February 1, 2024 • 28 mins
The liver is the primary site for drug metabolism in the body, but it can be severely damaged by medicines or their toxic compounds. Rita Baião from the North Lisbon University Hospital Center reviews what pharmacovigilance professionals should know about drug-induced liver injury (DILI).
Tune in to find out:
- Who is most at risk of developing DILI
- How to diagnose the condition and control the damage
- How to assess case reports of DILI
Want to know more?
- This infographic in Nature Reviews nicely summarises the mechanisms, diagnosis, and management of drug-induced liver injury.
- In this report, the Council for International Organizations of Medical Sciences provides a global perspective on DILI detection, susceptibility factors, outcomes, and more.
- In this Drug Safety article, industry representatives outline how to identify, mitigate, and communicate the risk of DILI during drug development.
- The PRO-EURO DILI NETWORK coordinates research efforts on DILI across Europe and provides a forum to exchange knowledge and training on the topic. Similar initiatives include the Spanish DILI Registry and the Latin American DILI Network.
- The free online tool LiverTox contains up-to-date information on drug-induced liver injury for medicines and herbal products.
To learn more about post-marketing surveillance and clinical care of DILI, check out Uppsala Monitoring Centre’s free online course on the topic.
For more on the clustering algorithm vigiGroup, revisit this interview with UMC scientists Jim Barrett and Joe Mitchell.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Federica Santoro (00:15):
Sooner or later, most of the medicines we
take pass through the liver,where they are chemically
altered, so the body can easilyget rid of them.
Normally, this process runssmoothly, but sometimes drugs
and their metabolites end updamaging the liver.
This condition, known asdrug-induced liver injury, can
(00:38):
be quite severe for patients andis not that easy to diagnose,
so it's crucial thatpharmacovigilance professionals
are aware of it.
My name is Federica Santoro,and this is Drug Safety Matters,
a podcast by Uppsala MonitoringCentre, where we explore
current issues inpharmacovigilants and patient
(01:00):
safety.
Joining me today is Rita Baião,medical doctor and clinical
pharmacologist from Lisbon,Portugal.
Rita is currently enrolled in amaster's programme at the
University of Bordeaux, and aspart of her thesis, she is
collaborating with UMCresearchers to explore if
(01:22):
VigiGroup, our clusteringalgorithm, can help detect and
assess signals of drug-inducedliver injury, and so I seized
the opportunity to chat to herwhile she was in our offices
last December.
I asked her how drugs damagethe liver, who is most at risk,
(01:44):
how to cope with the damage, andmuch more.
Enjoy our conversation.
Hi, Rita, and welcome to DrugSafety Matters.
I'm really glad we managed tosqueeze this interview in before
(02:04):
you leave UMC and head back toLisbon.
How was your time here so far?
Rita Baião (02:09):
Thank you, Federica, it has been a really wonderful
surprise.
Uppsala is a really amazingcity.
I managed to make a lot offriends here at UMC and also
learn a lot, which was the mainreason for me to come here.
Federica Santoro (02:24):
Lovely to hear that.
So today we're talking about atopic that you're especially
passionate about (02:29):
drug-induced liver injury, or DILI for short.
We'll probably be referring toit with the acronym mostly from
now on.
The term is somewhatself-explanatory, as one would
imagine.
DILI happens when medicalproducts damage the liver, but
of course, there's a lot more toit than just that.
(02:50):
So why don't we start with this?
How common is DILI?
Rita Baião (02:57):
So, DILI is actually a rare occurrence in terms of
frequency.
It is estimated that it canhappen from one in each 10,000
people exposed to one in 100,000people exposed to a drug.
Despite this rarity, it is oneof the leading causes of drug
(03:18):
attrition in drug development,so a lot of drugs in development
phase stop because of liverinjury.
And also it's one of theleading causes of drug warnings
by regulatory agencies and evenmarket withdrawals.
Federica Santoro (03:36):
That's interesting and that leads
nicely into my second question,actually, because I was going to
ask you how relevant DILI is topharmacovigilance professionals
.
And so, how many cases areactually spotted already in
clinical trials versus picked upin the post-marketing stage?
From what you said, it soundslike both happen, but what's the
(03:57):
relative frequency?
Rita Baião (03:58):
So, we cannot estimate accurately how many
happen during clinical trials,because in clinical trials we
have a clue because of liverenzymes' elevations and usually
the drug is either stopped orthe dose is reduced during
clinical trials.
And then if the drug makes itto approval and then exposed to
(04:20):
larger populations, itsfrequency starts to be more
relevant.
But we cannot really estimatethe actual frequency because for
cautionary measures usually thedrugs are stopped if the liver
enzymes reach a threshold, andso we don't wait for the patient
to develop severe symptoms.
(04:41):
And so we cannot reallyestimate a correct frequency,
although in post-marketingsetting and some registries have
shown that, for example inIceland and in France, that it
can be around 14 to 19 over10,000 people exposed annually.
Federica Santoro (05:02):
I understand that it's tricky, but it's
certainly something we wantpharmacovigilance professionals
to be aware of, right?
Rita Baião (05:07):
Exactly.
That is why, in post-marketingsetting, it's really important
that the professionals are awareof this type of injury, because
it's tricky to diagnose andalso, when it happens, can be
really severe.
Federica Santoro (05:21):
We'll get to all that – you mentioned patient
registries and the severity andthe diagnosis– we'll get to all
that in a bit.
First, I'd like to talk aboutmechanism.
