Liver Toxic Medications and Cancer Risk

Transcript

00:00 --> 00:02Funding for Yale Cancer Answers is
00:02 --> 00:04provided by Smilow Cancer Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers with
00:08 --> 00:11your host doctor Anees Chagpar.
00:11 --> 00:12Yale Cancer Answers features the
00:12 --> 00:15latest information on cancer care by
00:15 --> 00:16welcoming oncologists and specialists
00:16 --> 00:19who are on the forefront of the
00:19 --> 00:20battle to fight cancer. This week,
00:20 --> 00:22it's a conversation about liver toxic
00:22 --> 00:25medications and cancer risk with doctors,
00:25 --> 00:27Amy Justice and Vin Lo Rey.
00:27 --> 00:29Dr Justice is the CNH Long professor
00:29 --> 00:31of medicine in general Medicine and
00:31 --> 00:34Professor of public health and health
00:34 --> 00:36policy at the Yale School of Medicine.
00:36 --> 00:38Doctor Lo Rey is an associate professor
00:38 --> 00:41of medicine and epidemiology at
00:41 --> 00:42the University of Pennsylvania,
00:42 --> 00:44and Doctor Chagpar is a professor
00:44 --> 00:46of surgical oncology at Yale.
00:47 --> 00:50Maybe I'll start with you doctor Justice.
00:50 --> 00:53Can you tell us a little bit about yourself,
00:53 --> 00:56your research, and what you do?
00:56 --> 00:59So I'm a general internist and
00:59 --> 01:01a clinical epidemiologist,
01:01 --> 01:04and I have spent my career using
01:04 --> 01:06VA electronic health record data,
01:06 --> 01:09which is the paperless electronic health
01:09 --> 01:13record that the VA keeps nationally on.
01:13 --> 01:15Everyone who gets care in the system to
01:15 --> 01:17try to study important chronic diseases,
01:17 --> 01:20including HIV and cancer.
01:20 --> 01:21Among others,
01:21 --> 01:23and I've had the great pleasure of
01:23 --> 01:24being able to collaborate closely
01:24 --> 01:27with a number of wonderful investigators,
01:27 --> 01:29Vin Lo Rey being one of them so
01:29 --> 01:32that we can really leverage that
01:32 --> 01:35data to understand how best to
01:35 --> 01:37care for people using real-world
01:37 --> 01:39data in real world settings.
01:40 --> 01:41That's a very nice
01:41 --> 01:43segue for you, Doctor Lo Rey.
01:43 --> 01:45Tell us a little bit about
01:45 --> 01:47yourself and what it is that
01:47 --> 01:49you do and your research.
01:50 --> 01:53Yeah, so I'm an infectious disease
01:53 --> 01:55physician and clinical epidemiologist
01:55 --> 01:57at the University of Pennsylvania
01:57 --> 02:02and my focus has been on evaluating
02:02 --> 02:05factors associated with acute and
02:05 --> 02:08chronic liver disease progression.
02:08 --> 02:12Also using real-world electronic health
02:12 --> 02:16record or administrative claims data.
02:16 --> 02:20I, as of a infectious disease
02:20 --> 02:23physician care primarily for patients
02:23 --> 02:26with chronic viral hepatitis or
02:26 --> 02:29with or without HIV COINFECTION,
02:29 --> 02:32and my goal has been to try
02:32 --> 02:34to reduce the risk of adverse
02:34 --> 02:37outcomes in these populations.
02:37 --> 02:38So
02:38 --> 02:40Amy, one question that I always
02:40 --> 02:43start off with and it's a
02:43 --> 02:45little tangential to where this
02:45 --> 02:47conversation will ultimately take us,
02:47 --> 02:49but tell me a little bit more about
02:49 --> 02:51how this collaboration formed.
02:51 --> 02:53I'm always interested in how
02:53 --> 02:55people from different backgrounds,
02:55 --> 02:57different institutions can kind
02:57 --> 02:59of get together to make really
02:59 --> 03:01meaningful collaborations.
03:01 --> 03:03So can you tell us a little
03:03 --> 03:04bit more about how you met?
03:05 --> 03:06Sure, happy to do that.
