. So these were people that
were typically Child B and C with a high median MELD
score, and for the most part, these are grade two encephalopathics, okay, so mild disorientation. Their triggers were essentially unknown, but the identifiable ones
were bacterial infection and poor compliance of
lactulose, and what they found, and I’ll editorialize while
I’m going through this, is that the drug was not
significantly associated with time to resolution of symptoms. So just if you take a step back and look at the inclusion criteria, you had to have an ammonia level greater than the upper limit
of normal per your lab. So in that 12-hour period, you’re getting an ammonia
level that says that it’s high. If this drug is scavenging ammonia, then that’s the only
way it’s going to work if you have a lot of ammonia
causing your symptoms. So here we are. The drug didn’t work, so
what they did is they looked at all of the samples that
were submitted and said, well, it turns out that your
lab was wrong in 30 patients. In 30 patients, your lab said
that ammonia was high when, in fact, it was normal, and if you look at just the
people who had normal ammonia, well, then we had a statistically
significant decrease in the time to resolution of symptoms. There were no adverse
events, and so basically, this is a new, safe kid on the block for inpatient management
of hepatic encephalopathy. Measurement of ammonia
is notoriously tricky. You need to have a very clear protocol if you’re going to do that. In fact, it’s not really
clear that it matters for most patients because you
can have overt encephalopathy without an elevated ammonia level, as did many of these patients. So you have to think about what kind of a patient needs a five-day infusion for hepatic encephalopathy, and I’m not sure it’s someone
with grade two encephalopathy but certainly someone that can’t take an oral
medication like lactulose, certainly someone that
you’re worried about in the intensive care unit with
a high-grade encephalopathy. So pivoting, there was
a study out of Denmark on the adverse effects
associated with PPIs. So PPIs have been associated
with a host of problems in the epidemiology literature,
including infections in cirrhotic patients,
readmissions in cirrhotic patients, hepatic encephalopathy, and SBP. Why are PPIs associated with infections? In part, we think maybe it
causes some bacterial overgrowth. There’s also a proton pump on neutrophils, and it does cause some degree
of immune paralysis in vitro. So if you wave your hands long enough, you do have a good reason to support the adverse
effects associated with PPIs, but there’s problems with all
of these database linkages. You’re giving PPIs to sick
people in the first place. So those people may be more
likely to generate outcome. So if you want to have a great study from an administrative database,
you turn to Scandinavia, where they have data on
every one of their patients. They looked at them from ’95 to 2014. This group does all their
studies on alcoholic cirrhotics, so they made it count twice, and they made sure they had patients with at least 30 days of follow-up, and they looked at the
development of SBP, pneumonia, and infectious colitis,
a.k.a., mainly C. diff. After they excluded people with cancer and other causes of liver disease, they ended up with 20,000 people, and they performed propensity matching to try to recapitulate the terms of a randomized control trial so that people were relatively balanced in terms of their demographics or whether they received a PPI or not. They had 10,000 people in this propensity score
matched population. Subtle differences, including
that there were more people in the PPI group that received alcohol, and there were more people
who were working in the group who did not receive a
PPI even after matching, and what they found is
that in this cohort, in the unmatched cohort,
PPIs were associated with a statistically significant decrease in the development of SBP. Take that for what it’s worth, but when you matched the cohort, there was no significant difference. Again, no difference when
you matched the cohort for the development of
pneumonia, no difference when you matched the cohort
for PPI use for the development of C. diff and other forms
of infectious colitis, which gets at we should not be giving PPIs to everybody willy-nilly, but if you have a person
who had a recent ulcer or severe quality of life limiting GERD who happens to have cirrhosis, then that is a person
who benefits from PPIs, but if, in your mind,
you can get that person off of a PPI without
making their life worse, then you should do it,
and you shouldn’t feel bad when you feel like your hands are tied and you keep them on PPI. So shifting to a study of a drug designed to increase platelet counts, this is getting at patients
who have thrombocytopenia, many of our patients with cirrhosis do, sometimes need to have
invasive procedures, and you find yourself on
the phone, late on a Friday, arguing with an interventional radiologist or pulmonologist that it is, in fact, safe for this patient who’s in extremis to have their paracentesis
or thoracentesis. That person gets a platelet transfusion, and for the most part, it’s safe, but every now and then, that platelet transfusion is associated with severe adverse events, including but not limited to TRALI, TACO, and all the other acronyms that pulmonologists have developed, and it’s associated with costs. Those platelets could be
used for other patients that need them, and if there was a way
to supplant the need for platelet transfusion
to prevent bleeding and cool everybody’s jets about doing invasive procedures
in patients with cirrhosis, then that’s a win-win situation. So thrombocytopenia is
common in liver disease, and I just wanna review very
briefly where this comes from. This is a cartoon I drew once upon a time, and I’m gonna highlight
a couple of things. Platelets are low in cirrhosis. In fact, the platelet count is
the most predictive lab test to help us predict who among our patients with liver disease has cirrhosis, and there’s a few reasons for that. One, portal hypertension
introduces splenic sequestration of platelets. Two, gut translocation and bacteria induces a
nonspecific immune response, which leads to platelet antibodies that destroy our patients’ platelets, and three, the hormone
that generates platelets in the first place, thrombopoietin,
is made by the liver, and so as our liver’s
functions decreases, so, too, does the production of thrombopoietin, and in vitro prior studies have found that a platelet count
less than 60 is associated with bleeding. Now, if your patient without cirrhosis
develops thrombocytopenia, they’re not going to bleed