So, how do drugs actually causeliver injury, and are there
certain types of drugs that aremore dangerous, so to say, than
(05:42):
others?
Rita Baião (05:43):
So, it's a really complex mechanism that is still
being studied, but we can dividein a gross manner drugs that
cause liver injury because theyare direct agents causing liver
toxicity and so they will bedose- dependent, this type of
injury,we can kind of predict at which
dose the drug will cause liverinjury, and those which are
(06:06):
independent of the dose and theydepend on the host that is
receiving the drug, so thepatient, and we cannot foresee
when it will happen, at whichdose it will happen and how
severe it will be.
And so this type of liverinjury, which we call
idiosyncratic liver injury,accounts for around 10% of all
(06:29):
types of drug- induced liverinjury.
Usually it is more severe andit's more rare, but when it
happens it's something that wereally are concerned about
because we don't know when thenext patient will appear,
because we cannot see a patternin terms of who will have drug-
induced liver injury of thistype.
(06:50):
As for which drugs are morelikely to cause drug- induced
liver injury, certain types ofdrugs, such as antibiotics,
anti-convulsants, some types ofnon-steroidal inflammatory drugs
, can cause more frequentlydrug- induced liver injury,
although any drug has thepotential to cause liver injury
(07:11):
because it also depends on thehost factors, so in the patient
that is receiving the drug.
Federica Santoro (07:17):
Right, and let's talk then about the
patient's factors you mentioned.
There's a type of DILI wherethe response is dose- dependent
and has more to do with thedrug's characteristics, and then
there's another type of DILIwhere it just seems to happen in
a bunch of different peoplewith no specific pattern.
But surely there must be somerisk factors that the community
(07:40):
has identified.
Who, in your experience, ismore likely to suffer from DILI?
Rita Baião (07:46):
So, the risk factors so far identified are age – so
older people are more at risk –those who have moderate to high
alcohol consumption, those alsothat have underlying liver
diseases, autoimmune hepatitis,or other types of autoimmune
diseases.
(08:06):
Also, we see that pregnantpeople are more prone to have
liver injury although becausepregnant people usually don't
take so many medicines duringpregnancy, we don't see it as
frequently.
And also people who take manymedicines at the same time, so
polypharmacy.
Then there's geneticpredisposition, which has been a
(08:28):
field which has developedlargely in the last 20 years,
and now we know with some typeof assurance that some HLA
alleles – so, human leukocyteantigen alleles – are connected
to liver injury when you takeantibiotic drugs such as
amoxicillin and clavulanic acidand also flucloxacillin.
(08:50):
So, for example, we have apatient that we are kind of sure
that has a liver injury thatwas caused by an antibiotic, but
we want to be sure.
And if by any chance we have aliver biopsy or we have some
type of genetic testing, we cantest for these HLA alleles and
if they have those in particular, we can be pretty sure that
(09:13):
most likely the drugs are theculprits.
Federica Santoro (09:16):
So you can do that kind of pharmacogenetic
screening nowadays.
Rita Baião (09:20):
Exactly, but it's not in all countries and it's
not as routine practice as inother types of diseases, such as
oncology, for example.
Federica Santoro (09:30):
All right, you're a medical doctor by
training, so you probably can'twait to get into the clinical
details of this conversation,and so let's go on to that.
How is DILI diagnosed and, moreimportantly, how do you tell it
apart from other conditionsthat affect the liver?
Rita Baião (09:51):
So DILI, and why it's so tricky in terms of both
the pre-marketing setting as thepost-marketing setting, is a
really tricky disease todiagnose.
It's what we call exclusiondiagnosis.
So first we have to rule out alot of different diseases before
we can start to say, okay, themedicine was the culprit.
(10:12):
And so we have to rule outfirst what would be most
frequent.
So viral hepatitis, for example.
Biliary obstruction, so forexample gallbladder stones or
liver cancer that is obstructingthe biliary tract.
Also alcoholism, because it canbe a risk factor but at the
same time can also be analternative diagnosis if we have
(10:35):
an exacerbation of alcoholicliver disease.
Also autoimmune diseases thatcan also cause exacerbation of
their chronic disease, also canbe an exclusion diagnosis.
And so we go through it bysteps.
So we try to rule out the mostfrequent ones, which in most
(10:56):
countries would be viralhepatitis.
Of course, in countries wherewe know that some types of
infections, such as parasites orsome types of other virus, we
also have to consider those, butmostly viral hepatitis, from A
to B to C and also E, hepatitisE, is also an important cause to
rule out.
And after that then we startconsidering okay, maybe the drug
(11:20):
was the culprit, but we don'tusually wait for confirmation of
other diagnosis before stoppingthe drug.
So if there's even a slightsuspicion of drug- induced liver
injury, most of the drugs –unle ss essential ones which
assure life maintenance – westop all of them.
To protect the patient.
(11:42):
Exactly.
Federica Santoro (11:43):
Right, and is there anything you can do to
reverse the damage once some hasoccurred?
Rita Baião (11:51):
So, there's no antidote for liver injury.
What we can do is removing thesuspect drug that can be the
culprit.
So maintenance therapy, sosupporting symptoms.
For example, lots of patientsdevelop jaundice and so they get
pruritus, and so we give themantihistamine drugs or other
(12:12):
drugs that are off-label tosupport with the pruritus, that
can be really disturbing forsome patients.
And also, for example, if theyde veloped coagulation issues,
we monitor coagulation v aluesto see if we need to start some
type of therapy to preventhemorrhage.