03:07 --> 03:08One of the things
03:08 --> 03:12that working with the VA national
03:12 --> 03:14database has allowed me to do is to
03:14 --> 03:16provide a resource to other people
03:16 --> 03:18who want to ask clinically relevant
03:18 --> 03:20questions and get a little guidance
03:20 --> 03:23from me about how to do that.
03:23 --> 03:25Then and I met in two ways.
03:25 --> 03:28One was I had been at his alma
03:28 --> 03:30mater or where he is now,
03:30 --> 03:31University of Pennsylvania for a
03:31 --> 03:33number of years and actually worked
03:33 --> 03:35with one of his mentors, Brian Strom.
03:35 --> 03:39So he he knew of me through Brian,
03:39 --> 03:40I believe, and also through the
03:40 --> 03:41University of Pennsylvania.
03:41 --> 03:44And we also attended an international
03:44 --> 03:47meeting of people who work with
03:47 --> 03:49large cohorts called I WAD,
03:49 --> 03:51which is always held someplace in
03:51 --> 03:53Europe in the offseason so that
03:53 --> 03:56we can get lower rates on hotels.
03:56 --> 03:58And it's a small group of people,
03:58 --> 04:00about 100 people who all work
04:00 --> 04:01with observational data.
04:01 --> 04:04Real-world data to try to understand
04:04 --> 04:05issues around health outcomes,
04:05 --> 04:06particularly in people with
04:06 --> 04:08HIV and hepatitis C.
04:08 --> 04:09But the methodologic issues are
04:09 --> 04:11relevant for other questions as well.
04:13 --> 04:16So, so then let's pick up that conversation.
04:16 --> 04:18You had mentioned that you're
04:18 --> 04:19an infectious disease.
04:19 --> 04:21Doctor, you're particularly
04:21 --> 04:24interested in hepatitis and HIV.
04:24 --> 04:27So tell us a little bit more about how
04:27 --> 04:29this kind of coincides with cancer.
04:31 --> 04:35Yeah well so. As an infectious disease
04:35 --> 04:38physician caring for people with HIV and
04:38 --> 04:41viral hepatitis very early on in my career,
04:41 --> 04:46I was observing that many of them were
04:46 --> 04:49dying from advanced liver disease.
04:49 --> 04:50Either decompensated
04:50 --> 04:53cirrhosis or liver cancer.
04:53 --> 04:57And particularly in the setting of HIV,
04:57 --> 05:00chronic hepatitis B or C
05:00 --> 05:02really is accelerated.
05:02 --> 05:04There's an accelerated progression
05:04 --> 05:07of liver fibrosis to cirrhosis.
05:07 --> 05:12And then once cirrhosis develops,
05:12 --> 05:14there's a very rapid
05:14 --> 05:16progression to liver cancer.
05:16 --> 05:18What Amy and I have discovered
05:18 --> 05:19over the past several years,
05:19 --> 05:23specifically focusing on HIV
05:23 --> 05:26related hepatocellular carcinoma,
05:26 --> 05:30is that HIV viremia,
05:30 --> 05:33independent of other traditional factors,
05:33 --> 05:37is a really important determinant.
05:37 --> 05:41Of of primary liver cancer and
05:41 --> 05:45we've analyzed HIV VIRAEMIA in
05:45 --> 05:49many different ways to really
05:49 --> 05:54provide the first evidence that HIV
05:54 --> 05:57VIRAEMIA is an important reason
05:57 --> 06:00why this subgroup is observed.
06:00 --> 06:04To have such a high rate of of liver cancer.
06:04 --> 06:05So that's sort of the the link,
06:06 --> 06:07and he said if I can just
06:07 --> 06:08jump in there because I think.
06:08 --> 06:10But it points to a larger issue
06:10 --> 06:12which is relevant for cancers.
06:12 --> 06:14More generally, overtime we've come
06:14 --> 06:17to appreciate that any number of
06:17 --> 06:19chronic viral infections are associated
06:19 --> 06:21with risk of cancer in the future,
06:22 --> 06:24and HIV is just one of the more recent ones.
06:24 --> 06:26There's a there's a whole list of
06:26 --> 06:28viruses that are associated with cancer,
06:28 --> 06:31and this is not that well
06:31 --> 06:33appreciated by the general public.
06:33 --> 06:36So when people talk about getting
06:36 --> 06:37vaccinations to avoid cancer,
06:37 --> 06:39that's what part of what
06:39 --> 06:41we're trying to talk about.
