药物性肝损伤(dili)综述 共3篇

药物性肝损伤(dili)综述 共3篇 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- 药物性肝损伤(DILI)综述 共3篇 Drug-Induced Liver Injury An on-demand webinar Christopher Spitters, MD, MPH Curry International Tuberculosis Center Oakland, California October 16, 2013 00:00:00 [James Sederberg] 00:00:01 It is now my pleasure to introduce the faculty for today’ s seminar, Dr. Christopher Spitters. Chris has worked as faculty for over eight years, teaching at both our Seattle and Bay Area based clinical intensives, as well as serving as a medical consultant on our TB Warmline service. He’s also worked as part of Curry’s International wing, helping develop training programs in Suriname where he continues to serve as medical consultant for the national TB program there. Since 1993 he has been the medical director for Public Health Seattle and King County TB Clinic. Also serves as health officer for four other large Washington State counties, and is a clinical professor in the Department of Medicine at University of Washington. So we’re very proud to have him here today from his office in 1 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- Seattle to present on this important topic. Chris„ [Dr. Christopher Spitters] Thank you very much James for that kind introduction and the invitation to speak. I’m delighted to be a part of the program and spend some time with you today speaking about drug-induced liver injury and I also want to thank Monterey County for raising this as an important issue, that not only they but other listeners can learn from. So we have quite a bit to talk about and I want to leave some room for questions at the end. So without further ado, let’s proceed. 00:01:24 First, by the end of our time today I’d like you to feel like you’ve increased your ability to identify symptoms suggestive of anti-TB drug-induced liver injury, to implement appropriate medical management of patients identified with liver injury, and as well to identify TB patients who from the start of therapy are candidates for either liver-sparing regimens or at least very close monitoring of hepatic function. So let’s begin with a case. This is a 37-year-old recent immigrant from a high-risk country who was diagnosed with inactive pulmonary TB based on stable right upper lobe fibrosis, as you can see there in the figure, a positive tuberculin skin test and negative sputum AFB examination on smear and culture. 2 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- He had no reported risk factors for hepatotoxicity, did not drink alcohol, and per routine was started on Isoniazid therapy daily, self-administered at home with monthly follow up visits. At the first two monthly follow up visits he reported no adverse effects, the next month was dispensed, and on things went„ 00:01:57 00:02:45 until midway through the third month he returned to clinic as a walk-in patient and reported that his family had suggested he come in because he looked tired, had not been eating for several weeks, and his sclera were now yellow- he looked jaundiced. So on evaluation in the clinic that day his sclera were enteric, his skin is brown so it was harder to pick up the jaundice there. He had mild right upper quadrant tenderness and epigastric tenderness on exam, and otherwise had an unremarkable exam. LFTs were drawn- and you see the results there. Transaminases were elevated approximately ten times the upper limit of normal and the total bilirubin was about two times the upper limit of normal. At that time, because this represents severe liver injury, with these indiceselevated transaminases above three to five times the upper limit of normal and total bilirubin at least twice the upper limit of 3 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- normal- he has about a ten percent risk of progressing to fulminant hepatic necrosis and death unless he’s able to get a transplant, which on that timeline is very difficult. Nevertheless, he declines hospitalization and so we negotiated a two-day follow up with him back in the clinic. At that time his transaminases had gone even higher, and he was more jaundiced- clinically as well as you can see in his blood work with a total bilirubin of seven, mild elevation of alkaline phosphatase, albumen still relatively normal, and at that time because of our heightened concern about his climbing transaminases as well as his noting that he’s tired and not eating and grossly jaundiced, he accepted referral to a tertiary medical center here that we’re affiliated with. On further evaluation there, his PT INR was prolonged, that’s indicating that hepatic synthetic function is being impacted. Ammonia was not elevated – that’s a marker of detoxification function of the liver. When ammonia climbs that’s a signal of impending liver failure. It also gets into the brain and alters mental status. So his viral hepatitis serologies were negative, aside from hepatitis A immunity and he had an abdominal ultrasound that was consistent with an acute hepatitis. So this gentleman has severe drug-induced liver injury due to Isoniazid 4 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- and a roughly ten percent risk of mortality. There’s no specific intervention, other than admission to the hospital, close monitoring, so that if he begins to deteriorate then there’ s a chance to get him set up for a transplant. There’s no specific medical therapeutic intervention here besides supportive care: acetylcysteine has only been shown to be definitively helpful in acetaminophen toxicity. Some clinicians will still try it in this setting, in fact it was used in his setting, it’s not clear whether that contributed to his outcome or not. But acetaminophen toxicity is the only acute drug-induced liver injury for which acetylcysteine is indicated. As a side bar, valproic acid toxicity also is amenable to L-Carnitine; L-Carnitine as sort of an antidote. 00:04:10 Well while this patient is being observed let’s- and we’ ll come back to him- let’s turn our attention to„ 00:06:49 the entire spectrum of anti-TB drug-induced liver injury. And I just want to review for you the general classes of liver injuries that occur. You’ll see on the fourth row there HC stands for hepatocellular- that’s our patient we’re talking about now- case one- he has severe hepatocellular injury. But before we come to that, let’s just start at the top and talk 5 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- about the most common transaminases abnormality, which is a mild low level – less than three times upper limit of normal, rise in serum transaminases. Not associated with jaundice or hyperbilirubinemia and not associated with symptoms. It’s a transient, limited cellular injury that occurs in the liver while adaptation is occurring, which I’ve read as being best characterized as: the up regulation of survival enzymes involved in oxidation, conjugation, and excretion of toxins. So during the initial month or two of therapy with Isoniazid, for instance, about 20% of patients will develop this if you look for it. When you encounter it, clinical management is just continued clinical monitoring, judicious use of transaminases testing, based on the patient’s underlying risk factors and clinical status, and proceed with therapy without interruption. When we progress to hepatocellular injury, that is not transient in time and space in the liver, but continues, than that typically, it can be asymptomatic, even up to the moderate category I’ll mention in a minute. But more commonly patients begin to experience fatigue, anorexia as the initial cardinal symptoms that then can progress to abdominal pain, nausea, and then ultimately to jaundice. Enteric manifestations like dark urine and light stools all related to the impact of a liver 6 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- injury on the ability to conjugate and excrete bilirubin, but with mild hepatocellular liver injury you don’t see any of those abnormalities, it’s just usually fatigue, anorexia, maybe some nausea and abdominal pain, and transaminases that are elevated in the three to five times the upper limit of normal range. Now that’s an indication for interrupting therapy, and then following the patient at roughly weekly intervals to assess their return to baseline status. And when they do that, there’ s no sequelae that one would anticipate from that occurring and they are then relatively proscribed from reusing that causative agent and if it’s imperative you would look at treating with another agent. Hepatocellular injury that is moderate is similar in clinical presentation to what I described above, but more likely patients will be symptomatic, again with fatigue, anorexia, malaise, being the initial constellation of symptoms. Transaminases in this setting are elevated 5-10 times the upper limit of normal, so that’s like the 250-500 range. Bilirubin is variable- if it’s elevated, usually only minimally so. It’ s unusual for these patients to be jaundiced or to have prolonged clotting times- or prolonged coagulation times. But clinical management is essentially the same. Stop the offending agent, and follow them at weekly intervals to 7 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- improvement. Sometimes if the levels are up toward 500, we’ ll do an initial follow up LFTs in just a couple of days, just to make sure they are not continuing to climb. Then we come to the syndrome we’re seeing in case one, which is severe hepatocellular injury- again the constellation of symptoms I described abovebut in this setting typically the patient has progressed to enteric manifestations of jaundice- dark urine, light stools- along with all the others I’ve mentioned, and if they are in acute hepatic failure and not detoxifying they may also have mental status changes as that progresses to fulminant hepatic necrosis other phenomena including bleeding, Ascites, or Anasarca can occur and as I said altered mental status; the hepatic function is severely impaired, and this patient is at high risk for death. Again, the intervention is to stop therapy, but the difference between this and lower levels of injuries, that that patient merits admission for hospital care. OK, now let’s downshift a little bit in terms of anxiety and health risks to cholestatic liver injury, which should still merit intervention, but instead of being characterized by hepatocyte cell death- typically this is a dysfunction of bilirubin conjugation and/or excretion into the bile canaliculi and it’s only rarely associated with 8 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- significant transaminases elevations. Usually they’re less than five times, or even three times the upper limit of normal, otherwise there’s no impairment of coagulation times or albumen. The typical culprit there is Rifampin- I’ll cut to the chase with that- and if the bilirubin continues to climbthat needs to be interrupted. 