The only drug that has anantidote for liver injury is
(12:37):
paracetamol or acetaminophen,which is N- acetylcysteine.
And so if we have, for example,intoxication by paracetamol in
high doses, one antidote that isusually given N-acetylcysteine,
but it's an antidote that it'sa bit controversial and not all
clinicians agree on, but it'sthe only antidote that we have
(12:59):
for drug-induced liver injury,but it's only for that specific
drug.
Federica Santoro (13:04):
I'm also thinking this is a particularly
important adverse event.
I mean, it's potentiallylife-threatening and how does
that affect patients' feelingsabout medicines in general?
I imagine it can be difficultfor someone who experiences an
adverse event of that severityto take medicines again after
(13:25):
that.
Is that something you thinkabout?
Rita Baião (13:28):
Yes, so definitely, patients become reluctant of
taking the same drug, even ifafterwards you actually rule out
that the drug, so even if youfind an alternative diagnosis
that was actually most likely tobegin with, since you've told
them that might be the drugs andyou actually stopped the drugs
for a while they might still bereluctant to take drugs.
(13:50):
And so you really have to bepatient and explain that there
is also a benefit–riskassessment.
And with the patient, you haveto also respect their choices,
of course, and try to make themunderstand that, yes, it could
have been the drug.
If it was the case, then themedication has to be changed.
(14:12):
But if it wasn't the drug, weneed to rebuild the trust on the
therapy.
There's also the opposite,actually.
So there are some cases inwhich we know that some type of
medicine causes drug-inducedliver injury, but because these
medicines are life-saving andthey are the only therapeutic
option for some diseases,patients really cling on to them
(14:36):
.
And so, even if the doctor orhealth care professional says,
'we need to stop this drugbecause it's damaging your
liver', the patients say, 'butthis medicine makes my life
better and so I'd rather risk itand have a comfortable
day-to-day life or (at least ifit's, for example, oncology
drugs) I still want to have achance'.
(14:58):
And that can be a bitconflicting, because you don't
want to remove their chance of abetter life but at the same
time you know that the medicineis hurting the liver and
damaging the liver.
So it can be tricky and it's apatient and doctor relationship
that has to be built to regainthe trust of the patient.
Federica Santoro (15:19):
Yeah, I understand, and that's when it's
so important to have thosereally frank and clear
conversations on the benefitsand risks, as you say, so that
the patients can make the bestinformed decision they can.
Rita Baião (15:31):
There's also, there's a case that is actually
not that long ago with amedicine.
This is public knowledge.
So, it was a drug that was usedfor uterine fibroids, for women
with the symptoms of uterinefibroids who'd had menstrual
cramps, hemorrhages, veryfrequently.
And the drug was introduced in2012 in the European market and
(15:57):
then by 2017, some cases hadaccumulated of liver transplant.
And so, of course, adrug-induced liver injury very
severe, enough severe for thepatients to need a liver
transplant, and then therecommendation of regulatory
agencies at first would be toremove the drug from the market
because this was too severe.
(16:18):
But then, at the same time,there was no alternative for
these women to treat theirsymptoms of their daily life, so
they had to live with theamaryngis and anemia from their
day-to-day life, and removingthis drug from the market for
them was not an option, becausethis was a drug that was used
for women who could not undergosurgery for uterine fibroids.
(16:42):
And so it's a case where itdoesn't happen what you expect
it to be, which would bepatients advocating for the drug
to be removed from the market.
Federica Santoro (16:52):
Exactly, one of those cases where the
regulators think they're takingthe best decision for the
patients, but actually thepatients want something else.
Rita Baião (17:01):
Yeah, now it's restricted, now there's heavy
liver monitoring.
But so there is this option andnow there are more options, but
now it's restricted but notwithdrawn from the market.
Federica Santoro (17:14):
Let's give some practical advice to our
fellow pharmacovigilancecolleagues who are listening in.
When they are analysing casereports for DILI, is there
anything special they should door look out for?
Rita Baião (17:29):
So, I'd say the most important thing would be to do
what you usually do inpharmacovigilance, which is make
a calendar or make a graph ofexposure: start and stop dates
and time to onset or time fromcessation of the drug.
That's a rule for allpharmacovigilance causality
assessment and it's no differentfor drug- induced liver injury.
(17:51):
Here the difference is thereare some causality assessment
tools that are very specific forliver injury, aside from the
general ones that we alreadyknow, like the WHO- UMC
causality assessment tool.
And so there is a very popularone which was invented and
developed in the late 80s, whichis the RUCAM scale or Roussel
(18:14):
Uclaf Causality AssessmentMethod, and that very recently
was updated by a team of expertsto RECAM scale.
So these are other tools thatare very liver- specific to do
causality assessment.
Of course, the basic rules ofcausality assessment for other
(18:34):
types of drugs still apply.
So, exclusion of other causesis very important since DILI is
an an exclusion diagnosis.
Time to onset, course of actionafter de- challenge, and when
re-challenge is conducted, whichis risky in case of DILI, how
does the re-challenge occur?
Federica Santoro (18:55):
And so, in addition to those criteria that
are included in standardcausality assessment methods, do
these DILI- specific methodsinclude then other parameters?
Rita Baião (19:05):
It's a score method and so you point, but it's
mostly a guidance, so you don'tneed to be attached to the score
to decide the probability.
Of course the score points to apossible, probable, or unlikely
causality, but in the end youcan decide for yourself, and it
helps you do a mental process ofthinking, 'is this drug the
(19:30):
culprit or not'?
