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or or to is - Gastroenterology & Hepatology Volume 8, Issue 5 May 2012 May 5 Issue 8, Volume Hepatology & Gastroenterology a disease. did developed 20 (Cognex), a relatively JHL injury? liver severe more with associated G&H recurrent problems. (sometimes and nytoin, include (ULN) agents accompanied symptoms. patients with usually estolate, including low-level the hepatotoxicity clinical determining iftolerancewilldevelop. drug tology times clinical not Fortunately, patients Other a

that Can drugs causing tolerance ever be be ever tolerance causing drugs Can higher remain associated Upward hepatic chlorpromazine, valproate, and progress taking the ketoconazole, uncommon, elevations a elevations which drugs setting, can number Nevertheless, after are ULN. were statin prevalence less and statins cause enzyme of not further are was and halting able 50% with than severe and In need approval, continue of in associated associated extreme previously will nearly as 6-mercaptopurine. to antibiotics, the and 3 ALT of elevations amiodarone, drug and for most of times restart DILI develop patients the owing drug drug isoniazid. LAE all levels, came elevations which to drugs tolerance. medication the with cases, with in is the used cause tolerance monitoring, in ALT taking often to upper such down the sometimes are mentioned a medication the any nicotinic these to the prevalence Agents elevations, consternation United in safe as stopped treat 10–20% this limit Up toward An hepatic-related ALT erythromycin enzyme labeling temporarily), (up with

medication example to Alzheimer even associated as acid, of is to States a without prior normal normal high of 5% respect tacrine risk range, which 25%) levels

such phe- sub- that to of in of of as is 333

Hepatology to the liver. Nevertheless, nearly all of the drugs that US Food and Drug Administration (FDA) guidance have been reported to cause subclinical ALT elevations in the arena of preventing drug-induced hepatotoxicity

Hepatology are capable of causing more severe hepatotoxicity. The has been quite helpful. The stopping rules that have been frequency with which DILI occurs is usually quite low. put into place for new drugs under development can also In the case of statins, only about 1% of patients will have be used by clinicians who prescribe existing medications. ALT values that exceed 3 times the ULN, and symptom- These recommendations suggest that if a patient’s ALT atic hepatitis is unusual. A similarly low frequency of level rises above 3 times the ULN but is not associated symptomatic LAE elevations is seen with amiodarone. with any symptoms or evidence of hepatic impairment, Isoniazid leads to overt liver injury in 1–4% of cases and such as a rise in bilirubin, the drug can likely be con- is usually age-related. Overall, symptomatic liver injury tinued safely with periodic enzyme monitoring. For ALT occurs in just a fraction of patients who develop lower- rises above 5 times the ULN, more intensive monitoring level ALT elevations. should be performed, and if the ALT rises above 8 times The most feared form of acute DILI is acute liver the ULN, clinicians should consider stopping the drug failure (ALF). There are estimated to be 2,000–2,500 ALF at that time. If there are no alternatives to the drug being cases of all causes annually in the United States, based on used, in some cases the drug may be restarted once the estimates from various registries, including the US Acute patient’s ALT level returns toward normal. Liver Failure Study Group. Approximately 40–50% of Although the exact level of ALT elevation that signals these cases are due to intentional or inadvertent overdoses the risk for the development of ALF is not known with with acetaminophen. Among the remainder, only about any certainty, an 8-fold rise from a normal baseline is gen- 12% of ALF cases are due to all other drugs, including erally felt to represent the threshold below which DILI herbal therapies and other supplements. From the point is still considered to be reversible for most drugs causing of view of absolute numbers, this percentage represents hepatocellular injury. However, for any patient who devel- only 250–300 instances of ALF from these other agents. ops a rise in ALT above 3 times the ULN in association Acute viral hepatitis accounts for approximately the same with a total serum bilirubin level greater than twice the number of cases of ALF per year in the United States. ULN (implying impaired liver function from the injury) With respect to specific drugs causing ALF, isoniazid or any hepatic-related symptoms, the FDA guidance states leads the list, with about 50 cases per year. ALF from statins, that Hy’s Law criteria have been met, which implies that while reported anecdotally, appears to be extremely rare, the patient is at increased risk for developing ALF. Hy’s on the order of 1 case per million users. This frequency is Law, named for the clinical observation made by the late not dissimilar to the background rate of ALF in the United Hyman Zimmerman, predicts that patients who develop States, which occurs without any specific cause. drug-induced hepatocellular jaundice have a mortality rate that can exceed 10%. In terms of specific drugs, the G&H At what point should elevations in liver mortality rate associated with isoniazid was 10–20%, and enzyme levels prompt discontinuation of a drug? anticonvulsant drugs such as phenytoin had mortality rates of up to 50% in the pre–liver transplantation era. JHL Despite the low frequency of ALF seen with most This rule continues to be used by the FDA as well as drug drugs, it is important to recognize that a small percent- developers, and it calls for enhanced vigilance on the part age of patients in whom LAEs begin to rise can go on to of all clinicians when invoked. develop progressive injury and even ALF. Patients taking such agents, in whom ALF is a recognized consequence G&H What is the mechanism by which of treatment, generally need to be monitored more elevated LAEs normalize in some patients? closely. To prevent ALF from developing, clinicians must be vigilant when treating such patients and moni- JHL This is the key question when we are dealing with tor not only the biochemical levels of ALT and bilirubin, what appears to be an adaptive response or drug tolerance. but also pay attention to the development of symptoms Although mild ALT elevations are assumed to represent of hepatitis, such as loss of appetite, malaise, fatigue, some form of subclinical hepatocellular injury, the fact nausea, abdominal pain, and jaundice. If any of these that these enzymes fail to progress further and are not symptoms develop, the medication must be stopped associated with any hepatitis-related symptoms indicates at that point. While the adaptive response is thought that reparative or other protective processes are at work, to prevent injury in the majority of patients, clinicians which prevent more serious injury from occurring. Very need to be aware that certain patients may cross a thresh- little information is available concerning any histologic old after which liver injury is no longer reversible when correlates of drug tolerance in such patients. Liver biopsies the medication is discontinued. are rarely, if ever, performed in patients who develop mild

