Should There Be a Standard of Care (SOC) for Drug-Induced Liver Injury (DILI)? Leonard B Seeff, MD

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1 Should There Be a Standard of Care (SOC) for Drug-Induced Liver Injury (DILI)? Leonard B Seeff, MD Drug-Induced Liver Injury: Are We Ready to Look? March 23-24,2011 AASLD, FDA/CDER, PhRMA

2 A Common Statement in Drug Labels And Accompanying Pamphlet Inserts If abnormal liver function tests are noted in a person receiving drug x, and the values exceed a specified level (often >5 times the upper level of normal), the drug should be stopped and treatment undertaken according to the SOC

3 Inferences That Can Be Drawn From This Statement 1. The term, liver function tests clearly refers to the serum aminotransferases (ALT, AST) as evidenced by the phrase...the values exceeding 5 times the upper limit of normal 2. The abnormal liver function tests are presumably a consequence of injury to the liver from the drug being received, hence the need to discontinue the drug. 3. There is an established SOC for dili

4 Are These Inferred Issues Valid? 1. Serum aminotransferases are NOT, repeat NOT, liver function tests 2. There are many more entities than dili that cause serum enzyme abnormalities, even among those receiving a drug 3. There is currently no established SOC for dili

5 How Often Are Raised Serum Enzymes In a Person Receiving a Drug a Consequence of DILI? The answer is uncertain because without a specific biomarker, it can be difficult to establish the diagnosis. Accordingly, dili is often not recognized, but even if identified, it is generally poorly reported by health care workers, even including specialists. Furthermore, surveillance programs are mostly inadequate.

6 Retrospective Studies of Drug-Induced Liver Injury in the Clinical Setting Author Number of Number (%) with Patients Idiosyncratic dili De Valle (6.6%) Hussaini (8.1%) Meier (1.4%) Russo (6.0%) Vuppalanchi 732 5(0.25%) Jinjuvadia (1.1%) Duh (22.8%) De Abajo /100,000 persons per year Bell & Chalasani Epidemiology of Idiosyncratic Drug- Induced Liver Injury. Semin Liver Dis. 2009;29:

7 DILI Frequency May Vary According To Scenario Dili probably accounts for new onset abnormal liver tests more frequently in the course of pre-marketing controlled clinical trials than when abnormalities are encountered in general clinical practice since subjects enrolled in clinical trials are carefully selected to have as few pathologic conditions as possible. However, in both arenas, causes other than dili probably predominate.

8 Importance of Determining Cause For Identified Liver Test Abnormalities Raised serum enzymes may well be the result of dili, in which case it is necessary to consider discontinuing the drug. However, if they are caused by another etiology, discontinuing the drug may be unnecessary and may deny the patient much needed effective therapy

9 Initial Response to Observed New Onset Liver-Related Test Abnormalities Dili is clearly a possible diagnosis if an affected person is taking a drug, herbal or dietary supplement. Establishing the diagnosis, however, is time-consuming, requiring methodical exclusion of all conditions that mimic dili. In the interim, a decision to immediately discontinue the drug needs to be based on several factors: how severe are the liver test abnormalities, how grave is the illness being treated, and how unique and important is the medication?

10 Response to Observed New Onset Liver-Related Test Abnormalities (contd) If the only abnormalities are raised serum enzyme levels without accompanying symptoms, and the values do not exceed a specified level (~5-8 x ULN), and the product received is important, it may be decided to continue the drug but to re-test the hepatic panel (ALT, AST, AP, bilirubin) 1-2 days later and repeatedly thereafter if they fail to resolve. The drug should be withdrawn, however, if the serum bilirubin becomes abnormal or aminotransferases increase to >10 x ULN

11 Response to Observed New Onset Liver-Related Test Abnormalities (contd) In contrast, if liver test abnormalities consist of abnormal levels of both serum enzymes and serum bilirubin (more severe disease) or there is evidence of impending liver failure (e.g., increased INR, encephalopathy), the drug must be withdrawn immediately without awaiting evidence for dili. Whether the liver disease is mild, moderate, or severe, it is nevertheless necessary to establish the cause since treatment will vary accordingly

12 Beginning Workup for Potential Drug-Induced Liver Injury Is dili plausible based on an appropriate temporal relationship between the use of the drug and the onset of the liver injury? (Start and stop dates for all conventional drugs, herbals and dietary supplements relative to identified onset of liver injury) If so, sequentially and methodically eliminate all conditions that can mimic dili

13 Evaluation For Drug-induced Liver injury Elimination of competing causes should be guided by the phenotype of the liver-related biochemical dysfunction (hepatocellular vs cholestatic vs mixed injury) using the R ratio equation: R value = (ALT/ULN) (Alk Phos/ULN) R >5 = hepatocellular; R <2 = cholestatic; R 2< but <5 = mixed hepatocellular/cholestatic

14 Evaluation For Drug-Induced Liver Disease (contd) Hepatocellular (and mixed) Phenotype Exclude: Hepatitis viruses A,B,C,E,CMV,EBV Autoimmune hepatitis (ANA, ASMA, serum globulins) Metabolic disorders (iron overload, Wilson, α1-at def) Hypotension, congestive heart disease Fatty liver disorders Cholestatic (and mixed) Phenotype Intrahepatic (PBC: AMA) Extrahepatic (Causes for CBD obstruction; imaging)

15 Evaluation For Drug-Induced Liver Injury (contd) Drug or HDS a credible cause for abnormal chemistries Assess presenting features: Latency, sequential biochemical values, dechallenge, rechallenge Review past history implicating drug/hds and Its phenotypic expression

16 Evaluation For Drug-Induced Liver Injury (contd) Once dili considered likely, perform causality assessment to grade likelihood that the drug was responsible for the liver injury (RUCAM, predefined expert review). NIH/DILIN grades: Definite > 95%; Highly Likely 75%-95%; Probable 50%-74%; Possible 25%-49%; Unlikely 5%-24%; Insufficient evidence <5%.

17 Evaluation for Drug-Induced Liver Injury (condt) In addition to grading the likelihood of dili, the severity of the liver injury also should be graded, if not already done. This involves assessing whether the presentation consists of serum enzyme elevations only, whether it includes raised levels of the serum bilirubin, or whether there is incipient liver failure. One system is to grade the severity as mild, moderate, moderate-severe, severe, or fatal

18 Treatment Options Always consider dili as a possible cause for identified abnormal liver-related biochemical tests in a person receiving a drug ALWAYS ask about the use of herbals or dietary supplements Once recognized, modify or withdraw the drug/ HDS Corticosteroids / UDCA?? Liver transplantation

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20 Summary, Standard of Care for DILI Abn. liver chemistries Drug being received Appropriate temp. relationship Dili diagnosis possible Define phenotype (R ratio) Hepatocell/mixed pattern Eliminate hep A,B,C,E,CMV,EBV AIH, hypotension/chf, Wilson Dis., α-1-at defic., hemochrom., fatty liver diseases Choilestatic/mixed pattern Eliminate PBC, EH obstruction Assess clinical characteristics: latency, sequential labs., dechallenge, rechallenge Review past history of drug Causality assessment: Dili likelihood and severity Treat STOP DRUG!!! Steroids/UDCA?? Liver transplant