And so it has some parametersthat are liver- specific, such
as, 'which diagnosis have youexcluded so far'?
Federica Santoro (19:39):
Okay, so guided thinking.
Exactly.
Another way we can learn aboutDILI, aside from spontaneous
reporting systems, is throughpatient registries, and you
mentioned them at the start ofthe interview.
I'd like to go back to that,because back in Portugal, where
you're normally based, you'reinvolved with one such registry,
(20:00):
the PRO-EURO DILI NETWORK.
How does that work?
Rita Baião (20:06):
So fortunately, and I'm very thankful to have been
incorporated by some colleaguesback in Lisbon into this network
.
This network is a Europeanconsortium of hospitals
throughout Europe whichcollaborate in gathering
evidence for liver disease.
(20:26):
And so it's a prospectiveobservational study in which the
patients that arrive to ourhospitals, be it through the
emergency room or consultations/appointments, and if we suspect
they have drug- induced liverinjury, we ask them, 'would you
like to participate in thisstudy?
'.
And so we get the informedconsent, and if they do consent,
(20:48):
we gather clinical data, so wemake an interview to ask them,
'how have you been feeling?
', their symptoms.
We also collect laboratoryassessments.
So if they are going to dolaboratory assessments, we
gather extra blood tubes, and sowe try to avoid getting extra
(21:09):
laboratory assessments, becausethat can be uncomfortable for
the patients.
And if their liver diseaseprogresses and by some chance
they do have to do a liverbiopsy, we also keep a piece for
the biobank.
And so this is stored in abiobank, and then their cases
are presented within a Delphipanel of hepatologists and
(21:30):
experts which decide if the caseis most likely DILI or most
likely a control.
And a control doesn't mean thatthey don't have liver disease,
just means that they have othertypes of liver diseases.
If we don't have enoughinformation to decide whether
it's DILI or a control, thepatient is excluded from the
study and then we can comparehow DILI differentiates itself
(21:55):
from other liver diseases and weget clues from the biological
samples of what difference wecan see in this type of liver
injury.
And it's really interesting.
Federica Santoro (22:08):
Are there more networks like this around the
world?
Rita Baião (22:11):
Yes, so the PRO-EURO DILI started out.
Before there was the SpanishDILI registry, which still
exists, and then PRO-EURO DILIdeveloped into a European effort
.
And there's also the NorthAmerican.
Maybe there are more that I'mnot aware of, but at least these
two are two big ones that areknown and are doing really great
(22:34):
work in trying to understandDILI.
Federica Santoro (22:36):
And we'll link to them in the show notes,
along with other resources, soif people are interested, they
can read up.
So, lately though, as we said,you took a break from your usual
work in Lisbon and spent sometime here at UMC as a visiting
scientist.
What did you research then inthe last few months?
Rita Baião (22:57):
So, my current research focuses on using a
method that was developed hereat UMC, vigiGroup, which is a
clustering method to aggregatereports based on the co-reported
adverse drug reactions thatthey have inside.
And my research is trying tosee if, using this method, we
(23:20):
can find DILI or if we can builda case series that is
clinically coherent.
And so we've been focusing moreon this latter part, because
this is an extensive work and tofind new DILI signals we still
need to do a bit more research.
But for now what we're doing istrying to see if with known
(23:42):
drugs, drugs that have beenknown for the past, I don't
know, 40- 50 years, those thatwe are very comfortable with
their safety profile, we can seethe patterns of DILI in their
clusters that we get fromvigiGroup.
And we compare, for example,drugs that we know are pretty
safe for the liver, so drugs notusually associated with DILI,
(24:05):
and we compare their clusterswith drugs that we know that
cause DILI.
And so we're trying to see ifthe patterns of clusters are
very distinct.
And so we're using a positiveand a negative control, and if,
within the clusters of drugsthat are associated with DILI,
if the clusters are clinicallycoherent – and so if the adverse
(24:28):
drug reaction terms that wefind within the clusters make
sense together.
And we'll see the results.
We hopefully will have positiveresults, but we still have to
work a little bit more on this.
Hopefully it will be useful atleast for case management, so
for signal assessors to have acase series that is more
(24:52):
specific and more manageable interms of human resources and
time.
Federica Santoro (24:57):
We have an episode on vigiGroup in our
archive, so people can listen tothat if they'd like to know
more about the method.
But for those who haven'tlistened to it yet, can you
explain briefly what theadvantage is, then, of using a
clustering algorithm compared totraditional pharmacovigilance
methods?
Rita Baião (25:15):
And so this clustering method will aggregate
reports.
So usually we start withdisproportionality analysis and
then we build a case seriesbased on the adverse drug
reaction that we found wasdisproportional.
But sometimes countries orreporters have different
(25:37):
reporting practices and so, forexample, if a patient has a
drug- induced liver injury, theywill complain of jaundice or
yellow eyes or pruritus.
But if it's the doctor that isreporting the same adverse drug
reaction, he will reporthepatitis or colostatic liver
(25:58):
injury.
Maybe if it's a pharmaceuticalindustry, they will report liver
enzymes abnormal or increased.
And so with vigiGroup, based onthe co-reported terms, we're
trying to see if we can groupthe reports that make sense
together and this can build caseseries that are more coherent.
(26:21):
And so for signal assessors andfor signal management it's much
more directed than just usingStandardised MedDRA Queries that
sometimes can be too broad.
Federica Santoro (26:33):
And again, for those who want to know more, go
dig in the archive.