00:12:41 We’ll go to the next slide and now that we’ve classified these liver injuries- I’m gonna talk in general terms about relative incidence and risk of liver injury with use of anti-TB agents. It’s also important to keep in mind that of the whole constellation of acute liver injury, due to drugs, which is now the leading cause of acute liver failure in the United States, anti-TB drugs are but a minority. Other drugs: acetaminophen is the leading one, but also amoxicillin coagulanate, other penicillins, sulfonamides, amiodarone, and a host of other drugs are in the aggregate- much more common than TB drug-induced liver injury, I just want to mention that, and let’s focus back in on anti-TB drugs. So adaptation is most commonly associated with Isoniazid because I think that‘s where we encounter it. But it probably occurs as well in the context of treatment for active disease with multiple drugs and as I mentioned earlier, we see that about 20% of the time. In patients being treated for active TB, (I’ 9 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- m gonna use the pointer here) with four drugs the incidence of drug-induced liver injury varies widely, estimates as low as 5%-I’ve seen as high as 25%- but the general range is 5-15%. Last year in the clinic I work in we had seven cases among about 80 patients treated, so just under 10%. Isoniazid mono therapy- a much rarer cause of severe liver injury- maybe 1 in 1,000 to 1 in 200 with ideal clinical monitoring and judicious use of LFTs – those figures come out of the King County TB Clinic, San Diego County, and a program in Tennessee in the past couple of decades. The highest risk agent is Pyrazinamide which is associated with, by deduction we find it to be the most common cause in drug-induced liver injury associated with active disease and then when we see it paired up with other drugs for treatment of latent TB; for instance, the old transiently recommended regimen from about a decade ago of Rifampin/Pyrazinamide that is now off the books and contraindicated because of this: about 5-10% of patients developed liver injury and PZA tends to cause a more severe and lasting liver injury than Isoniazid or Rifampin. Rifampin intermediate in risk in terms of data; I have to admit in my personal experience I see Rifampin as a relatively low risk agent that merits monitoring when it’s used 10 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- in patients with risk factors for liver injury but I see it causing less – you know most patients who have liver injury tolerate it on reintroduction and most patients, the vast majority of patients who take it for latent TB have no problem. So I view it as a relatively benign agent that should be used judiciously and cautiously in patients with liver injury, but nonetheless can be used. Last among the commonly used TB medicines or somewhat commonly, Ethionamide the second-line drug is the one most commonly associated with drug-induced liver injury- about 1 in 50 patients. Other second- line drugs not commonly associated with drug-induced-liver injury, and in fact, these three fluoroquinolones, Levofloxacin or Moxifloxacin, Ethambutol and Streptomycin, form the core of what we call a liver-sparing regimen and we’ll discuss that later. Not that liver injury has never been reported with them, but it’s exceedingly unusual. And then last, cholestasis with Rifamycins, maybe 1 or 2% incidence. 00:17:03 So what other conditions might present with the symptoms I discussed earlieran abnormal transaminases or bilirubin. Or what other, these could also be factors that are concurrent with a drug-induced liver injury and then exacerbating it. Well, first and the most commonly in my experience is alcohol. Which it 11 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- appears to inhibit some of the adaptive mechanisms involved in oxidation and detoxification of drugs. It itself is directly hepatotoxic. One of the keys to separating out drug-induced liver injury from alcohol-induced toxicity is that the AST tends to be higher than the ALT, whereas the reverse tends to be true for other drug-induced liver injury; that’s not universal but it’s a general trend that you can plug in when you’re making an assessment of a patient. Second most common I think is acute or chronic viral hepatitis- hepatitis B and hepatitis C. Hepatic involvement with TB can present from the beginning with a cholestatic picture, typically bilirubin 2, 3, 4 and transaminases elevated but generally less than say 200. That’s particularly prominent in patients with miliary TB or other forms of dissemination. It’s always important to keep in mind acetaminophen which is unlikely to present in our setting as acute ingestion of a fatal dose, but asking about whether a patient has taken a lot or regularly taken acetaminophen, say for fever or joint aches associated with therapy. Then a host of other drugs that I discussed before, but most commonly in our setting, statins and anti-retrovirals, and then last but certainly not least would be just primary biliary disease, due to stones or other 12 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- obstructing phenomena. So when working up a patient with drug-induced liver injury, keep these things in mind, check for viral hepatitis serology, ask about alcohol. If you are getting a cloudy history add a GGT to the LFTs and consider whether this could be due to TB itself or other drugs. 00:19:31 So this is a little bit of a rehash of the last slide but as we’re looking at a patient and starting to prescribe anti-TB therapy, we have to ask ourselves what patients merit just clinical monitoring, which is everyone, clinical monitoring and education about reporting adverse effects and interrupting therapy until those adverse effects are assessed. And what patients merit periodic liver function testing? This is the group around which there’ s the most consensus: patients who have a high level of alcohol intake, which I’ve never actually read a good, clear number on ounces of alcohol per week or what have you, I generally use more than seven alcoholic drinks a week, but if those all seven are coming on the weekend, on one day, that’s probably more injurious and might lower your threshold for testing. Certainly alcohol intake that results in baseline transaminases elevations. Moving on: active, chronic active hepatitis B and C, other hepatotoxic drugs in the patient’s therapeutic regimen, anti-retroviral therapy, (I will note as an aside in the absence 13 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- of anti-retroviral therapy and Bactrim – there is no apparent elevated risk of drug -induced liver injury in HIV infected patients. In fact, in the study of the two months Rifampin/Pyrazinamide regimen which the studies were done in HIV infected patients, there were no reports of elevated risk of liver injury, it only occurred when that regimen was disseminated and used widely. Increasing age, particularly for Isoniazid, although I also suspect for Pyrazinamide, so as we go up a decade at a time in age, we go from essentially zero risk of liver injury in individuals under 20 years of age up to as much as 5 or 10% in patients who are 75, 80 years old. And the other age groups in between being intermediate. And then the pregnancy and the post-partum period is a period of elevated risk for drug-induced liver injury. Now, so those are patients in whom baseline and monthly LFTs are generally recommended and if a patient has active liver disease baseline transaminases elevations, let’s say less than three times the upper limit of normal that you would not interrupt therapy for, or withhold therapy for, you might modify therapy as we describe later, but you probably want to check them at two weeks and then if things are stable, go to the four weeks and Q4 weeks after that. Just for the purposes of discussion, not clinical 14 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- intervention or treatment policy, there have been reported data suggesting that women are at higher risk, that’s the preponderance of data, it’s not unanimous, but that’s what I see when I look at the literature. And then these next few bullets are actually connected- anectyltransforase acytelates, the reactive free radical intermediate that Isoniazid is oxidized to in the liver, and so this P450 2E1 is involved in that oxidation creating the reactive intermediate that is hostile to hepatocyte health and survival and anectyltransforase throws an acetyl group on that, not once but twice, and then that gets excreted. So it’s believed that slow acytelators have greater cumulative exposure to those reactive intermediates and so the polymorphisms between patients and potentially between population groups for these two enzymes may be predictive of risk of liver injury. I see a question- “How long is the post-partum period” – I’m jumping back, I just looked down at that question. Generally out to three months post-partum. It may not be quite that long, but we pick a generous window. I’m gonna proceed to the next slide. 