at a platelet count of 60. So what’s unique about cirrhosis is that the liver function also affects the coagulation cascade. In general, it’s balanced because they’re also making
less protein C and S, but at a certain point, their
ability to produce thrombin, their ability to
coagulate becomes hampered because the platelet is itself a biologically active catalyst for the production of thrombin. When you’re platelet count is 40 or lower, you’re much less likely to make thrombin, and the platelet is affecting the coagulation protein cascade. So in vitro 60 was a good tipping point, but of course, there’s a lot
of uncertainty around that. So there have been prior
drugs that have looked at replacing thrombopoietin
through thrombopoietin agonism. One of them was eltrombopag, and this was published in
the New England Journal a few years ago by my original mentor, and what they found was that
you were able to increase the platelet count through
giving thrombopoietin. You did reduce bleeding episodes. You did reduce the need
for platelet transfusions, but several people developed
portal vein thrombosis, and in some cases, this was a significant
life-changing event. Many of these patients had
very high platelet counts at the time of that thrombosis. Many of these people had
hepatocellular carcinoma. So in view of these safety concerns, eltrombopag hasn’t really
penetrated into the market in this situation. So avatrombopag launched two simultaneous randomized
controlled trials designed to look at a follow-on
thrombopoietin agonist. In this study, the notable
differences are these. One, the treatment was only five days, and it was stopped before the time of the invasive procedure. Two, they looked at people who had low baseline count
platelet counts, less than 40, and high baseline
platelet counts, 40 to 50, and they adjusted the dose
of avatrombopag accordingly. The efficacy endpoint is obvious. They’re looking for the proportion of people not needing
a platelet transfusion or any form of bleeding rescue treatment, be it any kind of treatment
or interventional therapy and secondary efficacy endpoints looking at just achieving a target platelet count. Looking at adverse events, of course, they are actively screening people for portal vein thrombosis. What you see here are that most of these people are a
little more compensated than in our HE trial, mean MELD
score 11, most of them Child A, but a portion of patients who did not need a platelet transfusion
was significantly higher in both of these cohorts when they received avatrombopag
compared to placebo, and the proportion of patients who achieved the target
platelet count of 50 or greater was significantly higher. If you look at the kinetics
of these platelet changes, you can see that at the day of the procedure they had
their peak platelet count on average 80, a little bit lower than in prior trials, and this would taper back
to baseline by the end of the month. There was only one person who developed a partial portal vein thrombosis and fewer than in the eltrombopag studies but obviously something that needs to be followed moving forward. So obviously, there is a persistent, unmet need to thrombocytopenic
patients requiring a procedure to avoid transfusion, and the question is whether
this is cost-effective and how that would change our practice. Those data are pending. So my last study is a follow-on
about a viral hepatitis. So we’re treating everybody. We’re curing virtually everybody except for small groups that have
a high rate of failure, and those include people
with decompensated cirrhosis. So one of the other things
that we don’t often talk about when treating patients with
decompensated cirrhosis is that their liver function
could get better, and sometimes, it does not, and if your liver function gets better, but you maintain your ascites, this is a pretty bad place to be because if you have a low MELD score but you still have
ascites or encephalopathy, then you’re not going to have a MELD score that would garner you a liver transplant, but you’re living the life of somebody with decompensated cirrhosis, and your liver disease
is stable moving forward. We call that MELD purgatory. So who in our patients with
decompensated cirrhosis is going to benefit from DAA therapy, and what this study did, and I was involved with the analysis, is that they included all of
the data from the SOLAR trial and ASTRAL-4. So that is, when we
took Harvoni and looked at what happened to patients with decompensated cirrhosis
and ASTRAL-4 was Epclusa in patients with decompensated
cirrhosis published in the New England Journal last year, and this other one with a long
acronym was a wild fantasy, where you could give people Harvoni and reduce their portal pressure, but they were all decompensated, so if you take everybody
with decompensated cirrhosis who got a sofosbuvir-containing
regimen and looked at their data for 12 to
24 weeks after treatment. So the primary outcome was
sustained Child A cirrhosis. This is the win. You’ve taken someone with a decompensation and returned them back to the
state from whence they came, and the secondary outcome
here is MELD purgatory, including, of course, all modeling looking at death or transplantation. So the overall SVR rate in this group 85%, mean follow-up under a year,
17 transplants, and 35 deaths. Of the patients who developed
SVR, Child A was achieved in 36, so one in three patients returning to a compensated state when
they had Child B to begin with and only one in eight
when they had Child C. So these are good numbers
to quote for your patients SVR was associated with
a sustained Child class A and also a transplant or death. This was highly protective of the need for transplantation or death. So if we wanted to look
at a baseline risk score to tell us who among our
patients is likely to benefit, likely to develop Child A cirrhosis, then the answer are these, BMI less than 25, no
encephalopathy, no ascites, an ALT that’s elevated, and an albumin that’s elevated, okay, so you had a relatively
compensated albumin and you hadn’t developed encephalopathy. As you start to rack up
points in this scheme, you develop a very high chance of developing Child A cirrhosis with relatively tight confidence intervals until you get very high up. So the ratio for achieving
Child A is highest for the groups with the
highest BEAAA scores. 32% of patients with
SVR12 became compensated when they had Child B
cirrhosis after DAA therapy, and a five-point score
that takes into account whether your patient
has a normal BMI, a lack of encephalopathy, a lack
of ascites, a high ALT, and a relatively normal
albumin will predict which of our patients with
a decompensation will become Child-Pugh class A with treatment. Thank you.

1 Comment

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