We'll link to the vigiGroupepisode in the show notes as
well.
Well, that was all I had foryou, Rita, today.
Thank you very much for takingthe time to join me.
I wish you all the best inwrapping up your research here,
and we look forward to seeingthe results when available.
Rita Baião (26:54):
Thank you, Federica, and thank you for having me
here at UMC.
Federica Santoro (27:05):
That's all for now, but we'll be back soon
with more conversations onmedicines safety.
If you'd like to know moreabout drug-induced liver injury,
check out the episode shownotes for useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
(27:26):
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
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do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn and X, and
(27:51):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank Rita Baiãofor her time, Matthew Barwick
for post-production support, andof course you for tuning in.
(28:14):
Till next time.
Sooner or later, most of the medicines we
take pass through the liver,where they are chemically
altered, so the body can easilyget rid of them.
Normally, this process runssmoothly, but sometimes drugs
and their metabolites end updamaging the liver.
This condition, known asdrug-induced liver injury, can
(00:38):
be quite severe for patients andis not that easy to diagnose,
so it's crucial thatpharmacovigilance professionals
are aware of it.
My name is Federica Santoro,and this is Drug Safety Matters,
a podcast by Uppsala MonitoringCentre, where we explore
current issues inpharmacovigilants and patient
(01:00):
safety.
Joining me today is Rita Baião,medical doctor and clinical
pharmacologist from Lisbon,Portugal.
Rita is currently enrolled in amaster's programme at the
University of Bordeaux, and aspart of her thesis, she is
collaborating with UMCresearchers to explore if
(01:22):
VigiGroup, our clusteringalgorithm, can help detect and
assess signals of drug-inducedliver injury, and so I seized
the opportunity to chat to herwhile she was in our offices
last December.
I asked her how drugs damagethe liver, who is most at risk,
(01:44):
how to cope with the damage, andmuch more.
Enjoy our conversation.
Hi, Rita, and welcome to DrugSafety Matters.
I'm really glad we managed tosqueeze this interview in before
(02:04):
you leave UMC and head back toLisbon.
How was your time here so far?
Rita Baião (02:09):
Thank you, Federica, it has been a really wonderful
surprise.
Uppsala is a really amazingcity.
I managed to make a lot offriends here at UMC and also
learn a lot, which was the mainreason for me to come here.
Federica Santoro (02:24):
Lovely to hear that.
So today we're talking about atopic that you're especially
passionate about (02:29):
drug-induced liver injury, or DILI for short.
We'll probably be referring toit with the acronym mostly from
now on.
The term is somewhatself-explanatory, as one would
imagine.
DILI happens when medicalproducts damage the liver, but
of course, there's a lot more toit than just that.
(02:50):
So why don't we start with this?
How common is DILI?
Rita Baião (02:57):
So, DILI is actually a rare occurrence in terms of
frequency.
It is estimated that it canhappen from one in each 10,000
people exposed to one in 100,000people exposed to a drug.
Despite this rarity, it is oneof the leading causes of drug
(03:18):
attrition in drug development,so a lot of drugs in development
phase stop because of liverinjury.
And also it's one of theleading causes of drug warnings
by regulatory agencies and evenmarket withdrawals.
Federica Santoro (03:36):
That's interesting and that leads
nicely into my second question,actually, because I was going to
ask you how relevant DILI is topharmacovigilance professionals
.
And so, how many cases areactually spotted already in
clinical trials versus picked upin the post-marketing stage?
From what you said, it soundslike both happen, but what's the
(03:57):
relative frequency?
Rita Baião (03:58):
So, we cannot estimate accurately how many
happen during clinical trials,because in clinical trials we
have a clue because of liverenzymes' elevations and usually
the drug is either stopped orthe dose is reduced during
clinical trials.
And then if the drug makes itto approval and then exposed to
(04:20):
larger populations, itsfrequency starts to be more
relevant.
But we cannot really estimatethe actual frequency because for
cautionary measures usually thedrugs are stopped if the liver
enzymes reach a threshold, andso we don't wait for the patient
to develop severe symptoms.
(04:41):
And so we cannot reallyestimate a correct frequency,
although in post-marketingsetting and some registries have
shown that, for example inIceland and in France, that it
can be around 14 to 19 over10,000 people exposed annually.
Federica Santoro (05:02):
I understand that it's tricky, but it's
certainly something we wantpharmacovigilance professionals
to be aware of, right?
Rita Baião (05:07):
Exactly.
That is why, in post-marketingsetting, it's really important
that the professionals are awareof this type of injury, because
it's tricky to diagnose andalso, when it happens, can be
really severe.
Federica Santoro (05:21):
We'll get to all that – you mentioned patient
registries and the severity andthe diagnosis– we'll get to all
that in a bit.
First, I'd like to talk aboutmechanism.
So, how do drugs actually causeliver injury, and are there
certain types of drugs that aremore dangerous, so to say, than
(05:42):
others?
Rita Baião (05:43):
So, it's a really complex mechanism that is still
being studied, but we can dividein a gross manner drugs that
cause liver injury because theyare direct agents causing liver
toxicity and so they will bedose- dependent, this type of
injury,we can kind of predict at which
dose the drug will cause liverinjury, and those which are
(06:06):
independent of the dose and theydepend on the host that is
receiving the drug, so thepatient, and we cannot foresee
when it will happen, at whichdose it will happen and how
severe it will be.
And so this type of liverinjury, which we call
idiosyncratic liver injury,accounts for around 10% of all
(06:29):
types of drug- induced liverinjury.
