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Detecting Liver Injury: Drug-Induced or Not ?

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).

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Detecting Liver Injury: Drug-Induced or Not ?

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  1. 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) NCAC Society of Toxicology

  2. 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. NCAC Society of Toxicology

  3. 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 NCAC Society of Toxicology

  4. 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 NCAC Society of Toxicology

  5. 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 NCAC Society of Toxicology

  6. 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 NCAC Society of Toxicology

  7. 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 NCAC Society of Toxicology

  8. 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 NCAC Society of Toxicology

  9. 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 NCAC Society of Toxicology

  10. 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 NCAC Society of Toxicology

  11. Looking for Liver Disease/Injuryhow 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 NCAC Society of Toxicology

  12. Distribution of Abnormalitiespeak valuesamong 3301 studied for 5 years NCAC Society of Toxicology

  13. The “First 44” Cases trt sex age ALTx3 ASTx2 ALPx2 TBLx2 CPKx5 P M 61 2.45 2.35 5.59 7.0 0.72 P M 52 1.50 2.19 0.50 0.8 10.83 P M 70 9.60 3.54 2.42 2.9 0.68 P F 65 5.00 2.59 0.50 0.8 0.55 P F 56 4.35 3.30 1.45 0.6 1.45 P M 59 3.15 7.95 6.65 6.7 4.10 P M 55 3.90 3.03 0.55 0.9 1.12 P M 57 50.25 40.76 1.38 8.8 0.84 etc. to 44 cases NCAC Society of Toxicology

  14. Case M 61, placebo Day ALTx ASTx ALPx TB Lx CPKx -34 0.45 0.38 0.47 0.7 0.44 -14 0.53 0.41 0.48 0.7 0.36 1 0.50 0.38 0.45 0.7 0.23 43 0.38 0.32 0.49 0.8 0.28 85 0.50 0.41 0.51 1.0 0.22 127 0.38 0.30 0.42 0.5 0.30 169 0.53 0.38 0.40 0.7 0.27 211 0.48 0.43 0.36 0.6 0.27 253 0.40 0.35 0.40 0.8 0.46 295 0.40 0.41 0.43 0.7 0.35 337 0.38 0.41 0.42 0.8 0.72 421 0.40 0.35 0.42 0.8 0.41 547 0.45 0.43 0.40 0.7 0.54 729 0.75 0.62 0.58 0.4 0.71 839 2.20 1.97 2.710.9 919 2.45 2.35 5.59 7.00.36 NCAC Society of Toxicology

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  23. The “Next 87” Cases - 2 • Liver function abnormality (no symptom) 27 • Cholecystitis, cholelithiasis, or both 37 • 3 acute, 1 gangrenous, 1 perforated, 1 pancreatitis • Pruritus 9; Fatty Liver 7; Cholesteatoma 2 • Cholangiocarcinoma, Hepatitis, Liver Cyst, Cholestasis, Jaundice: 1 each NCAC Society of Toxicology

  24. Sensitivity-Specificity for 6 of 3248 NCAC Society of Toxicology

  25. 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 NCAC Society of Toxicology

  26. 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 NCAC Society of Toxicology

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

  28. The “First 44” Cases trt sex age ALTx3 ASTx2 ALPx2 TBLx2 CPKx5 P M 61 2.45 2.35 5.59 7.0 0.72 P M 52 1.50 2.19 0.50 0.8 10.83 P M 70 9.60 3.54 2.42 2.9 0.68 P F 65 5.00 2.59 0.50 0.8 0.55 P M 59 3.15 7.95 6.65 6.7 4.10 P M 55 3.90 3.03 0.55 0.9 1.12 P M 57 50.25 40.76 1.38 8.8 0.84 etc. to 44 cases NCAC Society of Toxicology

  29. But, no evidence of liver disease: trt sex age ALTx3 ASTx2 ALPx2 TBLx2 CPKx5 P M 52 1.50 2.19 0.50 0.8 10.8 So, why the rises in transaminases? NCAC Society of Toxicology

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  31. AST & ALT and CPK Rises sort data by ascending CPK values: NCAC Society of Toxicology

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  33. Two questions: 1) Whatis the source of the elevated serum transaminase activities? 2) Does CPK >10xULN really indicate muscle disease (“myopathy”)? NCAC Society of Toxicology

  34. Organ/Serum Activity Ratios 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 NCAC Society of Toxicology

  35. 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 NCAC Society of Toxicology

  36. Non-Liver Transaminasemia 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) NCAC Society of Toxicology

  37. 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 NCAC Society of Toxicology

  38. 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. NCAC Society of Toxicology

  39. 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 ! NCAC Society of Toxicology

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

  41. 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” • elevated serum ALT activity MAY indicate hepatocellular injury NCAC Society of Toxicology

  42. 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 NCAC Society of Toxicology

  43. Two questions: 1) Whatis the source of the elevated serum transaminase activities? 2) Does CPK >10xULN really indicate muscle disease (“myopathy”) or rhabdomyolysis ? NCAC Society of Toxicology

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  47. “Myopathy” (muscle disease) ? : 1) Unexplained muscle pain or weakness 2) CPK >10xULN NCAC Society of Toxicology

  48. Rhabdomyolysis: 1) Severe muscle breakdown 2) Myoglobinuria 3) Renal insufficiency NCAC Society of Toxicology

  49. rhabdo - myo - lysis (striped - muscle - dissolution) NCAC Society of Toxicology

  50. Hemoglobinuria from red blood cells MW 64,500 4 hemes/molecule Cren slow, pink plasma methemalbuminemia HbO2 576-8 nm COHb 571 nm Myoglobinuria from muscle cells MW 17,500 1 heme/molecule Cren fast, clear plasma no methemalbuminemia MbO2 581-3 nm COMb 579 nm Heme-positive Urine NCAC Society of Toxicology

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