00:24:07 We’re gonna turn back to case one, who’s now been in the hospital- let’s say for a week- and what you’re gonna see in the upper left window here is his transaminases trend. Which 15 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- promptly went down upon withdrawal of Isoniazid and got below the critical levels within several weeks and then returned to normal within about 6-8 weeks. That’s what you see when the offending agent is withdrawn. Better yet we saw his detoxification function here as manifested as bilirubin decline in a biphasic fashion, where it returned to normal – was prolonged- it took him a couple of months for him to get there. Synthetic function also returned with return of PT INR down to the normal range, or near normal range pretty quickly. And then again a biphasic improvement over time where he got back to normal. Similar pattern here with the albumen returned to normal. So he recovered. He was one of the 9 in ten that do not develop fulminant hepatic necrosis resulting in death. What would it look like if he had? Alright so that’s this slide, and this is just a duplicate of the prior slide but I’ve introduced some red dotted lined here. Showing you where things tend to go under that circumstance. So the transaminases still declined because the inciting agent is withdrawn, cell death ceases but if there’s insufficient organ reserve then the detoxification and synthetic functions are permanently impaired. The abnormalities persist and increase- that’s the patient that progresses to hepatic encephalopathy, bleeding 16 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- manifestations, ascites, and ultimately death in the absence of transplant. Which, in this timeline, is generally low- fortunately I’ve only seen this a couple of times, but it’s a- even those are unfortunate. But along the course of about 6-8 weeks after the initial injury is recognized, is when the patient tends to succumb to these complications. OK, next slide. 00:26:43 So turning back to case one, just what are our options with him? He’s just had a harrowing experience and not too many people are game for treating an asymptomatic condition that might one day result in active TB, right? He’s got inactive TB, assuming the two months of INH didn’t severely reduce, or didn’t significantly reduce his risk of future TB. He’s probably looking at about a 1% per year risk of developing active TB. Maybe a little bit less, he’s about 40 years old, lifetime risk is still substantial, but many patients will just elect to not proceed. In his case he was concerned about developing active TB, but didn’t want to take more therapy, and you know we were reticent likewise. Our tendency is to want to wait and see what happens with him and treat him if he develops active disease – we did some active monitoring, quarterly clinical exams, and radiographs and he passed through that time stably without 17 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- reactivation and then, now that he was feeling better and a bit out from that experience, he did request treatment. And so we treated him with what I consider the leading choice for liver-sparing regimen for latent or inactive TB, which is Rifampin. Rifabutin is also an option- out of our center here we’ve reported that patients who cannot tolerate Rifampin even, due to liver injury, have about an 80% completion rate without adverse effects from Rifabutin; that’s observational data, that’s retrospective, there’s no clinical trials at this point, but our data is some suggestion that patients who have a problem with Rifampin can tolerate Rifabutin. As a sidebar, when the reason for interrupting Rifampin was due to hypersensitivity- rash and such, Rifabutin was not so useful. And then if the patient for some reason is not a candidate for Rifampin –let’ s say drug interactions or ongoing transaminases elevations, for another reason, but you still really want to treat them because let’s say that they are going to be immunosupressed for some reason- you could go off guideline and sort of manage them as you would an MDR latent TB patient using what are these liver sparing regimens say Moxifloxacin or Moxifloxacin and ethambutol. I see a question- “Is it necessary to follow both AFT and ALT levels in patients with active TB or LTBI. The 18 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- guidelines suggest either one or the other. I’m going to speak to you practically, first, ALT is the preferred I think because AFT is the more non-specific. Hemolysis, other phenomena can lead to elevated AFT, that’s less specific for liver injury than ALT. So if you’re gonna follow one, use the ALT. But I just order a panel of hepatic function value because the cost difference between ordering an ALT and a full panel of LFTs as a marginal cost over the whole cost of engaging the patient is pretty negligible. So I’m an advocate for just doing an LFT panel. There’s another question about patient education and informed consent with respect of liver injury- I’m gonna come to that later in the discussion. But not too far from now. “What is the treatment regimen for Moxifloxacin- 400mg a day for 6-12 months. There’s no real outcome, systematic outcome data with that yet, that’s just expert opinion level recommendations for treatment of latent TB due to MDR, you can find that on the Curry Center website in the Drug Resistance Survival Guide addressing treatment of latent TB due to MDR. 00:31:08 OK, let’s move ahead. 19 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- So what lessons did we learn from this harrowing experience for both the patient and us? First was the communication and cultural gaps was at the core of the severity with which his liver injury presented, based on follow up interviews with him which were generously done by ourseleves, but also in a systematic fashion- by Dr. Jareb from CDC. Who investigates these severe episodes. We learned that this is a very retiring lowkey guy who’s from a place where speaking up isn’t always appropriate or even safe and so I think that that his desire to be an agreeable, compliant patient probably led him to not let us know about things as soon as he could have and we even learned that he had been Googling his symptoms before reporting to us. Which just highlights the importance of- you know not a single episode of drug safety education but at every single encounter. It’s important to talk to patients about adverse effects and what to do if they occur. Also this episode just is a typical scenario where fatigue and anorexia presented without a lot of abdominal pain and nausea. And I really see them as the tip of the iceberg that we’re looking for because if we get to icterus – jaundice - - dark urine light stools, which is what we often tell the patients –that’s fine tell them that – but you’re really close to the waterfall at that 20 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- point, we wanna get patients further upstream where they can get to shore when we interrupt therapy without going over the fulminant hepatic necrosis waterfall. And then to get back to addressing a question that was raised: transparency, both up front, with the patient about the risks of liver injury associated with these drugs. I think it’s perfectly fine to just share the figures with them, share with them information about their annual and future risk of developing active TB, here’s the risk of hypersensitivity, here’s the risk of mild drug-induced injury and severe drug induced liver injury. Also provide them with reassurance that with this education, good communication and appropriate monitoring, we can prevent severe drug-induced liver injury – we can’t prevent mild. In fact I view mild as a success, because that means we caught them far enough upstream. Also transparency at the tail end in patients who develop drug induced liver injury, just make it clear to them what the cause is, when you knew it happened, and now what’s gonna happen to them and then staying connected with them through the process. Until they reach the shore because I think that’s good compassionate medicine- it’ s also good risk management. Avoiding these patients which is a natural tendency once they’re hospitalized it’s kinda bad 21 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- news, it makes you nervous about what’s gonna happen with them, but it’s really best to stay engaged with them and their care providers right on throughgood medicine good risk-management. OK, next slide. 