06:41 --> 06:44And by studying HIV and its
06:44 --> 06:45association with cancer,
06:45 --> 06:47we also hope to gain insights
06:47 --> 06:48into these other viruses as well.
06:50 --> 06:56And so. So, so that's a good a good point.
06:56 --> 06:59So back to you've in you know when we
06:59 --> 07:03talk about HIV viremia increasing the risk
07:03 --> 07:07of of hepatocellular or liver cancers.
07:07 --> 07:10What I mean is there what's
07:10 --> 07:12the downstream effect of that?
07:12 --> 07:16I mean, is it that we we don't currently,
07:16 --> 07:19to my knowledge, have a vaccine against HIV?
07:19 --> 07:22Are there ways that we can reduce viral
07:22 --> 07:26load that we know would be beneficial in
07:26 --> 07:28terms of preventing hepatocellular cancer?
07:30 --> 07:33In fact, that's that's a key point that
07:33 --> 07:37you bring up that antiretroviral therapy,
07:37 --> 07:40which can suppress HIV.
07:40 --> 07:44Viraemia can reduce the rates of
07:44 --> 07:47primary liver cancer, and in fact,
07:47 --> 07:51whether you have HIV and hepatitis B or C,
07:51 --> 07:55Co infection or HIV alone,
07:55 --> 07:59durable suppression of HIV viremia.
07:59 --> 08:03Can really reduce risk of primary
08:03 --> 08:05liver cancer considerably.
08:07 --> 08:10And so, Amy, you know you had you
08:10 --> 08:13had mentioned vaccines and when
08:13 --> 08:15we think about liver disease,
08:15 --> 08:19certainly we have a hepatitis B vaccine.
08:19 --> 08:24Do we know that that actually prevents
08:24 --> 08:27people from getting a liver cancer,
08:27 --> 08:30or at least reduces their risk? It
08:30 --> 08:32substantially reduces their risk.
08:32 --> 08:34Hepatitis B infection is actually one of
08:34 --> 08:37the worst actors in terms of risk of.
08:37 --> 08:39Liver cancer, the associated risk
08:39 --> 08:41with hepatitis B is quite large,
08:41 --> 08:44so by getting the vaccine and
08:44 --> 08:45avoiding hepatitis B infection,
08:45 --> 08:47one can certainly decrease
08:47 --> 08:49one's risk of liver cancer.
08:49 --> 08:51Liver cancer, like most other cancers,
08:51 --> 08:54is a multi hit phenomenon.
08:54 --> 08:55So there's the issue of viral exposure
08:55 --> 08:57that we've just been talking about.
08:57 --> 09:00There's the issue of alcohol harmful
09:00 --> 09:03use of alcohol can also increase risk.
09:03 --> 09:05There's the risk of toxicity from other
09:05 --> 09:07medications, which Ben is focused on.
09:07 --> 09:09All of these factors can influence the
09:09 --> 09:11total risk that an individual faces,
09:11 --> 09:13and so we're trying to attack
09:13 --> 09:15this issue on multiple fronts.
09:17 --> 09:20And so I want to pick up on on
09:20 --> 09:22what you said Amy about medications
09:22 --> 09:24that are toxic to the liver,
09:24 --> 09:27but just to kind of round out the
09:27 --> 09:29discussion with regards to hepatitis,
09:29 --> 09:33I think one of the important
09:33 --> 09:35contributions that have been made
09:35 --> 09:38over the last several years is a
09:38 --> 09:41medication that purportedly can
09:41 --> 09:43actually eliminate hepatitis C.
09:43 --> 09:48Do we know that people who are treated with.
09:48 --> 09:52This medication can reduce their risk
09:52 --> 09:54even if they had hepatitis C. Even
09:55 --> 09:58yes, hepatitis C, direct acting
09:58 --> 10:01antiviral treatment can dramatically
10:01 --> 10:03reduce the risk of liver cancer.
10:03 --> 10:06Cure of hepatitis C really is
10:06 --> 10:09a key factor in decreasing risk
10:09 --> 10:13of liver disease and liver
10:13 --> 10:16cancer from chronic hepatitis.
10:16 --> 10:18These are therapies that are
10:18 --> 10:21taken orally once daily.
