1. Underwriting Screening Liver Test Abnormalities:
“Why” –  Not, “How High”
Robert W. Lund, MD
January 30, 2012

2. Case # 1 The facts of the case: Male 48, NS 5’11” 205lbs ALP: 100
Bilirubin: 1.1
AST: 89
ALT: 122
GGT: 95
Hep B & C negative
CDT/HAA negative

3. Perfect screening laboratory test
HIV
Antibody

4. Pretty good screening laboratory test
Hepatitis C Viral Antibody
Hepatitis C Viral Antibody

5. Interpretation of liver test results is MORE difficult

6. The challenge of liver tests
Elevations are from different sources, and are not disease specific
The “transferases”
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Almost exclusively from the liver
Alkaline phosphatase (ALP)
Gamma glutamyl transferase (GGT)
Total bilirubin

7. Many Causes of Abnormal Liver Tests2
Alcohol abuse, viral hepatitis B & C, fatty liver (steatosis), non alcoholic steatohepatitis (NASH), various medications, autoimmune hepatitis, “chronic non-B, non-C viral hepatitis,” hemochromatosis, Wilson’s disease, alpha 1-antitrypson deficiency, celiac spru, sarcoidosis, lymphoma, primary biliary cirrhosis, granulomatous liver disease, sclerosing cholangitis, hepatoma, metastatic cancer, various toxins

8. Traditional assessment of abnormal liver tests
Hepatocellular – Inflammatory Pattern
Obstructive – Infiltrative Pattern
Abnormal liver test grouping patterns
“Times Normal” [ X Nl. ]
Degree of abnormality
Viral hepatitis screens, alcohol markers (HAA, CDT)
Specific screening tests and markers
Title of presentation and name of speaker
17/09/2018

9. Traditional assessment of abnormal liver tests
Hepatocellular – Inflammatory Pattern
Obstructive – Infiltrative Pattern
Abnormal liver test grouping patterns
“Times Normal” [ X Nl. ]
Degree of abnormality
Viral hepatitis screens, alcohol markers (HAA, CDT)
Specific screening tests and markers
Title of presentation and name of speaker
17/09/2018

10. Abnormal Liver Test Grouping Patterns
Hepatocellular - Inflammatory
Transaminase (AST and/or ALT) elevations relatively greater
Most insurable
Obstructive - Infiltrative
Non-transaminase (ALP, GGT) elevations relatively greater
Most not insurable
Title of presentation and name of speaker
17/09/2018

11. Hepatocellular inflammatory pattern liver test abnormalities Found in > 90 % of insurance applicants having liver test abnormalities
Most common causes of abnormal liver tests having hepatocellular inflammatory pattern
Nonalcoholic Fatty Liver Disease (NAFLD)
Steatosis
Nonalcoholic steatohepatitis (NASH)
Effects of alcohol use
Hepatitis
Almost all due to viral infections
Medication side effects

12. Nonalcoholic Fatty Liver Disease (NAFLD)
Excluding excessive alcohol, viral hepatitis or medication side effect:
80 – 90 % with unexplained ALT elevations have NAFLD
Steatosis
Simple fatty infiltration of the liver
No association of increased mortality risk
Nonalcoholic Steatohepatitis (NASH)
Fatting infiltration of the liver with inflammation that, in some cases, may progress to fibrosis or even cirrhosis
NASH having fibrosis or cirrhosis is associated with some increase in mortality
Increased mortality less than other causes of fibrosis / cirrhosis
No increased mortality in those having NASH with only inflammation
Title of presentation and name of speaker
17/09/2018

13. Nonalcoholic fatty liver disease – an increasing problem

14. Trends in overweight, obesity & extreme obesity in the US
Obesity is increasing
Trends in overweight, obesity & extreme obesity in the US
BMI = 40 and above
BMI =
BMI = 25 = 29
Proportion
of US
Population
Year
Adapted from:
Accessed April 25, 2011
Title of presentation and name of speaker
17/09/2018

15. Obese people tend to have fatty livers!
4.3 / 100,000
38 / 100,000
Increasing prevalence of NAFLD
Prevalence of NAFLD has increased with increasing US obesity
ALT elevated in 7.3% of non-alcohol using US population and in 9% of insurance applicants
~ 1/3 of US population has excessive fat in liver (most not due to ETOH)
17/09/2018
Title of presentation and name of speaker