Usually it is more severe andit's more rare, but when it
happens it's something that wereally are concerned about
because we don't know when thenext patient will appear,
because we cannot see a patternin terms of who will have drug-
induced liver injury of thistype.
(06:50):
As for which drugs are morelikely to cause drug- induced
liver injury, certain types ofdrugs, such as antibiotics,
anti-convulsants, some types ofnon-steroidal inflammatory drugs
, can cause more frequentlydrug- induced liver injury,
although any drug has thepotential to cause liver injury
(07:11):
because it also depends on thehost factors, so in the patient
that is receiving the drug.
Federica Santoro (07:17):
Right, and let's talk then about the
patient's factors you mentioned.
There's a type of DILI wherethe response is dose- dependent
and has more to do with thedrug's characteristics, and then
there's another type of DILIwhere it just seems to happen in
a bunch of different peoplewith no specific pattern.
But surely there must be somerisk factors that the community
(07:40):
has identified.
Who, in your experience, ismore likely to suffer from DILI?
Rita Baião (07:46):
So, the risk factors so far identified are age – so
older people are more at risk –those who have moderate to high
alcohol consumption, those alsothat have underlying liver
diseases, autoimmune hepatitis,or other types of autoimmune
diseases.
(08:06):
Also, we see that pregnantpeople are more prone to have
liver injury although becausepregnant people usually don't
take so many medicines duringpregnancy, we don't see it as
frequently.
And also people who take manymedicines at the same time, so
polypharmacy.
Then there's geneticpredisposition, which has been a
(08:28):
field which has developedlargely in the last 20 years,
and now we know with some typeof assurance that some HLA
alleles – so, human leukocyteantigen alleles – are connected
to liver injury when you takeantibiotic drugs such as
amoxicillin and clavulanic acidand also flucloxacillin.
(08:50):
So, for example, we have apatient that we are kind of sure
that has a liver injury thatwas caused by an antibiotic, but
we want to be sure.
And if by any chance we have aliver biopsy or we have some
type of genetic testing, we cantest for these HLA alleles and
if they have those in particular, we can be pretty sure that
(09:13):
most likely the drugs are theculprits.
Federica Santoro (09:16):
So you can do that kind of pharmacogenetic
screening nowadays.
Rita Baião (09:20):
Exactly, but it's not in all countries and it's
not as routine practice as inother types of diseases, such as
oncology, for example.
Federica Santoro (09:30):
All right, you're a medical doctor by
training, so you probably can'twait to get into the clinical
details of this conversation,and so let's go on to that.
How is DILI diagnosed and, moreimportantly, how do you tell it
apart from other conditionsthat affect the liver?
Rita Baião (09:51):
So DILI, and why it's so tricky in terms of both
the pre-marketing setting as thepost-marketing setting, is a
really tricky disease todiagnose.
It's what we call exclusiondiagnosis.
So first we have to rule out alot of different diseases before
we can start to say, okay, themedicine was the culprit.
(10:12):
And so we have to rule outfirst what would be most
frequent.
So viral hepatitis, for example.
Biliary obstruction, so forexample gallbladder stones or
liver cancer that is obstructingthe biliary tract.
Also alcoholism, because it canbe a risk factor but at the
same time can also be analternative diagnosis if we have
(10:35):
an exacerbation of alcoholicliver disease.
Also autoimmune diseases thatcan also cause exacerbation of
their chronic disease, also canbe an exclusion diagnosis.
And so we go through it bysteps.
So we try to rule out the mostfrequent ones, which in most
(10:56):
countries would be viralhepatitis.
Of course, in countries wherewe know that some types of
infections, such as parasites orsome types of other virus, we
also have to consider those, butmostly viral hepatitis, from A
to B to C and also E, hepatitisE, is also an important cause to
rule out.
And after that then we startconsidering okay, maybe the drug
(11:20):
was the culprit, but we don'tusually wait for confirmation of
other diagnosis before stoppingthe drug.
So if there's even a slightsuspicion of drug- induced liver
injury, most of the drugs –unle ss essential ones which
assure life maintenance – westop all of them.
To protect the patient.
(11:42):
Exactly.
Federica Santoro (11:43):
Right, and is there anything you can do to
reverse the damage once some hasoccurred?
Rita Baião (11:51):
So, there's no antidote for liver injury.
What we can do is removing thesuspect drug that can be the
culprit.
So maintenance therapy, sosupporting symptoms.
For example, lots of patientsdevelop jaundice and so they get
pruritus, and so we give themantihistamine drugs or other
(12:12):
drugs that are off-label tosupport with the pruritus, that
can be really disturbing forsome patients.
And also, for example, if theyde veloped coagulation issues,
we monitor coagulation v aluesto see if we need to start some
type of therapy to preventhemorrhage.
The only drug that has anantidote for liver injury is
(12:37):
paracetamol or acetaminophen,which is N- acetylcysteine.
And so if we have, for example,intoxication by paracetamol in
high doses, one antidote that isusually given N-acetylcysteine,
but it's an antidote that it'sa bit controversial and not all
clinicians agree on, but it'sthe only antidote that we have
(12:59):
for drug-induced liver injury,but it's only for that specific
drug.
Federica Santoro (13:04):
I'm also thinking this is a particularly
important adverse event.
I mean, it's potentiallylife-threatening and how does
that affect patients' feelingsabout medicines in general?
I imagine it can be difficultfor someone who experiences an
adverse event of that severityto take medicines again after
(13:25):
that.