10:21 --> 10:24For 8 to 12 weeks and have a 95
10:24 --> 10:27plus percent cure rate and with
10:27 --> 10:30cure of chronic hepatitis C,
10:30 --> 10:32the risk of liver cancer dramatically
10:32 --> 10:34reduces over the long term.
10:34 --> 10:38So Amy, this brings us to the question of,
10:38 --> 10:40you know, if you already had hepatitis C,
10:40 --> 10:44but that you can take a drug which cures you,
10:44 --> 10:47you can reduce your risk of liver cancer.
10:47 --> 10:49So with all of these other
10:49 --> 10:50toxins that you mentioned,
10:50 --> 10:54whether it's alcohol or other drugs
10:54 --> 10:59that cause an injury to the liver.
10:59 --> 11:01These are those irreversible.
11:01 --> 11:04It sounds like these all might be
11:04 --> 11:06in fact reversible if they follow
11:06 --> 11:09the same kind of pattern as,
11:09 --> 11:11as with hepatitis C, is that right?
11:12 --> 11:15Well, that's a very important and
11:15 --> 11:17interesting question. As we age,
11:17 --> 11:20our bodies undergo a number of insults.
11:20 --> 11:22At some point, though,
11:22 --> 11:24the cumulative injury from those
11:24 --> 11:26insults on almost any organ
11:26 --> 11:28system in the liver is included.
11:28 --> 11:29Becomes largely irreversible,
11:29 --> 11:32so the trick is to try to catch
11:32 --> 11:35it before that happens and reverse
11:35 --> 11:37those behaviors or those exposures
11:37 --> 11:39before they cross that threshold
11:39 --> 11:42into a a more irreversible state.
11:42 --> 11:45We talk a lot about liver cirrhosis
11:45 --> 11:47and we used to think that even liver
11:47 --> 11:49cirrhosis was that liver cirrhosis
11:49 --> 11:51wasn't reversible to some extent.
11:51 --> 11:52It can be,
11:52 --> 11:55but obviously the earlier we intervene
11:55 --> 11:59and stop those exposures stop those harms.
11:59 --> 12:01The less likely this process
12:01 --> 12:02will become irreversible.
12:04 --> 12:06So then I wanna pick up the
12:06 --> 12:08conversation with you on medications
12:08 --> 12:11that are toxic to the liver.
12:11 --> 12:13I mean, we've all heard about
12:13 --> 12:16alcohol and I I think our listeners
12:16 --> 12:18know that alcohol certainly
12:18 --> 12:21is is toxic to the liver.
12:21 --> 12:23Maybe before we get to medications,
12:23 --> 12:25I'll ask you the question that
12:25 --> 12:27everybody is going to ask.
12:27 --> 12:29Is there a safe dose of alcohol
12:29 --> 12:31that is not toxic to the liver?
12:32 --> 12:34Well, I think that,
12:34 --> 12:36particularly with people with
12:36 --> 12:38pre-existing chronic liver disease,
12:38 --> 12:42there really may be no safe
12:42 --> 12:44level of of alcohol.
12:44 --> 12:47Amy and I had done a study several years
12:47 --> 12:50back where we looked at particularly
12:50 --> 12:54the extent of consumption of alcohol,
12:54 --> 12:57non hazardous, hazardous abuse,
12:57 --> 13:00dependence according to different
13:00 --> 13:02presences of hepatitis.
13:02 --> 13:05In HIV, and particularly for persons
13:05 --> 13:09with HIV and hepatitis coinfection,
13:09 --> 13:12even those who had non hazardous drinking,
13:12 --> 13:15it was associated with pretty substantial
13:15 --> 13:18advanced liver fibrosis and cirrhosis.
13:23 --> 13:24In those instances,
13:24 --> 13:26there really is no safe level of alcohol use.
13:27 --> 13:30Well, that certainly is a sobering
13:30 --> 13:32comment to end our first half of
13:32 --> 13:35our segment on and no pun intended.
13:35 --> 13:36But we're going to take a short
13:36 --> 13:38break for a medical minute.
13:38 --> 13:40Please stay tuned to learn more
13:40 --> 13:42about liver toxic medications and
13:42 --> 13:43cancer risk with my guests doctor
13:43 --> 13:46Amy Justice, and Doctor Vin Lo Rey.