00:34:41 OK, let’s do some more cases. I’m gonna just let you read the slide, but I’ll relate briefly that this is a case of bilateral upper lobe, seemingly cavitary smear positive pulmonary TB and culture and the drug susceptibility results are pending- this is in a homeless patient who does not drink alcohol and has no known risk factors for liver injury. He goes to the- we put these patients in a motel until they’ re no longer infectious and can either find- try to find them some permanent housing, or get them back to a shelter. But while they’re infectious out at the motel and the outreach worker and the nurse go out to provide therapy and safety supervision. So he’s headed down this pathway – of the standard anti-TB regimen, four drugs for the first couple of months, stopping Ethambutol if he’s fully sensitive when the drug resistance, drug sensitivity results come back. Two months of three drugs and then and an additional four to seven months of continuation phase therapy depending on timing of culture conversion. Right, standard regimen. But he was not destined to be on this track because on day 10 he reported that this sort of daily post-dose 22 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- nausea he had been having progressed to be around the clock nausea and he hadn’t eaten much for a couple of days and was worried. Appropriately so, so the outreach worker brought him into the clinic, we did LFTs and you see the results- 4 to 5 times upper limit of normal on the transaminases, total bilirubin is right about at the upper limit of normal, and alk phos is slightly elevated. Hepatitis serology was requested with the results pending, but I’ll tell you that later they came back negative. So that raises the question, what do you want to do now? So continue therapy, providing anti-emetics, and reassess in 3-5 days. Stop potentially hepatotoxic agents and treat with a liver-sparing regimen, stop INH alone and reassess in 3-5 days, stop PZA alone- continue the other drugs reassess in 3-5 days, or refer him for hospitalization for evaluation and management there. So, we’ll wait a few minutes- or not minutes but moments to get a consensus rolling. OK, responses are now slowing down, wait a few more seconds„why don’t we give you about 10 more seconds to put in any lingering answers. This is anonymous, you won’t be graded for this. OK, so I think James when you’re ready. So we see that quite a few people actually, in summary about 40% would stop one or the other of the more hepatotoxic agents and see what happens. About 23 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- 1/3 of you would 00:35:35 00:36:43 stop all drugs, all hepatotoxic drugs, and start a liver sparing regimen, and maybe you can see the rest, the other responses got some votes as well. So a fairly broad distribution. I’m gonna close this, and I’m gonna tell you what we did, which is, the standard is when you’ve exceeded 3-5 times the upper limit of normal, which he has and he has symptoms, you wanna stop meds. At least stop all the potentially hepatotoxic agents. And then you have a choice. 00:39:05 So we’ve interrupted therapy, checked LFTs and now we have a choice. We could proceed with what we call a liver sparing regimen of an injectible of Fluoroquinolone and Ethambutol. If there are pressing clinical or disease control reasons to do so. So, he’s smear positive, cavitary, febrile, coughing up sputum, and out at a motel. Not in his usual place, so lots of reasons for us to probably try and stay on things while his liver is recovering. Alternatively, for patients who are not very ill, and their isolation status isn’t a big problem for us or the patient- they aren’t rushing to get back to work, they not around immunocompromised or really young kids at home, they’re not particularly ill, you could 24 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- probably just withdraw medications and wait the week or two that it’s gonna take for the transaminases to normalize. Then, once that’s occurred, then if they are on a liver sparing regimen you’d add Rifampin and Isoniazid serially, and if they weren’ t on any drugs you’d add Rifampin plus Ethambutol which is unlikely to be a cause of liver injury-so you have them on two drugs, you kinda don’t want them hanging out there just on one drug. Follow them for about a week, repeat LFTs and then add Isoniazid. OK, I suspect we’ll have some discussion about this at the Q and A session. But let’s talk about this patient, that’ s how we proceeded with a liver sparing regimen. Streptomycin, Ethambutol, Moxifloxacin, all daily. Follow up LFTs improved serially. Culture confirmation was then obtained. DST results were still pending, so then we had a decision to make, what do we do now? He’s on three drugs, doing better clinically, both in terms of TB and liver injury. So our next step, as I described on the last slide we added Rifampin. And a week later his LFTs were normal, so he’s doing fine, tolerating the Rifampin, excluding that as a cause- I mentioned the viral serologies are negative. So he’s now tolerating those four drugs and we didn’ t have a lot of anxiety about drug resistance, although the DFTs were pending, he was from an epidemiological group where we 25 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- haven’t seen any drug resistance. We stopped the Streptomycin, kept him on those three drugs. Then two weeks later the DST results come back, he’s sensitive to INH, Rif, Ethambutol and Strep, so what do you want to do now? You can stop Moxifloxacin and continue that standard 12 month regimen, Rifampin and Ethambutol. You could keep Moxifloxacin in there and treat him 00:40:37 00:41:09 00:41:48 for 12 months. Some people„ [MISSING AUDIO from 42:04 to 42:37] „ maybe reassess LFTs in 4-7 days and go down that pathway. So let’s have about 30 seconds here for voting. Again, remember your responses are anonymous. And as the final answers here are trickling in, I think James you can turn it off when you are ready. I think we see the general trend. And I’m gonna confess that there’s no single wrong answer here and there’ s certainly no single right answer. I think the least desirable is the one that got the fewest votes. Adding back PZA: in the absence of drug resistance, in the ability to treat with less hepatotoxic drugs following a liver injury. Certainly when I read the ATS guidelines on this, which I recommend to all of you, the ATS guidelines on hepatotoxicity of TB drugs published 26 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- in 2006. They generally discourage that, and that’s my clinical preference as well. It’s perfectly defensible to keep the patient on either Rifampin and Ethambutol or Rif-Moxi- Ethambutol for 12 months. But my tendency is to try and give the patient the benefit of INH just because my experience is that most patients tolerate Isoniazid upon reintroduction. You want to do it carefully, but there you have it. So let’s proceed from here. 00:44:32 So I did add Isoniazid, LFTs remained normal. On further follow up- so we had Isoniazid and Rifampin going in a patient who’s sensitive to those drugs, problem solved. Stop Ethambutol and Moxifloxacin, he subsequently cleared his sputum, got out of isolation, culture converted in a timely fashion, but we still treated him for the prolonged period of 9 months because why, he didn’t have enough PZA at the front end to merit a 6 month regimen. Case three. Is a real case, but hypothetically we‘ll connect her to this fellow this fully sensitive case of pulmonary TB. She’s a hepatitis C infected woman who’s a girlfriend of his and has clinical suspicion of pleural TB, by virtue of a lymphocytic exudate, positive tuberculin skin test. Lung fields are clear there except for the effusion, sputum AFB smears are negative, and she declined a pleural biopsy. So it’s time to go, it’s time to start anti-TB 27 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- therapy. She reports not only the hep C, which is confirmed in the lab, but she’s a little bit of a binger, not a huge one but has a six-pack a couple of times a week. And the liver cuts on her chest CT that were done for this evaluation do show a nodular liver architecture suggestive of cirrhosis. Her transaminases are mildly elevated, bilirubin mildly elevated, albumen a bit low, again consistent with underlying cirrhosis, hepatitis C, alcohol use. So I’m gonna ask you what you feel about starting her on therapy„ „for active disease, what’ s your preferred approach? Standard four drugs and close monitoring, use an oral liver-sparing regimen akin to what we arrived at temporarily with her contact like Rif Ethambutol Mox, or be really risk-averse with respect to the liver and start Strep Moxi and Ethambutol. Alright, we’re 00:45:02 00:46:16 seeing the votes come in we’ll give it another 15 seconds. Seems to be, I think people are... oh, a few more coming in. I’m ready when you are, James. So, it’s a tie! Essentially a tie, some people would start her on a standard regimen, others would use an oral liver-sparing regimen, including Rifampin, some others would either call us and talk about it or even avoid 28 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- Rifampin. Again, I would go with either one or two, I think either is defensible. I personally avoid Pyrazinamide in patients with that many strikes going against them. Chronic active hep C, cirrhosis, heavy alcohol intake. We’re sacrificing some time, she’s gonna need to be treated probably for 9-12 months. So my preference to treat in that situation with that many strikes going against her liver, with a liver sparing regimen from the start. And maybe think about introducing INH later to see if we can get her down to 9 months. It is defensible to do what you’ve done there, but I have seen bad outcomes- that’s a numerator not a rate, but certainly bad outcomes can occur in patients with cirrhosis and PZA, and potentially if things go bad that’s a medical legal risk management problem. So I tend to avoid PZA in patients with that many risks for liver injury. But let’s talk a little bit more about that. If could close down that window, James. 