16. Hepatocellular pattern liver test abnormalities
NAFLD
Steatosis
NASH
Effects of alcohol use
Hepatitis
Almost all due to viral infections
Medication side effects
Most common cause of transaminase elevations in insurance applicants
No increased morbidity or mortality
No definitive diagnostic test except liver biopsy

17. What is the mortality risk represented by an elevated ALT?

18. Traditional assessment of abnormal liver tests
Hepatocellular - Inflammatory
Obstructive - Infiltrative
Abnormal liver test grouping patterns
“Times Normal” [ X Nl. ]
Degree of abnormality
Viral hepatitis screens, alcohol markers (HAA, CDT)
Specific screening tests and markers
Title of presentation and name of speaker
17/09/2018

19. Traditional Underwriting Approach to Abnormally Elevated Liver Tests
3 x Nl
+ 50
Ratings determined by degree of transaminase
(ALT) elevation above the upper limit of the laboratory’s normal range: Haphazaard
2 x Nl
+ 25
Title of presentation and name of speaker
17/09/2018

20. The Truth About “Times Normal” Rating Schemes for Elevated ALT’s
No correlation between ALT levels and liver histology on biopsy
No increased mortality is represented by those with negative hepatitis C serology having ALT levels up to 150 U / L
Title of presentation and name of speaker
17/09/2018

21. Insurance Laboratory Overall Mortality As Expressed by ALT
Levels in Those With And Without Positive Hepatitis C Antibody (SSA-DMF)
Mortality
Ratio
5 x Nl
Std.
ALT
Winsemius D, eEnvoy July 2009, Heritage Labs

22. Distribution of elevated ALT values in insurance applicants%
of all elevated ALT’s
ALT values from 46 through 150 U /represent
96.5 %
of all abnormal ALT’s in insurance applicants 46
150
ALT U / L
96.5 %
Title of presentation and name of speaker
17/09/2018

23. AST & ALT levels and etiology
Level of transaminase elevation is limited in determining likely etiology
Chronic viral hepatitis and alcoholic hepatitis never have AST or ALT levels
>250 U / L
Values >250 U / L are associated with acute inflammation (usually due to infection – especially due to acute viral hepatitis)
Levels of AST and ALT (relative to alkaline phosphatase and/or GGT) are helpful in determining if hepatocellular (usually the case) or obstructive problem is present

24. How do we identify those applicants most likely having the most favorable prognosis... That is... Those having benign steatosis and early (“inflammation only”) NASH?

25. Identifying benign steatosis and best prognosis NASH
BMI
AST / ALT Ratio
(when ALT elevated)

26. ALT more often elevated with obesity
Average BMI when ALT is normal = 27
Average BMI when ALT is elevated = 30
Title of presentation and name of speaker
17/09/2018

27. BMI Is Significant When ALT > 45 U/L
69 % have NAFLD
BMI > 25
12 % have NAFLD (“essential steatosis”)
BMI < 25
Title of presentation and name of speaker
17/09/2018

28. AST/ALT ratio is significant…
when ALT is elevated!

29. AST / ALT ratio (when ALT is elevated)
Steatosis (benign fatty liver disease), early (“inflammation only”) NASH
Viral hepatitis
Other (including ETOH)
AST/ALT ratio < 1
Varying stages of fibrosis due to NASH
Cirrhosis (viral, NASH)
ETOH liver disease including cirrhosis
Especially if GGT X 2 and up
AST/ALT ratio
ETOH more than 90 % of time (acute alcoholic hepatitis)
Especially if GGT elevated
AST/ALT ratio > 2

30. (no associated increased mortality risk)
When ALT is elevated and AST/ALT < 1 and BMI > 25
85% of insurance applicants
are likely to have benign fatty liver!
(no associated increased mortality risk)

31. Underwrite by most likely etiology
AST/ALT ratio (when ALT is elevated)
Degree of obesity (BMI)
Pattern of liver test abnormality
Hepatocellular inflammatory vs. obstructive infiltrative
Determine most likely etiology:
Viral hepatitis serology screening helpful when available
Rule out medication (or toxic, e.g., ETOH) effects on liver

32. Non-steroidal anti-inflammatory drugs (NSAIDS) Antibiotics
Medications That May Produce Transaminase Elevations (This list is not exclusive)
Non-steroidal anti-inflammatory drugs (NSAIDS)
Antibiotics
Anti epileptics (anti-seizure medication)
HMG Co A Reductase Inhibitors
Medications that lower blood lipids such as Lipitor
Anti tuberculous medications