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14:55 --> 14:58Welcome back to Yale Cancer Answers.
14:58 --> 15:00This is doctor Anees Chagpar and I'm
15:00 --> 15:02joined tonight by my guests doctor Amy
15:02 --> 15:04Justice and Doctor Vin Lo Rey.
15:04 --> 15:07We are learning about liver toxic medications
15:07 --> 15:11and the risk of developing liver cancer.
15:11 --> 15:13So then right before the break we
15:13 --> 15:16were starting to talk about some
15:16 --> 15:18of the medications that are toxic
15:18 --> 15:20to the liver and we talked about
15:20 --> 15:23the one that's the most ubiquitous,
15:23 --> 15:25which is alcohol,
15:25 --> 15:26but talk a little bit.
15:26 --> 15:28About medications that you found
15:28 --> 15:32are toxic to the liver and and how
15:32 --> 15:34that impacts on liver cancer.
15:35 --> 15:36Yeah, so you know,
15:36 --> 15:38we recognized that in this setting,
15:38 --> 15:42particularly of people with HIV,
15:42 --> 15:44Amy and I early on had recognized
15:44 --> 15:48that polypharmacy was quite common.
15:48 --> 15:51Polypharmacy is defined as
15:51 --> 15:55using five or more medications
15:55 --> 15:57outside of antiretroviral drugs.
15:57 --> 16:02And how these multiple other medications
16:02 --> 16:04that patients are prescribed,
16:04 --> 16:07how they may impact on?
16:07 --> 16:09Multiple different organ systems.
16:09 --> 16:13In particularly my interest in the liver.
16:13 --> 16:15You know, was something that
16:15 --> 16:17we really were focused on.
16:17 --> 16:19I think when we embarked
16:19 --> 16:21on studying liver cancer,
16:21 --> 16:23particularly in HIV,
16:23 --> 16:27we were interested in in exploring how
16:27 --> 16:31liver toxic medications might cause
16:31 --> 16:34either acute or chronic inflammation that
16:34 --> 16:38could exacerbate the risk of liver cancer.
16:38 --> 16:42And when we try to specifically
16:42 --> 16:44consider different.
16:44 --> 16:46Liver toxic drugs.
16:46 --> 16:48The classifications that really
16:48 --> 16:50existed were only based on
16:50 --> 16:52case studies and case reports,
16:52 --> 16:55and in fact the the National
16:55 --> 16:57Institutes of Health has a liver
16:57 --> 17:00tox website that assembles all of
17:00 --> 17:02the drugs with known hepatoxic,
17:02 --> 17:05either reports or or case series,
17:05 --> 17:08but no one has ever tried
17:08 --> 17:10to group those drugs.
17:10 --> 17:14Based on the likelihood of developing.
17:14 --> 17:17Liver injury or for that for that matter.
17:17 --> 17:21Liver cancer based on real world data
17:21 --> 17:25outside of just reports and so you know what?
17:25 --> 17:29What Amy and I wanted to do was to
17:29 --> 17:32utilize these existing categorizations of
17:32 --> 17:36apati toxic potential based on reports
17:36 --> 17:39and actually create real-world cohorts
17:39 --> 17:44of new initiators of these drugs.
17:44 --> 17:47From the standpoint of trying
17:47 --> 17:49to determine which had high
17:49 --> 17:52versus low rates of liver injury,
17:52 --> 17:55you see when you're using case reports,
17:55 --> 17:58you're ignoring the the denominator
17:58 --> 18:01data of of sort of the the.
18:01 --> 18:03The world of people who who are
18:03 --> 18:05actually using these drugs.
18:05 --> 18:07They're merely cases.
18:07 --> 18:11But if you have many users but just
18:11 --> 18:15very few cases, the rates of those.
18:15 --> 18:17Liver injury events is actually low,
18:17 --> 18:22So what Amy and I did was to identify
18:22 --> 18:25195 of the most hepatotoxic drugs
18:25 --> 18:28based on those that had at least
18:28 --> 18:31four or more reports of liver
18:31 --> 18:33injury in the medical literature.
18:33 --> 18:35Going back from the 1950s,
18:35 --> 18:38and we used the national VA data
18:38 --> 18:41to create new user cohorts of
18:41 --> 18:44each of these 195 drugs.
