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Approach to the Patient with Abnormal Liver Enzymes

Gastroenterology. Approach to the Patient with Abnormal Liver Enzymes. Jorge L. Herrera M.D. University of South Alabama College of Medicine, Mobile, AL. Gastroenterology. Take Home Message. Liver enzymes are not liver function tests! “True” liver function tests Albumin INR Bilirubin

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Approach to the Patient with Abnormal Liver Enzymes

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  1. Gastroenterology Approach to the Patient with Abnormal Liver Enzymes Jorge L. Herrera M.D. University of South Alabama College of Medicine, Mobile, AL

  2. Gastroenterology Take Home Message • Liver enzymes are not liver function tests! • “True” liver function tests • Albumin • INR • Bilirubin • The patient with elevated liver enzymes usually has normal liver function • LAE’s (Liver Associated Enzymes)

  3. Gastroenterology What are Transaminases? • Cytosolic enzymes, found in the many organs • ALT is particularly high in liver • Indicators of liver cell injury • Height of ALT elevation does not correlate with sevrity of liver damage • Liver enzymes are elevated in ~3% of healthy subjects

  4. Gastroenterology What is a normal ALT? We do not know! • Normal values vary among laboratories and geographic regions • Normal range 31-72 U/L • ALT levels correlate with BMI • Suggested normal level • Males <30 U/L, females <19 U/L Dutta A, et al. Hepatology 2009;50:1957-1962, Prati D, et al. Ann Intern Med 2002;137:1-9

  5. Gastroenterology NHANES 1999-2002 Prevalence of Elevated Transaminases in the US • If defined as • AST <37 or ALT <40 • No hepatitis C or alcohol use • ALT elevated – 7.3% • AST elevated – 3.6% • Either elevated – 8.1% • Prevalence of elevated liver tests was 2x higher compared to NHANES 1988-1994 Ioannou GN, et al. Am J Gastroenterol 2006;101:76-82

  6. Gastroenterology Is ALT a Sensitive Marker of Liver Disease? • Hepatitis C viremia • Historical normal values (up to 40 U/L) • Sensitivity 55%, specificity 97% • Updated normal values (males 30 U/L, females 19 U/L) • Sensitivity 76%, specificity 89% • Detection of fibrosis in NAFLD • 43% of normal ALT patients had fibrosis • 38% of elevated ALT patients had fibrosis Prati D, et al. Ann Intern Med 2001;137:1-9, Mofrad P, et al. Hepatology 2003;37:1286-1292

  7. Gastroenterology Is ALT a Good Predictor of Liver Damage? n=46 n=52 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●●●● ● ● ● ● ● ●●●●●● ● ● ● ● ● ● ● ● ● Grading Hepatitis C Infection ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 PNAL Abnormal ALT Puoty et al. Hepatology 1997;28:1393-11398

  8. Gastroenterology Serum ALT in Perspective • We don’t know what a normal level is • It lacks sensitivity for common liver diseases • Elevations may be seen in normal people • Degree of elevation does not correlate with severity of liver disease

  9. PRETTY LOUSY TEST!!!

  10. Should we Ignore Elevated ALT levels? Risk of death according to ALT level 142,055 Korean subjects applying for life insurance, ages 35-59 Kim H, et al. BMJ 2004;328:983

  11. Gastroenterology Elevated liver enzymes • Normal of abnormal • Normal ALT does not guarantee a normal liver • Do not overreact t0 elevated or fluctuating ALT levels

  12. Gastroenterology Case Presentation • 49 y/o female comes to establish care after moving to your area • Pertinent history • Hypertension • Obesity • Fibromyalgia • ROS • Weight gain of 45 pounds over the last year • Diffuse arthralgias and myalgias • No history of liver disease, denies alcohol use • Prior physician had a “concern” about lupus

  13. Gastroenterology Case Presentation • Medications • Gabapentin, • duloxetine, • lisinopril, • acetaminophen/hydrocodone PRN • Exam • BMI 39, BP 145/90 • No significant findings on exam

