1. The Use of Mortality Data to Improve Risk Assessment CTHOLUA Seminar February, 2011 Robert Stout, Ph.D., President and Director Clinical Reference Laboratory

2. Mortality studies… National studies of prevalence. –Behaviors –Disease(s) Clinical studies of markers of risk. Company studies of insured lives.

3. National population estimates… National Health and Nutrition Examination Survey (NHANES). National Cancer Survey (NCI) Center for Disease Control and Prevention (CDC). –Diseases and Conditions –Travel advice Others

4. Clinical studies… Bias in selection of the study group. Bias in the interpretation of the data. How does it apply to a healthy population?

5. Industry studies… Insured lives What about the ones we rated or declined?

6. Laboratory mortality studies… All comers, not just insured Huge data base –Numbers and duration Information on self reported impairments plus bp, BMI, EKG. All cause mortality

7. Liver enzyme elevations are pain in the neck for underwriters, agents and applicants. As an example:

8. QUESTIONS...  Is there liver disease?  What is the severity of the disease?  What is the mortality risk?

9. Is there liver disease? Applicant reported? Abnormal liver enzyme levels

10. The Underwriter‘s approach to elevated liver enzymes... Family history: hemochromatosis, familial hyperbilirubinemia, kryptogenic cirrhosis Country of birth: vertical transmission of hepatitis B in endemic countries Alcohol ingestion: unreliable, but have regard to lifestyle, weight, lipids Drug ingestion: liver toxic medications, antiepileptics History of blood transfusion, organ transplantation or other blood products before 1990: risk of hepatitis C

11. The pattern of liver enzymes elevations is important... HEPATITIC PATTERN AST, ALT ↑↑↑ think Viral hepatitis AST alcohol Autoimmune Drug induced CHOLESTATIC PATTERN ALP, GGT, Bili ↑↑↑ think Mechanic cholestasis (tumor, gall stones) If GGT heart disease and alcohol.

12. Causes of liver diseases... CommonUncommon Non-alcoholic fatty LDDrug-induced LD Hepatitis CAutoimmune hepatitis Hepatitis BAlpha-1-antitrypsin deficiency Alcoholic LDWilson’s Disease HemochromatosisMiscellaneous

13. QUESTIONS...  Is there any liver disease?  What is the severity of the liver disease?  Prognosis of the liver disease?

14. Copyright ©2005 Canadian Medical Association or its licensors Giannini, E. G. et al. CMAJ 2005;172:367-379 Serum aminotransferase levels in various liver diseases…

15. Markers of liver function... Indirect: platelets  (very sensitive!) Prothrombin time or INR  Serum Albumin  Cholinesterase  Serum cholesterol  (very late!) Bilirubin  …. THESE TELL US MUCH MORE ABOUT LIVER DAMAGE THAN DO SERUM LIVER ENZYMES LEVELS.

16. QUESTIONS...  Is there any liver disease?  What is the severity of the liver disease?  Prognosis (mortality)of the liver disease?

17. What risk can we exclude?

18. Hints towards diagnosis of ALD... Serum alcohol GGT = most common elevation, may be isolated –Sensitivity and specificity 50% AST > ALT, AST: ALT >1 MCV ↑↑. Fatty liver on imaging (ultrasound, CT) –100%, if alcohol consumption >60g/d Carbohydrate deficient transferrin (CDT)

19. Hepatitis C- Why is it important? Prevalence in US about 3-4 million cases, about 0.5%. Chonic disease in -85%, only 15-25% heal spontaneously 20% cases have normal liver enzymes with a fairly benign course. Time to cirrhosis varies from 10 to 50 years, largely dependent on at what age the HCV acquired. Cofactors (alcohol, obesity, hepatotoxic drugs) play an important role.

20. Risk factors for HCV infection…

21. THE MOST LIKELY REASON FOR ELEVATED LFTs – THE WINNER IS……

22. When to suspect NAFLD? IF ONE OR MORE OF THE FOLLOWING: Overweight/obesity Diabetes Hyperlipidemia Hypertension Medication (cortisone, amiodarone etc) History of gastro-jejunal bypass surgery History of rapid weight loss

23. Liver enzyme distribution

24. Liver enzyme distribution… Number Fraction of population NEG58235890.8108 ALT4316670.0601 GGT3534360.0492 ALKPHOS2407270.0335 AST1608490.0224 AST GGT 87066 0.0121 GGT AK 50848 0.0071 AST AK 10428 0.0015 ALL + 23776 0.0033

25. GGT Mortality Ratio

26. Liver enzyme mortality… Fulk M Stout R Dolan V J Insur Med 2008; 40:191-203

27. DEATH RATE

28. AST, ALT for female applicants with a GGT>45…

29. Take home messages...  Laboratory studies will help define mortality risk and reshape underwriting guidelines.  AST, GGT, and AK are important in identification of risk.  In the absence of viral hepatitis moderately elevated ALT has little risk, if AST is elevated consider alcohol as a possible factor!  In the identification of preffered risk GGT is a better marker than cholesterol.