18:44 --> 18:47And we followed over a years time.
18:47 --> 18:50The rate of liver injury,
18:50 --> 18:53which we classified as severe.
18:53 --> 18:57Based on you know serious liver dysfunction.
18:57 --> 19:01And and using that approach we were
19:01 --> 19:05able to create a new hierarchy or
19:05 --> 19:09tiers of drugs that can cause liver
19:09 --> 19:13injury and what we found was 39 of
19:13 --> 19:17those drugs out of the 195 were had
19:17 --> 19:23rates that were fairly high for liver injury.
19:23 --> 19:23And interestingly,
19:23 --> 19:26the majority of almost half of
19:26 --> 19:28those jugs were antimicrobial.
19:28 --> 19:32Drugs so antibiotics, antivirals,
19:32 --> 19:33antifungals.
19:33 --> 19:36And our approach to using these
19:36 --> 19:38from a real world data standpoint
19:38 --> 19:41was now that we have a group of
19:42 --> 19:44drugs that we know are associated
19:44 --> 19:46with higher rates of liver injury.
19:46 --> 19:49We can now explore those in in terms of
19:49 --> 19:53their risk of developing liver cancer,
19:53 --> 19:57and these might be drugs that
19:57 --> 19:59could be evaluated
19:59 --> 20:02for for safety signals in many
20:02 --> 20:04different integrated delivery systems
20:04 --> 20:07like the VA you could create.
20:07 --> 20:10Electronic alerts to warn health
20:10 --> 20:13care providers to monitor patients
20:13 --> 20:16more closely on these drugs,
20:16 --> 20:17and I think future studies to
20:17 --> 20:19look at combinations of these
20:19 --> 20:21drugs and their risk of liver
20:21 --> 20:22injury will also be valuable.
20:23 --> 20:26So Amy, let me ask you a question.
20:26 --> 20:28I mean, you just that.
20:28 --> 20:31That explanation by VIN was
20:31 --> 20:32certainly enlightening,
20:32 --> 20:35but a lot of people you
20:35 --> 20:36know take antibiotics.
20:36 --> 20:38They might have, you know,
20:38 --> 20:41a touch of pneumonia or a urinary
20:41 --> 20:43tract infection and they they take
20:43 --> 20:44their week of antibiotics and
20:44 --> 20:46their doctors always tell them.
20:46 --> 20:48Make sure you finish the
20:48 --> 20:50whole week because we don't
20:50 --> 20:52want resistance to occur.
20:55 --> 20:57Did you find a dose response?
20:57 --> 20:59Like if you take, you know,
20:59 --> 21:02a course of antibiotics once in
21:02 --> 21:05your lifetime, does that really
21:05 --> 21:07increase your risk of liver injury
21:07 --> 21:09and liver cancer over that lifetime?
21:09 --> 21:12Or is it more the people who are
21:12 --> 21:14taking antibiotics on a regular basis?
21:14 --> 21:17That really increases the risk.
21:18 --> 21:20Well, certainly regular exposure would
21:20 --> 21:24be the bigger concern, but in terms of.
21:24 --> 21:27Trying to conduct this research in a
21:27 --> 21:30fairly clear way, we needed to start
21:30 --> 21:32with people who had not been exposed
21:32 --> 21:33and then look at initial exposure,
21:34 --> 21:36since that's one of the highest
21:36 --> 21:37risk periods for injury, right?
21:37 --> 21:39People who have very serious injury
21:39 --> 21:41are going to stop the medication.
21:41 --> 21:43Now that we have identified
21:43 --> 21:45which ones have the most signal,
21:45 --> 21:47we want to go on and look at OK.
21:47 --> 21:50If people actually do have chronic exposure
21:50 --> 21:53and a more low level signal for injury,
21:53 --> 21:55do we see cumulative effects?
21:55 --> 21:57So you make an excellent point in each,
21:57 --> 22:00but the initial study really had to look
22:00 --> 22:02at people who had not been previously
22:02 --> 22:04exposed and then look at acute exposure.
22:04 --> 22:05Yeah,
22:05 --> 22:08and so then you mentioned that the
22:08 --> 22:11majority of these 39 top offenders.
22:11 --> 22:17Were in the antimicrobial kind of spectrum.