334 Gastroenterology & Hepatology Volume 8, Issue 5 May 2012 asymptomatic rises in LAEs. Similarly, limited data can be drug. This is especially true in the case of statins, where gleaned from animal toxicology studies, which generally even today, many prescribers are quite concerned when do not perform liver biopsies for only trivial elevations in patients develop even these low-level enzyme elevations. Hepatology ALT or other LAEs. What is known from studying well- In many instances, the statin is stopped in the face of such established hepatotoxic agents such as acetaminophen is abnormalities, often despite the fact that the drug may that a number of protective cytokines and chemokines have been taken without incident for years. appear to be upregulated to counter the effects of injuri- It is important to note that the usual time frame in ous factors released in response to the formation of reac- which enzymes first rise and an adaptive response takes tive oxygen species or other causes of intracellular stress root is generally within the first 12 weeks after starting that activate mechanisms leading to drug injury. Elegant a new drug. This timeframe may reflect the postulated work to date concerning this anti-inflammatory cascade mechanism of injury for most drugs that do not act via suggests that interleukin-6 and interleukin-10, among a hypersensitivity or immunoallergic reaction (in which other protective proteins, combat the proinflammatory case, acute DILI often announces itself within days or effects of interferon-γ, fas-ligand, and tumor necrosis fac- weeks of exposure with typical symptoms of a fever, rash, tors, which if unregulated, would likely lead to a more or eosinophilia). When such a reaction occurs, it is most severe inflammatory response and cell death. prudent to discontinue the offending agent, whether or Exactly how the events leading to drug tolerance not LAE elevations are part of the event. For the major- relate to a patient’s innate or adaptive immune response ity of drugs causing DILI that act through the possible is a matter of ongoing study. Various host factors have formation of a reactive metabolite, it becomes less likely been cited to predict the likelihood of DILI. In general, that serious hepatic injury would develop de novo after women are more likely than men to develop liver injury, 6 months, and it is decidedly rare that any drug would and adults are more susceptible than children. Also, indi- be associated with acute injury after more than 1 year viduals who drink alcohol might be predisposed to adverse of continued use. Patients who have been on statins for reactions with some agents, and obesity may predispose a number of years who are found to have elevated liver patients to certain drug-induced hepatic reactions. How- enzyme levels after such a duration are often discontinued ever, the genetic make-up of the host very likely underlies from the statin at that time, even though it is unlikely to the balance between injurious and protective pathways. A have been the cause of the liver enzyme elevation. Patients number of genetic polymorphisms have been proposed as on statins can have heart disease, gallbladder disease, and potential biomarkers to identify patients at risk of certain many other comorbidities that affect such users, and drug injury. A recent example is HLA-B*5701, testing it is important that the clinician be able to perform an for which is recommended in patients receiving abacavir adequate causality assessment before blaming a particular (Ziagen, ViiV Healthcare) as part of an HIV treatment agent for an underlying illness. regimen. Patients who harbor that particular phenotype It is somewhat ironic that concern about statin- are at much higher risk of developing hypersensitivity related liver injury still remains a major source of con- reactions to the drug (which may involve DILI), and sultation in hepatology practices, given the increasing this drug is generally avoided in such individuals. Similar information demonstrating that statins are more likely HLA polymorphisms have been identified for patients at to be hepatoprotective than they are hepatotoxic. There risk of DILI from amoxicillin, flucloxacillin, and other are now numerous examples of patients with chronic antibiotics. The role of other genetic polymorphisms for hepatitis B or C virus infection who have improved predicting isoniazid-induced DILI also has been inten- responses to antiviral treatment when taking a statin. sively studied. For most other drugs, however, we lack an In addition, patients with underlying fatty-liver dis- accurate biomarker that would predict who is at risk of ease from nonalcoholic steatohepatitis have long been developing severe hepatic injury. shown to be able to safely receive statins, even in the face of mildly elevated liver enzyme levels. Randomized G&H Why do clinicians need to know about controlled prospective trials show that patients receiving this adaptive response? statins actually have fewer instances of hepatic events than patients not receiving statins. Such information JHL An understanding of drug tolerance is extremely is now reflected in new labeling from the FDA stating important because this phenomenon allows many drugs that patients with no sign of liver disease who are start- to be continued safely despite minor elevations in LAEs ing statins no longer need to have routine liver enzyme such as ALT. If clinicians know that such low-level enzyme monitoring; this revision is an acknowledgment of the elevations are not likely to continue to rise progressively, rarity of severe DILI from statins and suggests that much then the patient can benefit from remaining on that of our previous concern may have been unfounded.