  14. Gastroenterology Selected Laboratory data Current Labs One year ago • AST – 75 • ALT – 105 • AP – 98 • T. bilirubin – 0.4 • Albumin 4.2 • Total protein – 6.5 • AST 50 • ALT – 80 • AP – 105 • T. bilirubin – 0.5 • Albumin 4.0 • Total protein – 6.9 • ANA (+) 1:160

  15. Gastroenterology Initial Step Exclude common treatable liver diseases Our Patient’s Results • Chronic viral hepatitis • HBsAG, anti-HCV • Hemochromatosis • Serum iron, TIBC and ferritin • HBsAg (-) • Anti-HCV (-) • Iron 59 • TIBC 350 • Transferin saturation 17% • Ferritin 650 ng/ml

  16. Gastroenterology Could this be Hemochromatosis? • Common – 1/400 whites, penetrance of ~30% • Presents with mild (<4x ULN) transaminase elevations • End-organ damage in middle age • Best screening test – transferrin saturation >45% • Elevated ferritin may indicate inflammation • Genetic testing available to establish the diagnosis • C282Y homozygote Our Patient’s Results Iron 59 TIBC 350 Transferrin saturation 17% Ferritin 650 ng/ml Adams PC, Barton JC. Lancet 2007;370:1855-60

  17. Gastroenterology Could this be Autoimmune Hepatitis? • Treatable, fatal if untreated • Typical presentation • Significant ALT elevation (>5x ULN) • Elevated total protein, gamma globulin, IgG levels • Increased bilirubin is common • Autoimmune markers • ANA (+) in ~ 67% • F-actin Smooth Muscle antibody (+) in ~87% • Liver biopsy with typical but not diagnostic findings Our Patient’s Results AST – 75 ALT – 105 AP – 98 T. bilirubin – 0.4 Albumin 4.2 Total protein – 6.5 ANA (+) 1:160 IgG level - normal Krawitt EL. NEJM 2006;354-366

  18. Could this be alcoholic liver disease? • History unreliable • Alcoholics usually do not develop liver disease • Don’t assume alcohol use is the cause of elevated transaminases • Typical liver enzyme pattern • AST:ALT ratio >2 or 3 • Levels usually <200 U/dl • Diagnosis • Exclude other causes of liver disease Our Patient’s Results AST – 75 ALT – 105 AP – 98 T. bilirubin – 0.4 Albumin 4.2 Total protein – 6.5 Levitsky J, Mailliard ME. Sem Liv Dis 2004;24:233-247

  19. Gastroenterology What about Celiac Disease? • Affects 1% of the US population • Elevated liver enzymes • Most common hepatic presentation of celiac disease • 40% adults and 54% of children with Celiac disease • Up to 9% of patients with unexplained elevated liver enzymes have celiac disease • Diagnostic testing • TTG IgA antibodies Our Patient’s Results AST – 75 ALT – 105 AP – 98 T. bilirubin – 0.4 Albumin 4.2 Total protein – 6.5 Rubio-Tapia A, Murray JA. Hepatology 2007;46:1650-1658

  20. Gastroenterology Common Liver Diseases to Always Exclude • Chronic viral hepatitis • ►anti-HCV, HBsAg • Hemochromatosis • ►iron, TIBC, ferritin • Autoimmune hepatitis • ►typical presentation, elevated IgG, typical • liver biopsy • Non-alcoholic fatty liver disease • (NAFLD) Krier M, Ahmed A. Clin Liver Dis 2009;13:167-177

  21. Most common cause of elevated liver enzymes Fatty liver disease (NAFLD) The hepatic manifestation of the metabolic syndrome Hamaguchi M, et al. Ann Intern Med 2005;143:722-728

  22. The Metabolic Syndrome • Abdominal obesity • Hypertension • Elevated triglycerides • Low HDL • Fasting BS >100 mg/dL Our Patient’s Results √ √ AST – 75 ALT – 105 AP – 98 T. bilirubin – 0.4 Albumin 4.2 Cholesterol - 295 LDL – 175 HDL – 32 Triglycerides – 350 FBS – 99 mg/dL √ √ Driven by insulin resistance HOMA: Glucose x insulin / 405 – if > 2 indicates insulin resistance Cusi K. Clin Liv Dis 2009;13:545-563

  23. Gastroenterology NAFLD • Encompasses 2 diseases • Fatty liver – fat without inflammation • Steatohepatitis (NASH) – fat with inflammation • Prevalence in the US • NAFLD – 46% • NASH – 12.2% • Prevalence by race • Hispanics – 58.3% • Whites – 44.4% • African-Americans – 35.1% Williams CD et al. Gastroenterology 2011;140:124-131.