22:17 --> 22:19One of the drugs that a lot of people
22:19 --> 22:22know about use a lot and and we all kind
22:22 --> 22:25of think about in terms of liver injury.
22:25 --> 22:29Is acetaminophen plain old Tylenol?
22:29 --> 22:32Did you find that that ranked among
22:32 --> 22:35the highest or or was that in the
22:35 --> 22:37rest of the the population of drugs?
22:37 --> 22:40That really was not as toxic as you
22:40 --> 22:42might have thought to begin with?
22:43 --> 22:45Well, acetaminophen really causes its
22:45 --> 22:48toxicity in a dose dependent fashion,
22:48 --> 22:53so as long as the doses of the
22:53 --> 22:57acetaminophen are not at high at high doses,
22:57 --> 23:00then the the risk is generally low.
23:00 --> 23:04I would say that.
23:04 --> 23:06For those with pre-existing
23:06 --> 23:07chronic liver disease,
23:07 --> 23:10lower doses of acetaminophen
23:10 --> 23:13is is more advantageous because
23:13 --> 23:16with compromised livers the risk
23:16 --> 23:19of liver injury is much higher.
23:21 --> 23:23And and then raises a good point,
23:23 --> 23:25Amy, which is, you know,
23:25 --> 23:27and you had mentioned it before as well,
23:27 --> 23:30is that there is this kind of more
23:30 --> 23:32than one hit to to your liver.
23:33 --> 23:36And so when you did this study and you
23:36 --> 23:39were looking at people who had initiated
23:39 --> 23:41a potentially hepato toxic drug,
23:41 --> 23:44did you kind of stratify these patients by
23:44 --> 23:47other things that might put them at risk?
23:47 --> 23:49Whether that was alcohol use
23:49 --> 23:51or underlying fatty liver?
23:51 --> 23:54Or even happy *******.
23:54 --> 23:58So the answer to that is yes.
23:58 --> 24:00In fact, one of the things that
24:00 --> 24:02seems to be relevant for any number
24:02 --> 24:04of adverse outcomes is simply
24:04 --> 24:06how many medications are you on,
24:06 --> 24:07even after you adjust for
24:07 --> 24:09how sick someone is.
24:09 --> 24:10Physiologically, you know how much
24:10 --> 24:12organ system injury do they appear
24:12 --> 24:14to have based on laboratory data
24:14 --> 24:16and other clinical evaluations.
24:16 --> 24:18Simply counting up how many
24:18 --> 24:19chronic medications they are on,
24:19 --> 24:22especially when they get beyond five or ten,
24:22 --> 24:25has a very strong association with
24:25 --> 24:28any number of adverse health outcomes.
24:28 --> 24:30And that's one of the reasons why Vin was
24:30 --> 24:33talking about polypharmacy a few minutes ago.
24:33 --> 24:35It's very important to interpret exposures
24:35 --> 24:38in the context of how susceptible
24:38 --> 24:40to injury are you at that moment.
24:40 --> 24:42And if you're already on a lot
24:42 --> 24:44of medications and already have
24:44 --> 24:45evidence of liver injury,
24:45 --> 24:47you are highly susceptible to
24:47 --> 24:49injury from another exposure.
24:49 --> 24:51But I think in a niche what
24:51 --> 24:53you you bring up a good a good
24:53 --> 24:56question for this initial analysis,
24:56 --> 24:59we chose to specifically exclude
24:59 --> 25:02individuals with either viral hepatitis
25:02 --> 25:05or other non viral chronic liver diseases,
25:05 --> 25:08and even amongst those who
25:08 --> 25:10did not have diagnosed.
25:10 --> 25:11Chronic liver disease.
25:11 --> 25:14We looked in the year prior to their
25:14 --> 25:16initiation of the drug to see if
25:16 --> 25:19they had any evidence of any liver
25:19 --> 25:21aminotransferase abnormalities or any
25:21 --> 25:25any end of any evidence of of liver
25:25 --> 25:28inflammation and excluded those individuals.
25:28 --> 25:31So the the population that we studied,
25:31 --> 25:33at least at the outset,
25:33 --> 25:36was those who did not have
25:36 --> 25:37pre-existing liver disease,
25:37 --> 25:39either diagnosed or for that matter,
25:39 --> 25:40non diagnosed and.