00:48:45 What are the criteria for pursuing a modification of TB therapy up front in active liver disease? First, I think any baseline transaminases greater than three times the upper limit of normal, look at a liver sparing regimen, while you’re looking for the cause of that elevation. Cirrhosis, end stage liver disease, chronic active hep B and hep C, so not just surface 29 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- antigen positive e-antigen negative HBV DNA negative, but really be e- antigen positive with circulating DNA. Hep C positive with circulating RNA and abnormal transaminases. Heavy alcohol use that’s resulting in significant transaminases elevations, or other underlying active liver disease. Those are the general relative indications for looking at avoiding PZA and considering whether or not you want to use INH. And these two slides just make that visual. One option is to trade out Moxifloxacin for PZA and use these four drugs until sensitivities are known and then if they’re fully sensitive, complete therapy with INH and Rif. Alternatively, if the patient has a lot of factors going against them, then I tend to drop the Isoniazid as well and treat with those three drugs for 9-12 months. And some people would elect to stop the Moxifloxacin once you had the drug sensitivities, but with severe disease, there’s a tendency to continue the use of Fluoroquinolone. Let’s talk about two more quick cases and then I want to wrap things up for Q and A. This is a woman with smear positive, non-cavitary pulmonary TB. Started on therapy, no risk factors for liver injury, feels fine, is improving clinically on therapy at the end of the first week but she notices her eyes are turning yellow. 30 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- 00:49:43 00:50:00 00:50:57 So she comes into the clinic, you do LFTs, you see these results with a mild elevation of transaminases, but a significant bilirubin elevation. She feels fine but she’s a little bit yellow. So you can either decide to intervene then or maybe watch a few more days which is what we did, and she just got more yellow. And her bilirubin climbed more, but the transaminases remained in that just above the upper limit of normal range, so she is a case of Rifampin-induced cholestasis and the general approach there is that you don’t have to stop all meds but just interrupt the Rifamycin and if DFTs are pending, maybe introduce a Fluoroquinolone to replace that and then complete therapy„ 00:51:42 „with one of these regimens again the basis of a variety of sources of recommendations, but the general basis is an initial phase of INH Pyrazinamide and Ethambutol, plus or minus the Fluoroquinolone and then a 10-16 month continuation phase depending on severity and tolerance- the severity of disease and tolerance of drugs for 10-16 months with INH Ethambutol plus or minus the Fluoroquinolone. If you’ re feeling really bold and have experience with it, you might 31 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- try, after the bilirubin corrects, to challenge with Rifabutin, although I would imagine the patient’s at high risk for that to recur. If it does the consequence is just a little jaundice that should be reversible. You just want to watch that closely, both clinically and with lab monitoring. Final case. Pulmonary TB suspect being treated with four drugs, reports to the outreach worker on day three, you know after every dose, including day one, I’ve had abdominal pain, I feel a little nauseous for a few hours, yesterday I vomited, and then I vomit and feel OK. But something’s wrong- and so what would you do? The outreach worker calls you back, calls back into the clinic and says-“what should I do?” So do you stop medications and check LFTs? Stop Pyrazinamide only? Stop Rifampin only? Or provide some anti-emetics, proton pump inhibitor- pre-medication to suppress those inconvenient symptoms and reassess the patient in 3-5 days. OK, I think we are starting to reach diminishing return. So what we have is roughly a two to one response- 2/3 of you are saying let’s stop medications and check LFTs, 1/3 saying let’s make the patient comfortable and reassess in a few days. And I didn’t intend- this is not a trick question- I tend to go with option 4certainly option one is risk averse, certainly not contraindicated. But I want 32 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- to talk about this phenomenon that we just saw, this clinical syndrome. If you can close that down„ 00:54:39 Well, and that’ s to say that early gastrointestinal distress, from the get go, when you start therapy is really unlikely to be liver injury. The median time to liver injuries – a couple of weeks, the shortest I’ve ever seen it occur in is about 3 to 4 days. So patients who are nauseas and vomiting from the start that’s most likely 00:53:39 gastritis due to either Pyrazinamide, Rifampin, or both. You can check LFTs and should do so, particularly if more than a few days of therapy have passed. But if you are in that initial window, probably reasonable to just pre-medicate with an anti-emetic, give them a proton pump inhibitor, and premedication as well and then follow them closely, and now that you’re suppressing their nausea with premedication you’re obligated to follow LFTs. You know, if they are looking great, I’d still check again in 10-14 days and then maybe stretch things out after that. If on the other hand that intervention doesn’t mitigate their symptoms then look at your PZA dose- make sure you don’t have it up too high- sometimes that can be a source of a problem. And if that isn’t the problem or it 33 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- doesn’t resolve things then you probably face with the rare need to interrupt therapy, reintroduce meds sequentially at 3-4 day intervals and try to shake out which one it is. That doesn’ t necessarily mean you’ll discontinue it, but you may look at modifying the regimen based on that- for instance if you find out it’s Pyrazinamide- you could consider splitting the dose, that’s off guideline, but it’s one way of mitigating the situation. Rifampin- we don’t like to split the dose because of its pharmacokinetics. We don’t like to split any TB med doses but particularly not INH or Rifampin, so in that case maybe you’ d look at trying Rifabutin instead. OK, so in summary, first I want to talk about, summarize what we’ve covered with respect to latent TB, particularly on this slide. And that’s to remind you that there is no failsafe method for predicting or preventing drug induced liver injury. LFT monitoring is imperfect, if you target it, which I believe you should do to the groups we mentioned, you’re still not gonna catch everyone- people can develop drug-induced liver injury between screening intervals. And universal LFT monitoring will still miss people between intervals and generate lots of falsely positive – if you will- false positive results due to mild abnormalities associated with hepatic adaptation. So you can’t lean on 34 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- laboratory testing alone. What you should lean on primarily is patient education, because the intervals between returns for refills on patients who are not being directly supervised is long enough to get in trouble. So they really need to know to report fatigue, anorexia early and then interrupt therapy and not resume therapy until so advised. Treatment of latent TB is not an emergency, so if you lose a couple of days while sorting things out, that’s no crisis. And its problems in that communication axis that are what get people into the severe drug-induced liver injury category. And with that kind of close clinical monitoring, patient education and judicious use of LFTs in patients at risk, you can keep liver injury down at or below 1%. And you can try to eliminate severe liver injury. 00:58:37 With respect to active disease, about 5-15% of active TB cases experience druginduced liver injury on four drug therapy. Pyrazinamide appears to be the most common cause, and most patients subsequently do tolerate reintroduction of Isoniazid and Rifampin, and then there is a subset of patients with underlying active liver disease who should be considered for Pyrazinamide and in some cases also INH sparing regimens from the start. So with that I return it to you, James, to moderate any question and answer session. 