  24. Gastroenterology Diagnosing NAFLD • Exclude other causes of liver disease • Identify the typical phenotype • Metabolic syndrome criteria • Be aware that ultrasound may lead to an incorrect diagnosis in 10% to 30% of cases • A “bright liver” may indicate fibrosis, not fat • A normal liver may have up to 30% fat • Recognize common confounding variables • ANA is positive in up to 30% • Elevated ferritin is common in NAFLD Vuppalanchi R, Chalasani N. Hepatology 2009;49:306-317

  25. Liver Biopsy – Diagnostic Tool • Only tool that confirms fat in the liver • Differentiates NAFLD from NASH Bodini S, et al. Clin Liver Dis 2007;11:17-23

  26. Gastroenterology Selective Use of Liver Biopsy • Identify patients likely to have advanced fibrosis • Platelet count < 150,000 • AST:ALT ratio >0.8 • Elevated direct bilirubin • High levels of insulin resistance • Elevated MCV • Non-invasive tools to detect NASH or fibrosis may soon be available. Our Patient’s Results Platelets 325,000/mm3 AST - 75 ALT – 105 AST:ALT ratio 0.6 HOMA score: 6 Direct Bilirubin – 0.1 MCV – 89 RUQ Ultrasound – consistent with steatosis Dowman JK, et al. Aliment Pharmacol Ther 2011;33:525-540

  27. Gastroenterology Management of NAFLD • Weight loss and Exercise1 • Diet low in simple sugars • Favor low glycemic foods • Not a “low fat diet”! • Recognize that NAFLD is a marker for premature cardiac death2 1. Huang MA, et al. Am J Gastroenterol 2005;100:1072-1081, 2. Targher G, et al. NEJM 2010;363:1341-50

  28. Carotid Artery Intimal Media Thickness Increased risk for atherosclerosis Targher G, et al. NEJM 2010;363:1341-50

  29. Targher G, et al. NEJM 2010;363:1341-50

  30. Gastroenterology Diagnosis of Fatty Liver Disease Requires careful evaluation for cardiac disease risks

  31. Pioglitazone for NASH Impaired glucose tolerance or type II DM Biopsy confirmed NASH All patients placed on weight reduction program Pioglitazone 45mg/d Belfort R et al. NEJM 2006;355:2297-307

  32. Vitamin E for NASH Non-diabetics with NASH Pioglitazone 30mg/d or Vitamin E as d-tocopherol 800 IU/d Histologic improvement : vitamin E – 43% pioglitazone – 19%

  33. Gastroenterology Management of NAFLD - Recommendations • If diabetes present • Favor pioglitazone • Pro: reduces intrahepatic insulin resistance, clinical data shows benefit • Con: weight gain, other toxicity • Consider metformin • Pro: Weight loss • Con: No change in intrahepatic insulin resistance, clinical studies show limited to no benefit in NASH • All patients • Weight loss counseling • Consider d-tocopherol, 800 IU/d

  34. Gastroenterology Can you prescribe a statin? • Yes! • Dallas Heart Study1 • Statin use: • No increased prevalence of elevated ALT • No worsening hepatic steatosis • Histopathological study2 • Statin use: • Significant reduction in liver fat • Reduced progression to advanced fibrosis Our Patient’s Results Cholesterol - 295 LDL – 175 HDL – 32 Triglycerides – 350 FBS – 99 mg/dL AST - 75 ALT – 105 1. Browning JD. Hepatology 2006;44:466-471 2. Ekstedt M et al. J Hepatol 2007:47:135-141