Is that something you thinkabout?
Rita Baião (13:28):
Yes, so definitely, patients become reluctant of
taking the same drug, even ifafterwards you actually rule out
that the drug, so even if youfind an alternative diagnosis
that was actually most likely tobegin with, since you've told
them that might be the drugs andyou actually stopped the drugs
for a while they might still bereluctant to take drugs.
(13:50):
And so you really have to bepatient and explain that there
is also a benefit–riskassessment.
And with the patient, you haveto also respect their choices,
of course, and try to make themunderstand that, yes, it could
have been the drug.
If it was the case, then themedication has to be changed.
(14:12):
But if it wasn't the drug, weneed to rebuild the trust on the
therapy.
There's also the opposite,actually.
So there are some cases inwhich we know that some type of
medicine causes drug-inducedliver injury, but because these
medicines are life-saving andthey are the only therapeutic
option for some diseases,patients really cling on to them
(14:36):
.
And so, even if the doctor orhealth care professional says,
'we need to stop this drugbecause it's damaging your
liver', the patients say, 'butthis medicine makes my life
better and so I'd rather risk itand have a comfortable
day-to-day life or (at least ifit's, for example, oncology
drugs) I still want to have achance'.
(14:58):
And that can be a bitconflicting, because you don't
want to remove their chance of abetter life but at the same
time you know that the medicineis hurting the liver and
damaging the liver.
So it can be tricky and it's apatient and doctor relationship
that has to be built to regainthe trust of the patient.
Federica Santoro (15:19):
Yeah, I understand, and that's when it's
so important to have thosereally frank and clear
conversations on the benefitsand risks, as you say, so that
the patients can make the bestinformed decision they can.
Rita Baião (15:31):
There's also, there's a case that is actually
not that long ago with amedicine.
This is public knowledge.
So, it was a drug that was usedfor uterine fibroids, for women
with the symptoms of uterinefibroids who'd had menstrual
cramps, hemorrhages, veryfrequently.
And the drug was introduced in2012 in the European market and
(15:57):
then by 2017, some cases hadaccumulated of liver transplant.
And so, of course, adrug-induced liver injury very
severe, enough severe for thepatients to need a liver
transplant, and then therecommendation of regulatory
agencies at first would be toremove the drug from the market
because this was too severe.
(16:18):
But then, at the same time,there was no alternative for
these women to treat theirsymptoms of their daily life, so
they had to live with theamaryngis and anemia from their
day-to-day life, and removingthis drug from the market for
them was not an option, becausethis was a drug that was used
for women who could not undergosurgery for uterine fibroids.
(16:42):
And so it's a case where itdoesn't happen what you expect
it to be, which would bepatients advocating for the drug
to be removed from the market.
Federica Santoro (16:52):
Exactly, one of those cases where the
regulators think they're takingthe best decision for the
patients, but actually thepatients want something else.
Rita Baião (17:01):
Yeah, now it's restricted, now there's heavy
liver monitoring.
But so there is this option andnow there are more options, but
now it's restricted but notwithdrawn from the market.
Federica Santoro (17:14):
Let's give some practical advice to our
fellow pharmacovigilancecolleagues who are listening in.
When they are analysing casereports for DILI, is there
anything special they should door look out for?
Rita Baião (17:29):
So, I'd say the most important thing would be to do
what you usually do inpharmacovigilance, which is make
a calendar or make a graph ofexposure: start and stop dates
and time to onset or time fromcessation of the drug.
That's a rule for allpharmacovigilance causality
assessment and it's no differentfor drug- induced liver injury.
(17:51):
Here the difference is thereare some causality assessment
tools that are very specific forliver injury, aside from the
general ones that we alreadyknow, like the WHO- UMC
causality assessment tool.
And so there is a very popularone which was invented and
developed in the late 80s, whichis the RUCAM scale or Roussel
(18:14):
Uclaf Causality AssessmentMethod, and that very recently
was updated by a team of expertsto RECAM scale.
So these are other tools thatare very liver- specific to do
causality assessment.
Of course, the basic rules ofcausality assessment for other
(18:34):
types of drugs still apply.
So, exclusion of other causesis very important since DILI is
an an exclusion diagnosis.
Time to onset, course of actionafter de- challenge, and when
re-challenge is conducted, whichis risky in case of DILI, how
does the re-challenge occur?
Federica Santoro (18:55):
And so, in addition to those criteria that
are included in standardcausality assessment methods, do
these DILI- specific methodsinclude then other parameters?
Rita Baião (19:05):
It's a score method and so you point, but it's
mostly a guidance, so you don'tneed to be attached to the score
to decide the probability.
Of course the score points to apossible, probable, or unlikely
causality, but in the end youcan decide for yourself, and it
helps you do a mental process ofthinking, 'is this drug the
(19:30):
culprit or not'?
And so it has some parametersthat are liver- specific, such
as, 'which diagnosis have youexcluded so far'?
Federica Santoro (19:39):
Okay, so guided thinking.
Exactly.
Another way we can learn aboutDILI, aside from spontaneous
reporting systems, is throughpatient registries, and you
mentioned them at the start ofthe interview.
I'd like to go back to that,because back in Portugal, where
you're normally based, you'reinvolved with one such registry,
(20:00):
the PRO-EURO DILI NETWORK.
How does that work?
Rita Baião (20:06):
So fortunately, and I'm very thankful to have been
incorporated by some colleaguesback in Lisbon into this network
.