35 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- 00:59:13 [James Sederberg]: Alright, good job. So we ran into our hour here, so we understand if people have to sign off, this will be recorded and any questions that we answer here in our extra time will be on the recording. If you look down on the list here, Chris, your colleague Greg Stern, “Can you discuss the duration of treatment in druginduced liver injury 9 versus 12 months on non-standard treatments.” [Dr. Christopher Spitters]: Well, I think I’m just gonna default to the standard guidelines which is that if a patient is not on Isoniazid but is on Rifampin, plus one or two other drugs, standard duration of treatment is 12 months. Sometimes clinical judgment and experience will permit you to shorten that to 9 months- say focal smear negative, paucibacillary pulmonary TB, excised lymph node with no pulmonary disease, but the general recommendation is 12 months. And for patients who are not on Rifampin but who are tolerating Isoniazid, it’s 18 months. That’s the default, and again for similar indications, clinical judgment permitting, shortening duration to 12 months, but again the standard is 18. [James Sederberg]: OK, there’s one more that’s a little bit longer but it’s an interesting question. “In a patient with pleural TB with negative sputum smear and culture that develops severe hepatitis one week after starting 36 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- the four-drug regimen, she was restarted on RIF, EMB then PZA. She’s had weekly LFTs in clinical follow-up, everything has been normal for 8 weeks in the RIF, EMB PZA, at this point should the PZA be stopped and replaced with INH?” [Dr. Christopher Spitters]: Not if she’s tolerating it. There’s two possibilities going on. I think if she’ s tolerating it and you have a good relationship where she’ll report things- I think there’s two possibilities here, one, it’s been shown – sidebar to this- from the past, it’s been shown that many patients who develop Isoniazid-induced liver injury subsequently tolerate it. So it may be that that is also true for Pyrazinamide. I have never seen reports or data on that. But the good news is she tolerated it. I think the more likely or default deduction is that it was the INH that was causative in her situation. And I think you have two reasonable options from here, one would be to discontinue those three drugs for 6 months, you know leave well enough alone. If she’s doing fine just keep monitoring her. Alternatively, you could see if she tolerates INH and Rifampin, or excuse me, you could try a trial of INH and see how she tolerates that and that might permit you to narrow her therapy after the initial phase. My gut is that that’s tempting fate 37 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- a bit and not necessary, more importantly she’s doing well on those three drugs. [James Sederberg]: Great, can you read the question down at the bottom; I just don’t want to read it wrong, Chris, from Byron Marshall? [Dr. Christopher Spitters]: “When treating for gastritis without LFTs below three times the upper limit of normal, in the context of four month RIF regimen for LTBI, would you adjust the dosages of your proton- am I able to get that up there? [James Sederberg]: No. [Dr. Christopher Spitters]: Would you be able to adjust the doses of your proton pump inhibitor„ Drug-Induced Liver Injury An on-demand webinar Christopher Spitters, MD, MPH Curry International Tuberculosis Center Oakland, California October 16, 2013 00:00:00 [James Sederberg] 00:00:01 It is now my pleasure to introduce the faculty for today’ 38 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- s seminar, Dr. Christopher Spitters. Chris has worked as faculty for over eight years, teaching at both our Seattle and Bay Area based clinical intensives, as well as serving as a medical consultant on our TB Warmline service. He’s also worked as part of Curry’s International wing, helping develop training programs in Suriname where he continues to serve as medical consultant for the national TB program there. Since 1993 he has been the medical director for Public Health Seattle and King County TB Clinic. Also serves as health officer for four other large Washington State counties, and is a clinical professor in the Department of Medicine at University of Washington. So we’re very proud to have him here today from his office in Seattle to present on this important topic. Chris„ [Dr. Christopher Spitters] Thank you very much James for that kind introduction and the invitation to speak. I’m delighted to be a part of the program and spend some time with you today speaking about drug-induced liver injury and I also want to thank Monterey County for raising this as an important issue, that not only they but other listeners can learn from. So we have quite a bit to talk about and I want to leave some room for questions at the end. So without further ado, let’s proceed. 00:01:24 39 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- First, by the end of our time today I’d like you to feel like you’ve increased your ability to identify symptoms suggestive of anti-TB drug-induced liver injury, to implement appropriate medical management of patients identified with liver injury, and as well to identify TB patients who from the start of therapy are candidates for either liver-sparing regimens or at least very close monitoring of hepatic function. So let’s begin with a case. This is a 37-year-old recent immigrant from a high-risk country who was diagnosed with inactive pulmonary TB based on stable right upper lobe fibrosis, as you can see there in the figure, a positive tuberculin skin test and negative sputum AFB examination on smear and culture. He had no reported risk factors for hepatotoxicity, did not drink alcohol, and per routine was started on Isoniazid therapy daily, self-administered at home with monthly follow up visits. At the first two monthly follow up visits he reported no adverse effects, the next month was dispensed, and on things went„ 00:01:57 00:02:45 until midway through the third month he returned to clinic as a walk-in patient and reported that his family had suggested he come in because he looked tired, had not been eating for 40 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- several weeks, and his sclera were now yellow- he looked jaundiced. So on evaluation in the clinic that day his sclera were enteric, his skin is brown so it was harder to pick up the jaundice there. He had mild right upper quadrant tenderness and epigastric tenderness on exam, and otherwise had an unremarkable exam. LFTs were drawn- and you see the results there. Transaminases were elevated approximately ten times the upper limit of normal and the total bilirubin was about two times the upper limit of normal. At that time, because this represents severe liver injury, with these indiceselevated transaminases above three to five times the upper limit of normal and total bilirubin at least twice the upper limit of normal- he has about a ten percent risk of progressing to fulminant hepatic necrosis and death unless he’s able to get a transplant, which on that timeline is very difficult. Nevertheless, he declines hospitalization and so we negotiated a two-day follow up with him back in the clinic. At that time his transaminases had gone even higher, and he was more jaundiced- clinically as well as you can see in his blood work with a total bilirubin of seven, mild elevation of alkaline phosphatase, albumen still relatively normal, and at that time because of our heightened concern about his climbing 41 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- transaminases as well as his noting that he’s tired and not eating and grossly jaundiced, he accepted referral to a tertiary medical center here that we’re affiliated with. On further evaluation there, his PT INR was prolonged, that’s indicating that hepatic synthetic function is being impacted. Ammonia was not elevated – that’s a marker of detoxification function of the liver. When ammonia climbs that’s a signal of impending liver failure. It also gets into the brain and alters mental status. So his viral hepatitis serologies were negative, aside from hepatitis A immunity and he had an abdominal ultrasound that was consistent with an acute hepatitis. So this gentleman has severe drug-induced liver injury due to Isoniazid and a roughly ten percent risk of mortality. There’s no specific intervention, other than admission to the hospital, close monitoring, so that if he begins to deteriorate then there’ s a chance to get him set up for a transplant. There’s no specific medical therapeutic intervention here besides supportive care: acetylcysteine has only been shown to be definitively helpful in acetaminophen toxicity. Some clinicians will still try it in this setting, in fact it was used in his setting, it’s not clear whether that contributed to his outcome or not. But acetaminophen toxicity is the only 42 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- acute drug-induced liver injury for which acetylcysteine is indicated. As a side bar, valproic acid toxicity also is amenable to L-Carnitine; L-Carnitine as sort of an antidote. 00:04:10 Well while this patient is being observed let’s- and we’ ll come back to him- let’s turn our attention to„ 00:06:49 the entire spectrum of anti-TB drug-induced liver injury. And I just want to review for you the general classes of liver injuries that occur. You’ll see on the fourth row there HC stands for hepatocellular- that’s our patient we’re talking about now- case one- he has severe hepatocellular injury. But before we come to that, let’s just start at the top and talk about the most common transaminases abnormality, which is a mild low level – less than three times upper limit of normal, rise in serum transaminases. Not associated with jaundice or hyperbilirubinemia and not associated with symptoms. It’s a transient, limited cellular injury that occurs in the liver while adaptation is occurring, which I’ve read as being best characterized as: the up regulation of survival enzymes involved in oxidation, conjugation, and excretion of toxins. So during the initial month or two of therapy with Isoniazid, for instance, about 20% of patients will develop this if you 43 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- look for it. When you encounter it, clinical management is just continued clinical monitoring, judicious use of transaminases testing, based on the patient’s underlying risk factors and clinical status, and proceed with therapy without interruption. When we progress to hepatocellular injury, that is not transient in time and space in the liver, but continues, than that typically, it can be asymptomatic, even up to the moderate category I’ll mention in a minute. But more commonly patients begin to experience fatigue, anorexia as the initial cardinal symptoms that then can progress to abdominal pain, nausea, and then ultimately to jaundice. Enteric manifestations like dark urine and light stools all