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8 June 2004NCAC Society of Toxicology1 Detecting Liver Injury: Drug-Induced or Not ? John R. Senior, M.D., Hepatologist Associate Director for Science.

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Presentation on theme: "8 June 2004NCAC Society of Toxicology1 Detecting Liver Injury: Drug-Induced or Not ? John R. Senior, M.D., Hepatologist Associate Director for Science."— Presentation transcript:

1 8 June 2004NCAC Society of Toxicology1 Detecting Liver Injury: Drug-Induced or Not ? John R. Senior, M.D., Hepatologist Associate Director for Science Office of Pharmacoepidemiology and Statistical Science Food and Drug Administration (FDA)

2 8 June 2004NCAC Society of Toxicology2 Material presented here is based on the experiences of the speaker for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry. Then at the FDA, 4 years medical reviewer for new gastrointestinal drugs, 3 years senior scientific advisor for hepatology in the Office of Drug Safety, and 2 years as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science. The comments do not reflect official policies or positions of the Agency, but are personal opinions of the presenter based on the diverse experiences mentioned.

3 8 June 2004NCAC Society of Toxicology3 First Ask: Is there liver injury or disease? Is it progressive or serious? –progressive = getting worse or likely to do so –serious = disabling, life-threatening, fatal Drug-induced or some other cause? – no pathognomonic test for DILI, including biopsy – DILI may mimic any known liver disease

4 8 June 2004NCAC Society of Toxicology4 Let’s look first at “some other causes” What are they? –acute/chronic; viral, immune, vascular, metabolic How can they be detected? –serum transaminases, other enzymes, bilirubin, INR How to distinguish from DILI? –no pathognomonic test for DILI, including biopsy –DILI may mimic any known liver disease

5 8 June 2004NCAC Society of Toxicology5 Cooperative research between the pharmaceutical industry and FDA “ Adventures with a Placebo Database” October 2001 - present John R. Senior, M.D., FDA Robert W. Tipping, M.S., Merck

6 8 June 2004NCAC Society of Toxicology6 Special thanks to Peter Honig, M.D., (FDA); Merck Harry Guess, Ph.D., (Merck); UNC Paul Seligman, M.D., FDA...who made this work possible

7 8 June 2004NCAC Society of Toxicology7 Why study placebo participants? obtain data on incidence of AEs not due to drug – fundamental assumption: placebos do no harm they should be subtracted from those seen on drug focus on hepatic injury evidence: tests, symptoms search database for cases of liver injury or disease aim to establish background rate for incidence determine what tests are most accurate and how best to make true attribution of causality one of the initiatives of the PM “white paper” 2001

8 8 June 2004NCAC Society of Toxicology8 What to Look For and Why ? 1) evidence of serious or potentially serious liver disease not much interested in transient serum transaminase bumps; liver is a very adaptive organ, handles xenobiotics well 2) ultimate aim - to distinguish drug-induced liver injury diagnosis of exclusion; must rule out other causes 3) critical need for accurate differential diagnosis need to see serial data, time course of abnormal patterns what really is causing the abnormal pattern? need more information than just lab test numbers

9 8 June 2004NCAC Society of Toxicology9 AFCAPS/TexCAPS Study - 1 carried out 1990-7, San Antonio & Fort Worth TX 6605 participants (85% men), 3301 to placebo men >45 and women >55, up to 73; ambulatory no previously diagnosed cardiovascular disease modestly high total cholesterol, reduced HDL-chol no pre-existing liver disease, or other major disease willing and able to participate for 4-6 years aim: show lovastatin-related reduced cardiac events results published JAMA 1998 and AmJCardiol 2001

10 8 June 2004NCAC Society of Toxicology10 AFCAPS/TexCAPS Study - 2 5-year observation, 20 (+) visits/test sets/participant visits: 3 q 2wks (baseline); 8 q 6wks, 9 q 6 mos; each visit: serum ALT, AST, ALP, TBL, CPK we chose PLACEBO group (3248 had 5-yr data) search database for cases of liver injury or disease our aim: to establish background rate for incidence

11 8 June 2004NCAC Society of Toxicology11 Looking for Liver Disease/Injury how should the search be done ? We looked for; 1) any two: ALTx3; (AST/ALP/TBL)x2; CPKx5 @ peak 2) confirmed ALT or AST at least 3xULN 3) ALT or AST 3+xULN AND concurrent TBL 2+xULN 4) symptoms, complaints, diagnoses, AE reports 5) clinical narratives for selected cases 6) review of case report forms if lab abnormalities

12 8 June 2004NCAC Society of Toxicology12 Distribution of Abnormalities peak values among 3301 studied for 5 years

13 8 June 2004NCAC Society of Toxicology13 The “First 44” Cases trtsexageALTx3ASTx2ALPx2TBLx2CPKx5 PM612.452.355.597.00.72 PM521.502.190.500.810.83 PM709.603.542.422.90.68 PF655.002.590.500.80.55 PF564.353.301.450.61.45 PM593.157.956.656.74.10 PM553.903.030.550.91.12 PM5750.2540.761.388.80.84 etc.to 44 cases