33. Benign fatty liver is + 0 ! AST / ALT < 1 (when ALT is elevated)
Finding the sweet spot
Benign fatty liver is + 0 !
BMI ≥ 25
Benign fatty liver (steatosis) highly likely; this is + 0
AST / ALT < 1 (when ALT is elevated)
Cirrhosis not present
NASH with fibrosis/cirrhosis not present
Degree of ALT elevation in fatty liver carries no significance regarding mortality

34. BMI < 25 changes diagnostic likelihood
Steatosis (benign fatty liver disease)
Viral hepatitis
Other (including ETOH)
AST/ALT ratio < 1
Only ~ 15% of applicants with AST / ALT < 1 and BMI < 25
are likely to have benign fatty liver!
Major Concerns: viral hepatitis, alcohol effects, medication and other toxic effects

35. AST / ALT ratio (when ALT is elevated)
Varying stages of progressive fibrosis due to NASH
Cirrhosis (viral, NASH)
ETOH liver disease including cirrhosis
Especially if GGT X 2 and up
AST/ALT ratio

36. Cirrhosis (in 7 to 26% depending upon the series)
Predictors for Development of More Severe NASH (beyond the inflammatory stage)
Fibrosis (in up to 50 %)
Cirrhosis (in 7 to 26% depending upon the series)
Obesity (progressive) – BMI > 35 has some cirrhosis in 15%
Older age (> 45 years)
IGT/diabetes
AST/ALT between 1 and 2
Smoking
AST > 66
Title of presentation and name of speaker
17/09/2018

37. AST / ALT ratio (when ALT is elevated)
ETOH more than 90 % of time
Especially if GGT elevated
AST/ALT ratio > 2

38. Insurance Industry Laboratory Data
When ALT > 45 U / L
80.4 % of all elevated ALT’s
AST / ALT < 1, BMI > 25
14.1 % of all elevated ALT’s
AST / ALT < 1, BMI < 25
Title of presentation and name of speaker
17/09/2018

39. Insurance Industry Laboratory Data
When ALT > 45 U / L
4.2 % of all elevated ALT’s
AST/ALT 1 to 2, BMI > 25
1.0 % of all elevated ALT’s
AST / ALT 1 to 2, BMI < 25
Title of presentation and name of speaker
17/09/2018

40. Case # 1 The facts of the case: Male 48, NS 5’11” 205lbs (BMI = 28.6)
ALP: 100
Bilirubin: 1.1
AST: 89
ALT: 122
GGT: 95
Hep B & C negative
CDT/HAA negative

41. Hepatocellular inflammatory pattern BMI > 25 AST/ALT < 1
Case # 1
Hepatocellular inflammatory pattern
BMI > 25
AST/ALT < 1
Hepatitis screens negative
Highlights of the case:
Likely Benign Fatty Liver
Conclusion:
STD Case

42. Case # 2 The facts of the case: Female 36, NS 5’8” 153lbs (BMI = 23.3)
ALP: 100
Bilirubin: 1.0
AST: 55
ALT: 105
GGT: 60
Hep B & C negative
CDT/HAA negative

43. Case # 2 Hepatocellular inflammatory pattern BMI < 25
AST/ALT < 1
Hepatitis screens negative
Highlights of the case:
Less likely Benign Fatty Liver ( ~ 12 – 15 % probability )
Not Fibrosis/Cirrhosis
Possibly affects of Alcohol, medication or other toxin(s)
Conclusion:
+50 T65 (includes 25 credit for neg hep)

44. Case # 3 The facts of the case: Male 57, NS 5’9” 240lbs (BMI = 35.4)
ALP: 100
Bilirubin: 1.1
AST: 102
ALT: 88
GGT: 95
Hemoglobin A1c = 6.3 %
Hep B & C negative
CDT/HAA negative

45. Case # 3 Hepatocellular inflammatory pattern BMI > 25
AST/ALT 1 to 1.99
Hepatitis screens negative
Glucose intolerant
Age > 50
AST > 65
Highlights of the case:
Likely NASH with fibrosis / cirrhosis
Conclusion:
STD Case

46. Thank you for your attention rlund@munichre.com 770-350-3251