related to the impact of a liver injury on the ability to conjugate and excrete bilirubin, but with mild hepatocellular liver injury you don’t see any of those abnormalities, it’s just usually fatigue, anorexia, maybe some nausea and abdominal pain, and transaminases that are elevated in the three to five times the upper limit of normal range. Now that’s an indication for interrupting therapy, and then following the patient at roughly weekly intervals to assess their return to baseline status. And when they do that, there’ s no sequelae that one would anticipate from that occurring and they are then relatively proscribed from reusing that causative 44 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- agent and if it’s imperative you would look at treating with another agent. Hepatocellular injury that is moderate is similar in clinical presentation to what I described above, but more likely patients will be symptomatic, again with fatigue, anorexia, malaise, being the initial constellation of symptoms. Transaminases in this setting are elevated 5-10 times the upper limit of normal, so that’s like the 250-500 range. Bilirubin is variable- if it’s elevated, usually only minimally so. It’ s unusual for these patients to be jaundiced or to have prolonged clotting times- or prolonged coagulation times. But clinical management is essentially the same. Stop the offending agent, and follow them at weekly intervals to improvement. Sometimes if the levels are up toward 500, we’ ll do an initial follow up LFTs in just a couple of days, just to make sure they are not continuing to climb. Then we come to the syndrome we’re seeing in case one, which is severe hepatocellular injury- again the constellation of symptoms I described abovebut in this setting typically the patient has progressed to enteric manifestations of jaundice- dark urine, light stools- along with all the others I’ve mentioned, and if they are in acute hepatic failure and not detoxifying they may also have mental status changes as that progresses to 45 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- fulminant hepatic necrosis other phenomena including bleeding, Ascites, or Anasarca can occur and as I said altered mental status; the hepatic function is severely impaired, and this patient is at high risk for death. Again, the intervention is to stop therapy, but the difference between this and lower levels of injuries, that that patient merits admission for hospital care. OK, now let’s downshift a little bit in terms of anxiety and health risks to cholestatic liver injury, which should still merit intervention, but instead of being characterized by hepatocyte cell death- typically this is a dysfunction of bilirubin conjugation and/or excretion into the bile canaliculi and it’s only rarely associated with significant transaminases elevations. Usually they’re less than five times, or even three times the upper limit of normal, otherwise there’s no impairment of coagulation times or albumen. The typical culprit there is Rifampin- I’ll cut to the chase with that- and if the bilirubin continues to climbthat needs to be interrupted. 00:12:41 We’ll go to the next slide and now that we’ve classified these liver injuries- I’m gonna talk in general terms about relative incidence and risk of liver injury with use of anti-TB agents. It’s also important to keep in mind that of the whole constellation of acute liver injury, 46 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- due to drugs, which is now the leading cause of acute liver failure in the United States, anti-TB drugs are but a minority. Other drugs: acetaminophen is the leading one, but also amoxicillin coagulanate, other penicillins, sulfonamides, amiodarone, and a host of other drugs are in the aggregate- much more common than TB drug-induced liver injury, I just want to mention that, and let’s focus back in on anti-TB drugs. So adaptation is most commonly associated with Isoniazid because I think that‘s where we encounter it. But it probably occurs as well in the context of treatment for active disease with multiple drugs and as I mentioned earlier, we see that about 20% of the time. In patients being treated for active TB, (I’ m gonna use the pointer here) with four drugs the incidence of drug-induced liver injury varies widely, estimates as low as 5%-I’ve seen as high as 25%- but the general range is 5-15%. Last year in the clinic I work in we had seven cases among about 80 patients treated, so just under 10%. Isoniazid mono therapy- a much rarer cause of severe liver injury- maybe 1 in 1,000 to 1 in 200 with ideal clinical monitoring and judicious use of LFTs – those figures come out of the King County TB Clinic, San Diego County, and a program in Tennessee in the past couple of decades. The 47 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- highest risk agent is Pyrazinamide which is associated with, by deduction we find it to be the most common cause in drug-induced liver injury associated with active disease and then when we see it paired up with other drugs for treatment of latent TB; for instance, the old transiently recommended regimen from about a decade ago of Rifampin/Pyrazinamide that is now off the books and contraindicated because of this: about 5-10% of patients developed liver injury and PZA tends to cause a more severe and lasting liver injury than Isoniazid or Rifampin. Rifampin intermediate in risk in terms of data; I have to admit in my personal experience I see Rifampin as a relatively low risk agent that merits monitoring when it’s used in patients with risk factors for liver injury but I see it causing less – you know most patients who have liver injury tolerate it on reintroduction and most patients, the vast majority of patients who take it for latent TB have no problem. So I view it as a relatively benign agent that should be used judiciously and cautiously in patients with liver injury, but nonetheless can be used. Last among the commonly used TB medicines or somewhat commonly, Ethionamide the second-line drug is the one most commonly associated with drug-induced liver injury- about 1 in 50 patients. Other second- line drugs 48 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- not commonly associated with drug-induced-liver injury, and in fact, these three fluoroquinolones, Levofloxacin or Moxifloxacin, Ethambutol and Streptomycin, form the core of what we call a liver-sparing regimen and we’ll discuss that later. Not that liver injury has never been reported with them, but it’s exceedingly unusual. And then last, cholestasis with Rifamycins, maybe 1 or 2% incidence. 00:17:03 So what other conditions might present with the symptoms I discussed earlieran abnormal transaminases or bilirubin. Or what other, these could also be factors that are concurrent with a drug-induced liver injury and then exacerbating it. Well, first and the most commonly in my experience is alcohol. Which it appears to inhibit some of the adaptive mechanisms involved in oxidation and detoxification of drugs. It itself is directly hepatotoxic. One of the keys to separating out drug-induced liver injury from alcohol-induced toxicity is that the AST tends to be higher than the ALT, whereas the reverse tends to be true for other drug-induced liver injury; that’s not universal but it’s a general trend that you can plug in when you’re making an assessment of a patient. Second most common I think is acute or chronic viral hepatitis- hepatitis B and hepatitis C. Hepatic involvement 49 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- with TB can present from the beginning with a cholestatic picture, typically bilirubin 2, 3, 4 and transaminases elevated but generally less than say 200. That’s particularly prominent in patients with miliary TB or other forms of dissemination. It’s always important to keep in mind acetaminophen which is unlikely to present in our setting as acute ingestion of a fatal dose, but asking about whether a patient has taken a lot or regularly taken acetaminophen, say for fever or joint aches associated with therapy. Then a host of other drugs that I discussed before, but most commonly in our setting, statins and anti-retrovirals, and then last but certainly not least would be just primary biliary disease, due to stones or other obstructing phenomena. So when working up a patient with drug-induced liver injury, keep these things in mind, check for viral hepatitis serology, ask about alcohol. If you are getting a cloudy history add a GGT to the LFTs and consider whether this could be due to TB itself or other drugs. 