14 8 June 2004NCAC Society of Toxicology14 Case M 61, placebo DayALTxASTxALPxTB LxCPKx -340.450.380.470.70.44 -140.530.410.480.70.36 10.500.380.450.70.23 430.380.320.490.80.28 850.500.410.511.00.22 1270.380.300.420.50.30 1690.530.380.400.70.27 2110.480.430.360.60.27 2530.400.350.400.80.46 2950.400.410.430.70.35 3370.380.410.420.80.72 4210.400.350.420.80.41 5470.450.430.400.70.54 7290.750.620.580.40.71 8392.201.972.710.9 9192.452.355.597.00.36

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23 8 June 2004NCAC Society of Toxicology23 The “Next 87” Cases - 2 Liver function abnormality (no symptom)27 Cholecystitis, cholelithiasis, or both37 3 acute, 1 gangrenous, 1 perforated, 1 pancreatitis Pruritus 9; Fatty Liver 7; Cholesteatoma 2 Cholangiocarcinoma, Hepatitis, Liver Cyst, Cholestasis, Jaundice: 1 each

24 8 June 2004NCAC Society of Toxicology24 Sensitivity-Specificity for 6 of 3248

25 8 June 2004NCAC Society of Toxicology25 Conclusions - so far Serum transaminase elevations not “disease” often may represent transient adaptations Requiring “confirming” tests may miss cases unless done very promptly within a few days Additional information beyond lab test scores needed for making true causal attribution AST elevations don’t add much to ALTs, (see in alcoholic hepatitis, cirrhosis, muscle) Concurrent total bilirubin elevation suggests that serum ALT >3xULN may be serious “Hy’s Rule” may become validated by data

26 8 June 2004NCAC Society of Toxicology26 Rich Findings in Placebo Data I. Concurrent bilirubin rise adds specificity to ALT testing, without losing sensitivity II. Serum transaminase activities vary greatly, CPK even more, but ALP less so

27 8 June 2004NCAC Society of Toxicology27 Where Do Elevated Serum Transaminases Come From ? John R. Senior, M.D., FDA Robert W. Tipping, M.S., Merck

28 8 June 2004NCAC Society of Toxicology28 The “First 44” Cases trtsexageALTx3ASTx2ALPx2TBLx2CPKx5 PM612.452.355.597.00.72 PM521.502.190.500.810.83 PM709.603.542.422.90.68 PF655.002.590.500.80.55 PM593.157.956.656.74.10 PM553.903.030.550.91.12 PM5750.2540.761.388.80.84 etc.to 44 cases

29 8 June 2004NCAC Society of Toxicology29 But, no evidence of liver disease: trtsexageALTx3ASTx2ALPx2TBLx2CPKx5 PM521.502.190.500.810.8 So, why the rises in transaminases?

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31 8 June 2004NCAC Society of Toxicology31 AST & ALT and CPK Rises sort data by ascending CPK values:

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33 8 June 2004NCAC Society of Toxicology33 Two questions: 1) What is the source of the elevated serum transaminase activities? 2) Does CPK >10xULN really indicate muscle disease (“myopathy”)?

34 8 June 2004NCAC Society of Toxicology34 muscle liver alanine aminotransferase (ALT) 750:1 7600:1 aspartate aminotransferase (AST) 5200:1 9000:1 lactate dehydrogenase LDH) 1400:1 1400:1 pyruvate kinase (PK) 6200:1 1400:1 creatine phosphokinase (CK) 20000:1 300:1 Geigy Scientific Tables, 1984: Volume 3, page 169 Organ/Serum Activity Ratios

35 8 June 2004NCAC Society of Toxicology35 Body Composition (Geigy Scientific Tables, 1993; 70- kg man) skeletal muscle - 43% about 30 kg skin, s.c. tissues - 26% about 18 kg bony skeleton - 17% about 12 kg liver - 2.1% about 1.5 kg brain - 2.0% about 1.3 kg intestines - 2.0% about 1.3 kg kidneys - 0.5% about 0.3 kg heart - 0.5% about 0.3 kg

36 8 June 2004NCAC Society of Toxicology36 acute muscle breakdown - rhabdomyolysis (both ALT, AST and bilirubin elevations) various muscular dystrophies, myopathies muscular exertion; anorexia nervosa acute myocardial infarction intestinal celiac disease, untreated (becomes normal on gluten-free diet) Non-Liver Transaminasemia

37 8 June 2004NCAC Society of Toxicology37 Can Muscle Injury Be Confused with Hepatotoxicity ? aspartate (AST) & alanine aminotransferase (ALT), in addition to creatine phosphokinase (CPK) released; release of muscle myoglobin into plasma - contains one molecule of heme that can become bilirubin; renal failure (hepatorenal syndrome) also seen with acute liver failure... reversed by liver transplantation

38 8 June 2004NCAC Society of Toxicology38 But they’re still saying.. “Whereas ALT is localized primarily to the liver, AST is present in a variety of tissues, including liver, heart, skeletal muscle, kidney, brain, pancreas, lungs, leukocytes, and erythrocytes.” Zakim and Boyer. HEPATOLOGY, A Textbook of Liver Disease, 4th Edition, 2003. Friedman, Martin, Munoz: page 662.