25:40 --> 25:43And it was really when we presented
25:43 --> 25:46these results at to the FDA's division
25:46 --> 25:49of Hepatology that they really advocated
25:49 --> 25:52that we go the extra mile to really
25:52 --> 25:55exclude individuals who may have
25:55 --> 25:57as yet undiagnosed liver disease.
25:57 --> 26:00To ensure that this was an in a group
26:00 --> 26:02that wasn't necessarily at higher risk,
26:02 --> 26:04such as Amy had mentioned those
26:04 --> 26:05with pre-existing liver disease.
26:06 --> 26:08And so I mean all of this work
26:08 --> 26:10is is incredibly interesting,
26:10 --> 26:14but it begs the question and then what?
26:14 --> 26:17So you know, people who are on five or more
26:17 --> 26:20medication certainly are at increased risk,
26:20 --> 26:22but presumably they're on those
26:22 --> 26:23medications because they're needed.
26:23 --> 26:25If they're not needed,
26:25 --> 26:27then the obvious answer to the what
26:27 --> 26:29happens next is you get rid of the
26:29 --> 26:31medications that you don't need.
26:31 --> 26:34But for the people who really do need,
26:34 --> 26:36you know their antihypertensive
26:36 --> 26:38medication and maybe there.
26:38 --> 26:41Their insulin and and their
26:41 --> 26:43statin and whatever else.
26:43 --> 26:45And they're they're on,
26:45 --> 26:46say 5 medications that
26:46 --> 26:48they they truly do need.
26:48 --> 26:51And we know that polypharmacy would put
26:51 --> 26:53you at increased risk of liver disease.
26:53 --> 26:56What should physicians and patients do?
26:56 --> 26:57Amy like?
26:57 --> 26:58What's the answer?
26:59 --> 27:02Well, so anisha it's you know,
27:02 --> 27:03in the best of all possible worlds,
27:03 --> 27:05there would be one Doctor Who's
27:05 --> 27:08really helping to manage the total
27:08 --> 27:10picture for the patient in the room.
27:10 --> 27:12But the reality of our health care system
27:12 --> 27:14is that that is often not the case.
27:14 --> 27:17People see a number of different specialists.
27:17 --> 27:20And each of those specialists looks at
27:20 --> 27:22the patient and their list of medications
27:22 --> 27:24only with a view to the particular
27:24 --> 27:26organ system that they're treating.
27:26 --> 27:29Further, the guidelines for how we
27:29 --> 27:31recommend managing people with various
27:31 --> 27:33diseases in our country have been
27:33 --> 27:35developed with a similar neurofocus.
27:35 --> 27:37As a result,
27:37 --> 27:41people end up being on a lot of medications,
27:41 --> 27:43sometimes without each of the physicians
27:43 --> 27:46being totally aware of all the other
27:46 --> 27:47medications that the person is on.
27:47 --> 27:48And that's.
27:48 --> 27:49Part of the reason we've
27:49 --> 27:50gotten into this quandary,
27:50 --> 27:52so believe it or not,
27:52 --> 27:54the first step really is a total
27:54 --> 27:55view of the medication list and
27:55 --> 27:57decisions about what medications
27:57 --> 27:59are truly indicated for this
27:59 --> 28:00person and which ones are not.
28:01 --> 28:03Doctor Amy Justice is the CNH long
28:03 --> 28:05professor of medicine in general
28:05 --> 28:07medicine and professor of public
28:07 --> 28:09health and health policy at the Yale
28:09 --> 28:11School of Medicine and Doctor Van
28:11 --> 28:13Lowrey is an associate professor
28:13 --> 28:15of medicine and epidemiology at
28:15 --> 28:17the University of Pennsylvania.
28:17 --> 28:18If you have questions,
28:18 --> 28:20the addresses cancer answers at
28:20 --> 28:23yale.edu and past editions of the
28:23 --> 28:25program are available in audio and
28:25 --> 28:27written form at yalecancercenter.org.
28:27 --> 28:29We hope you'll join us next week to
28:29 --> 28:31learn more about the fight against
28:31 --> 28:33cancer here on Connecticut Public Radio.
28:33 --> 28:35Funding for Yale Cancer Answers is
28:35 --> 28:37provided by Smilow Cancer Hospital.

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January 9, 2022

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