00:19:31 So this is a little bit of a rehash of the last slide but as we’re looking at a patient and starting to prescribe anti-TB therapy, we have to ask ourselves what patients merit just clinical monitoring, which is everyone, clinical monitoring and education about reporting adverse effects and interrupting therapy until those 50 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- adverse effects are assessed. And what patients merit periodic liver function testing? This is the group around which there’ s the most consensus: patients who have a high level of alcohol intake, which I’ve never actually read a good, clear number on ounces of alcohol per week or what have you, I generally use more than seven alcoholic drinks a week, but if those all seven are coming on the weekend, on one day, that’s probably more injurious and might lower your threshold for testing. Certainly alcohol intake that results in baseline transaminases elevations. Moving on: active, chronic active hepatitis B and C, other hepatotoxic drugs in the patient’s therapeutic regimen, anti-retroviral therapy, (I will note as an aside in the absence of anti-retroviral therapy and Bactrim – there is no apparent elevated risk of drug -induced liver injury in HIV infected patients. In fact, in the study of the two months Rifampin/Pyrazinamide regimen which the studies were done in HIV infected patients, there were no reports of elevated risk of liver injury, it only occurred when that regimen was disseminated and used widely. Increasing age, particularly for Isoniazid, although I also suspect for Pyrazinamide, so as we go up a decade at a time in age, we go from essentially zero risk of liver injury in individuals under 20 years of age up 51 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- to as much as 5 or 10% in patients who are 75, 80 years old. And the other age groups in between being intermediate. And then the pregnancy and the post-partum period is a period of elevated risk for drug-induced liver injury. Now, so those are patients in whom baseline and monthly LFTs are generally recommended and if a patient has active liver disease baseline transaminases elevations, let’s say less than three times the upper limit of normal that you would not interrupt therapy for, or withhold therapy for, you might modify therapy as we describe later, but you probably want to check them at two weeks and then if things are stable, go to the four weeks and Q4 weeks after that. Just for the purposes of discussion, not clinical intervention or treatment policy, there have been reported data suggesting that women are at higher risk, that’s the preponderance of data, it’s not unanimous, but that’s what I see when I look at the literature. And then these next few bullets are actually connected- anectyltransforase acytelates, the reactive free radical intermediate that Isoniazid is oxidized to in the liver, and so this P450 2E1 is involved in that oxidation creating the reactive intermediate that is hostile to hepatocyte health and survival and anectyltransforase throws an acetyl group on that, not once but 52 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- twice, and then that gets excreted. So it’s believed that slow acytelators have greater cumulative exposure to those reactive intermediates and so the polymorphisms between patients and potentially between population groups for these two enzymes may be predictive of risk of liver injury. I see a question- “How long is the post-partum period” – I’m jumping back, I just looked down at that question. Generally out to three months post-partum. It may not be quite that long, but we pick a generous window. I’m gonna proceed to the next slide. 00:24:07 We’re gonna turn back to case one, who’s now been in the hospital- let’s say for a week- and what you’re gonna see in the upper left window here is his transaminases trend. Which promptly went down upon withdrawal of Isoniazid and got below the critical levels within several weeks and then returned to normal within about 6-8 weeks. That’s what you see when the offending agent is withdrawn. Better yet we saw his detoxification function here as manifested as bilirubin decline in a biphasic fashion, where it returned to normal – was prolonged- it took him a couple of months for him to get there. Synthetic function also returned with return of PT INR down to the normal range, or near normal range pretty quickly. And then again a biphasic improvement over time where he got 53 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- back to normal. Similar pattern here with the albumen returned to normal. So he recovered. He was one of the 9 in ten that do not develop fulminant hepatic necrosis resulting in death. What would it look like if he had? Alright so that’s this slide, and this is just a duplicate of the prior slide but I’ve introduced some red dotted lined here. Showing you where things tend to go under that circumstance. So the transaminases still declined because the inciting agent is withdrawn, cell death ceases but if there’s insufficient organ reserve then the detoxification and synthetic functions are permanently impaired. The abnormalities persist and increase- that’s the patient that progresses to hepatic encephalopathy, bleeding manifestations, ascites, and ultimately death in the absence of transplant. Which, in this timeline, is generally low- fortunately I’ve only seen this a couple of times, but it’s a- even those are unfortunate. But along the course of about 6-8 weeks after the initial injury is recognized, is when the patient tends to succumb to these complications. OK, next slide. 00:26:43 So turning back to case one, just what are our options with him? He’s just had a harrowing experience and not too many people are game for treating an asymptomatic condition that might one day result 54 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- in active TB, right? He’s got inactive TB, assuming the two months of INH didn’t severely reduce, or didn’t significantly reduce his risk of future TB. He’s probably looking at about a 1% per year risk of developing active TB. Maybe a little bit less, he’s about 40 years old, lifetime risk is still substantial, but many patients will just elect to not proceed. In his case he was concerned about developing active TB, but didn’t want to take more therapy, and you know we were reticent likewise. Our tendency is to want to wait and see what happens with him and treat him if he develops active disease – we did some active monitoring, quarterly clinical exams, and radiographs and he passed through that time stably without reactivation and then, now that he was feeling better and a bit out from that experience, he did request treatment. And so we treated him with what I consider the leading choice for liver-sparing regimen for latent or inactive TB, which is Rifampin. Rifabutin is also an option- out of our center here we’ve reported that patients who cannot tolerate Rifampin even, due to liver injury, have about an 80% completion rate without adverse effects from Rifabutin; that’s observational data, that’s retrospective, there’s no clinical trials at this point, but our data is some suggestion that patients who have a problem 55 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- with Rifampin can tolerate Rifabutin. As a sidebar, when the reason for interrupting Rifampin was due to hypersensitivity- rash and such, Rifabutin was not so useful. And then if the patient for some reason is not a candidate for Rifampin –let’ s say drug interactions or ongoing transaminases elevations, for another reason, but you still really want to treat them because let’s say that they are going to be immunosupressed for some reason- you could go off guideline and sort of manage them as you would an MDR latent TB patient using what are these liver sparing regimens say Moxifloxacin or Moxifloxacin and ethambutol. I see a question- “Is it necessary to follow both AFT and ALT levels in patients with active TB or LTBI. The guidelines suggest either one or the other. I’m going to speak to you practically, first, ALT is the preferred I think because AFT is the more non-specific. Hemolysis, other phenomena can lead to elevated AFT, that’s less specific for liver injury than ALT. So if you’re gonna follow one, use the ALT. But I just order a panel of hepatic function value because the cost difference between ordering an ALT and a full panel of LFTs as a marginal cost 56 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- [James Sederberg]: Or anti-emetics to account for possible interactions with risk. Thanks.” [Dr. Christopher Spitters]: Yeah. I guess if they’re working I wouldn’t worry about it. You know if it’s working, great, if it’s not working you could look at increasing the Omeprazole to 40 mg and I don’t know which anti-emetic that you’re using, but you could go up to 8 on Ondansetron and I’d have to review my drug interactions software on those two drugs. But if you see an interaction and there’s a- if Rifampin is accelerating their catabolism and you’re not getting a clinical effect, either try another agent or raise their dose in accordance with that. Yeah. So short answer is yes. [James Sederberg]: OK, we have a few more questions, so I think in the interest in time, and I see people are dropping off, we’ll just go to this last question. The others however will be addressed later in writing and we’ll have an FAQ that’ll be put on the website when we put up the archive webinar. This one: “You recommend that TB medications not be split; we have a number of patients who have not tolerated taking all the pills at one time due to GI symptoms. Is it OK in these circumstances to give INH and Rifampin together in morning 57 / 58 ---------------------------------------------------------------精品范文 ------------------------------------------------------------- observed, and have patients self-administer the other meds together later in the day?” [Dr. Christopher Spitters]: Yes. Sometimes what’s optimal is [audio missing 1:04:14 to 1:04:26]„that kind of thing. What we tend to try and avoid is splitting the dose of single drugs, like especially key ones like INH and Rifampin, because two small peaks is not as good as one big peak. So I think what you are doing in that case- you are getting the patient treated, they’re staying on board, that’s probably more important than perfection. [James Sederberg]: Thanks Chris. I think with that we’re going to wrap it up, and again if your question wasn’t answered we will get those online within about a month when we put up the archived webinar. Thank you so much, Dr. Spitters, you did a great job, very clear, really well done. The webinar evaluation link if it hasn’t been mailed to you that’s because you didn’t pre-register, if you have„ [Audio ends]. 58 / 58