39 8 June 2004NCAC Society of Toxicology39 Functions of the Adult Liver extract and process nutrients from gut synthesize proteins, other molecules regulate intermediary metabolism metabolize steroid hormones, insulin extract bilirubin from plasma, excrete control cholesterol metabolism/bile acids handle xenobiotic substances, drugs but NOT to regulate serum enzyme levels !

40 8 June 2004NCAC Society of Toxicology40 Commonly Used Tests enzymes “transaminases”: ALT (SGPT) AST (SGOT) alkaline phosphatase gamma-glutamyl transferase substances bilirubin albumin prothrombin injury hepatocellular obstructive function excretory synthetic

41 8 June 2004NCAC Society of Toxicology41 Is Serum ALT a Liver Function Test ? serum enzyme activity not just from liver but from skeletal and heart muscle, gut, etc.... so let’s not say “liver” it is not a function or job of the liver to regulate the level of serum enzyme activity... so let’s not say “function” MAYelevated serum ALT activity MAY indicate hepatocellular injury

42 8 June 2004NCAC Society of Toxicology42 Maybe we should look closer... Note if serum transaminases elevated at the same time as serum CPK; Work up immediately, with daily measures of CPK, AST, ALT, plus ALP, TBL and DBL, PT (INR), maybe GST, Cr; Get full history of muscle exertion or injury and of liver diseases, alcohol, viruses A-C

43 8 June 2004NCAC Society of Toxicology43 Two questions: 1) What is the source of the elevated serum transaminase activities? 2) Does CPK >10xULN really indicate muscle disease (“myopathy”) or rhabdomyolysis ?

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47 8 June 2004NCAC Society of Toxicology47 “Myopathy” (muscle disease) ? : 1) Unexplained muscle pain or weakness 2) CPK >10xULN

48 8 June 2004NCAC Society of Toxicology48 Rhabdomyolysis: 1) Severe muscle breakdown 2) Myoglobinuria 3) Renal insufficiency

49 8 June 2004NCAC Society of Toxicology49 rhabdo - myo - lysis ( striped - muscle - dissolution)

50 8 June 2004NCAC Society of Toxicology50 Heme-positive Urine Hemoglobinuria from red blood cells MW 64,500 4 hemes/molecule C ren slow, pink plasma methemalbuminemia HbO 2 576-8 nm COHb 571 nm Myoglobinuria from muscle cells MW 17,500 1 heme/molecule C ren fast, clear plasma no methemalbuminemia MbO 2 581-3 nm COMb 579 nm

51 8 June 2004NCAC Society of Toxicology51 Is it worthwhile ? “statins” becoming most used drugs in world widespread belief that the ALT, AST rises reflect liver injury hepatotoxicity probably vastly overstated mild muscle injury is not rhabdomyolysis, or even myopathy need data on closely time-related correlations of serum CPK, ALT, AST, other changes

52 8 June 2004NCAC Society of Toxicology52 More Conclusions serum transaminase elevations not all hepatic investigate AST, ALT elevations – do CPK statin hepatotoxicity probably much overstated moderate exertional mild muscle injury is not rhabdomyolysis, or even myopathy need data on closely time-related correlations of serum CPK, ALT, AST, other changes serum T 1/2 of CPK < AST { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/8/2297954/slides/slide_52.jpg", "name": "8 June 2004NCAC Society of Toxicology52 More Conclusions serum transaminase elevations not all hepatic investigate AST, ALT elevations – do CPK statin hepatotoxicity probably much overstated moderate exertional mild muscle injury is not rhabdomyolysis, or even myopathy need data on closely time-related correlations of serum CPK, ALT, AST, other changes serum T 1/2 of CPK < AST

53 8 June 2004NCAC Society of Toxicology53 Rich Findings in Placebo Data I. Concurrent bilirubin rise adds specificity to ALT testing, without losing sensitivity II. Serum transaminase activities vary greatly, as do CPK, and ALP less so III. Some AST, a little ALT comes from muscle IV. “Baseline” better determined by >1 point

54 8 June 2004NCAC Society of Toxicology54 It may be DILI if it’s nothing else 1. Diagnosis of exclusion; no test FOR DILI 2. Must gather data to rule out other causes 3. Need to educate people to do it better 4.Develop model for quantitative likelihood 5. Prospective large studies needed - for true incidence - for risk factors - for ‘omic analyses (gen-, prote-, metabon-) specimens - for mechanism elucidation


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