This network is a Europeanconsortium of hospitals
throughout Europe whichcollaborate in gathering
evidence for liver disease.
(20:26):
And so it's a prospectiveobservational study in which the
patients that arrive to ourhospitals, be it through the
emergency room or consultations/appointments, and if we suspect
they have drug- induced liverinjury, we ask them, 'would you
like to participate in thisstudy?
'.
And so we get the informedconsent, and if they do consent,
(20:48):
we gather clinical data, so wemake an interview to ask them,
'how have you been feeling?
', their symptoms.
We also collect laboratoryassessments.
So if they are going to dolaboratory assessments, we
gather extra blood tubes, and sowe try to avoid getting extra
(21:09):
laboratory assessments, becausethat can be uncomfortable for
the patients.
And if their liver diseaseprogresses and by some chance
they do have to do a liverbiopsy, we also keep a piece for
the biobank.
And so this is stored in abiobank, and then their cases
are presented within a Delphipanel of hepatologists and
(21:30):
experts which decide if the caseis most likely DILI or most
likely a control.
And a control doesn't mean thatthey don't have liver disease,
just means that they have othertypes of liver diseases.
If we don't have enoughinformation to decide whether
it's DILI or a control, thepatient is excluded from the
study and then we can comparehow DILI differentiates itself
(21:55):
from other liver diseases and weget clues from the biological
samples of what difference wecan see in this type of liver
injury.
And it's really interesting.
Federica Santoro (22:08):
Are there more networks like this around the
world?
Rita Baião (22:11):
Yes, so the PRO-EURO DILI started out.
Before there was the SpanishDILI registry, which still
exists, and then PRO-EURO DILIdeveloped into a European effort
.
And there's also the NorthAmerican.
Maybe there are more that I'mnot aware of, but at least these
two are two big ones that areknown and are doing really great
(22:34):
work in trying to understandDILI.
Federica Santoro (22:36):
And we'll link to them in the show notes,
along with other resources, soif people are interested, they
can read up.
So, lately though, as we said,you took a break from your usual
work in Lisbon and spent sometime here at UMC as a visiting
scientist.
What did you research then inthe last few months?
Rita Baião (22:57):
So, my current research focuses on using a
method that was developed hereat UMC, vigiGroup, which is a
clustering method to aggregatereports based on the co-reported
adverse drug reactions thatthey have inside.
And my research is trying tosee if, using this method, we
(23:20):
can find DILI or if we can builda case series that is
clinically coherent.
And so we've been focusing moreon this latter part, because
this is an extensive work and tofind new DILI signals we still
need to do a bit more research.
But for now what we're doing istrying to see if with known
(23:42):
drugs, drugs that have beenknown for the past, I don't
know, 40- 50 years, those thatwe are very comfortable with
their safety profile, we can seethe patterns of DILI in their
clusters that we get fromvigiGroup.
And we compare, for example,drugs that we know are pretty
safe for the liver, so drugs notusually associated with DILI,
(24:05):
and we compare their clusterswith drugs that we know that
cause DILI.
And so we're trying to see ifthe patterns of clusters are
very distinct.
And so we're using a positiveand a negative control, and if,
within the clusters of drugsthat are associated with DILI,
if the clusters are clinicallycoherent – and so if the adverse
(24:28):
drug reaction terms that wefind within the clusters make
sense together.
And we'll see the results.
We hopefully will have positiveresults, but we still have to
work a little bit more on this.
Hopefully it will be useful atleast for case management, so
for signal assessors to have acase series that is more
(24:52):
specific and more manageable interms of human resources and
time.
Federica Santoro (24:57):
We have an episode on vigiGroup in our
archive, so people can listen tothat if they'd like to know
more about the method.
But for those who haven'tlistened to it yet, can you
explain briefly what theadvantage is, then, of using a
clustering algorithm compared totraditional pharmacovigilance
methods?
Rita Baião (25:15):
And so this clustering method will aggregate
reports.
So usually we start withdisproportionality analysis and
then we build a case seriesbased on the adverse drug
reaction that we found wasdisproportional.
But sometimes countries orreporters have different
(25:37):
reporting practices and so, forexample, if a patient has a
drug- induced liver injury, theywill complain of jaundice or
yellow eyes or pruritus.
But if it's the doctor that isreporting the same adverse drug
reaction, he will reporthepatitis or colostatic liver
(25:58):
injury.
Maybe if it's a pharmaceuticalindustry, they will report liver
enzymes abnormal or increased.
And so with vigiGroup, based onthe co-reported terms, we're
trying to see if we can groupthe reports that make sense
together and this can build caseseries that are more coherent.
(26:21):
And so for signal assessors andfor signal management it's much
more directed than just usingStandardised MedDRA Queries that
sometimes can be too broad.
Federica Santoro (26:33):
And again, for those who want to know more, go
dig in the archive.
We'll link to the vigiGroupepisode in the show notes as
well.
Well, that was all I had foryou, Rita, today.
Thank you very much for takingthe time to join me.
I wish you all the best inwrapping up your research here,
and we look forward to seeingthe results when available.
Rita Baião (26:54):
Thank you, Federica, and thank you for having me
here at UMC.
Federica Santoro (27:05):
That's all for now, but we'll be back soon
with more conversations onmedicines safety.
If you'd like to know moreabout drug-induced liver injury,
check out the episode shownotes for useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
(27:26):
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn and X, and
(27:51):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank Rita Baiãofor her time, Matthew Barwick
for post-production support, andof course you for tuning in.
(28:14):
Till next time.
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