  35. Statin Therapy in Patients with Elevated LAE Gastroenterology Predominantly NAFLD patients Chalasani N, et al. Gastroenterology 2004;128:1287-1292

  36. High Dose Pravastatin in Liver Disease Patients Gastroenterology Percent of Patients Cumulative ALT elevation (2x ULN or 2x baseline ALT) • Similar results for -- Baseline normal vs. elevated ALT -- HCV vs. NAFL patients Lewis JH, et al. Hepatology 2007;46:1453-63

  37. Gastroenterology “The Stubborn Misconception” Pre-existing Liver Disease Makes Drug-Induced Liver Injury More Likely

  38. Gastroenterology Makes Sense • Acute and chronic liver disease are bad things • Drug-induced liver injury is bad • Adding them together = bad2 Do they occur together more frequently than would be predicted by chance?

  39. The Two Spheres Seldom Overlap Drug Induced Liver Disease Acute and Chronic Liver Disease Lee, WM. 2007

  40. Common Sense is not Always Correct! In most cases, risk of hepatotoxicity is not increased when a drug is used in a patient with liver disease Zimmerman HJ: Hepatotoxicity. The Adverse Effect of Drugs and Other Chemicals on the Liver. Lippincott Williams & Wilkins, Philadelphia

  41. Drug Induced Liver Disease Acute and Chronic Liver Disease Agents With Increased Risk Of Hepatotoxicity In Patients With CLD • Rifampin, INH, pyrazinamide(In HBV & ETOH patients) • Antiretrovirals(In HCV & HBV patients) • Methotrexate(in alcoholic & NAFLD) • Niacin (sustained-release formulation) • Antiandrogens (flutamide) • Valproic acid • Methimazole • Vitamin A (in large doses)

  42. Gastroenterology Take Home Message It is safe to prescribe most medications in patients with liver disease!1 1 Zimmerman HJ: Hepatotoxicity. The Adverse Effect of Drugs and Other Chemicals on the Liver. Lippincott Williams & Wilkins, Philadelphia

  43. Gastroenterology Rules for Detecting Hepatotoxicity • ALT elevation • <3x ULN no action needed • >3x ULN deserves close attention • >5x ULN discontinue the medication • Hy’s Law • ALT + bilirubin elevation with normal alkaline phosphatase = disaster! Black M, et al. Gastroenterology 1975;69:289-302 Reuben A, Hepatology 2004;39:574-578

  44. Gastroenterology Case Presentation • A liver biopsy was not done • Atorvastatin was prescribed • Vitamin E as d-tocopherol 800 IU daily • Weight loss program • Lost 45 pounds over 16 months • Cardiac evaluation revealed no premature atherosclerosis • Liver enzymes normalized

  45. Approach to Elevated Liver Tests Look for common treatable diseases a) viral hepatitis, b) hemochromatosis c) alcohol abuse Consider important treatable diseases Celiac sprue Autoimmune hepatitis Medication hepatotoxicity Features of the metabolic syndrome present? yes no Referral for expert evaluation liver biopsy NAFLD likely, look for evidence of advanced fibrosis, consider biopsy

  46. Gastroenterology What Will the Specialist Look For? • Wilson’s disease • Alpha-1 anti-trypsin deficiency • Occult hepatitis B infection • Occult HCV infection • Seronegative autoimmune hepatitis • NAFLD without metabolic syndrome • Others

  47. Gastroenterology A Final Note • Patients with primarily elevation of alkaline phosphatase are unique • Evaluation consists of • Liver imaging, AMA testing and possible biliary imaging • Differential diagnosis is different • Biliary obstruction • Liver mass lesions • Primary biliary cirrhosis • Primary sclerosing cholangitis • Medication toxicity • Granulomatous liver disease

  48. Gastroenterology Take Home Points • Liver enzymes are important markers of liver dysfunction but are not • Liver function tests • Accurate markers of severity of liver disease • Every patient with elevated ALT deserves an evaluation to detect treatable conditions • Month to month variation is expected, minor changes in levels have no prognostic significance

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