Gastroenterology & Hepatology Volume 8, Issue 5 May 2012 335 G&H What are the most important take-home ing for many agents, and permit clinicians to administer messages for clinicians who may be concerned a desired drug with greater confidence by diminishing the

Hepatology about elevations in LAEs? concerns that arise due to elevations in LAEs.

JHL For the present, the importance of stopping rules Suggested Reading such as Hy’s Law suggests that if the drug is discontinued before a patient crosses the threshold of hepatotoxic irrevers- Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994;271:992-998. ibility, then ALF can be prevented. As noted above, there are Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and out- relatively few drugs that are reported to cause ALF with any comes from a prospective study of drug-induced liver injury in the United States. regularity, including isoniazid, other antituberculosis medi- Gastroenterology. 2008;135:1924-1934. cations, and a number of anticonvulsant agents. Some herbal Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced medications, the antithyroid agent propylthiouracil, and acute liver failure: results of the U.S. multicenter, prospective study. Hepatology. other drugs are also part of this list. However, the vast major- 2010;52:2065-2076. ity of agents can be used quite safely, even though they may Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4:489-499. be associated with mild asymptomatic elevations in LAEs, Jones DP, Lemasters JJ, Han D, et al. Mechanisms of pathogenesis in drug hepato- toxicity putting stress on mitochondria. Mol Interv. 2010;10:98-111. owing to the hepatoprotective events that develop as a result Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731-739. of the drug tolerance adaptive response. This effect is particu- Bourdi M, Eiras DP, Holt MP, et al. Role of IL-6 in an IL-10 and IL-4 double larly important in the case of statins. Knowing the threshold knockout mouse model uniquely susceptible to acetaminophen-induced liver between an adaptive response and the development of ALF is injury. Chem Res Toxicol. 2007;20:208-216. crucial when it comes to prescribing potentially hepatotoxic Liss G, Rattan S, Lewis JH. Predicting and preventing acute drug-induced liver medications. injury: what’s new in 2010? Expert Opin Drug Metab Toxicol. 2010;6:1047-1061. Moving forward, the ultimate goal will be to develop Adams DH, Ju C, Ramaiah SK, Uetrecht J, Jaeschke H. Mechanisms of immune- biomarkers or genetic analyses that can accurately predict mediated liver injury. Toxicol Sci. 2010;115:307-321. who is at risk for severe hepatic injury prior to the drug Lewis JH. ‘Hy’s law,’ the ‘Rezulin Rule,’ and other predictors of severe drug- induced hepatotoxicity: putting risk-benefit into perspective. Pharmacoepidemiol being taken. In that way, we should be able to prevent Drug Saf. 2006;15:221-229. most instances of non–acetaminophen-related ALF in the Zamor PJ, Russo MW. Liver function tests and statins. Curr Opin Cardiol. future, lessen the need for frequent liver enzyme monitor- 2011;26:338-341.

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