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

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

Perfect screening laboratory test HIV Antibody

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

Interpretation of liver test results is MORE difficult

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

Many Causes of Abnormal Liver Tests 2 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

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

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

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

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

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

Nonalcoholic fatty liver disease – an increasing problem

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 = 30 - 39 BMI = 25 = 29 Proportion of US Population Year Adapted from: http://www.cdc.gov/nchs/data/hestat/overweight/overweight_adult.pdf Accessed April 25, 2011 Title of presentation and name of speaker 17/09/2018

Obese people tend to have fatty livers! 1980 - 85 1995 - 99 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

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

What is the mortality risk represented by an elevated ALT?

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

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

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

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

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

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

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

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

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

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

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

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 1 - 2 ETOH more than 90 % of time (acute alcoholic hepatitis) Especially if GGT elevated AST/ALT ratio > 2

(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)

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

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

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

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

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 1 - 2

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

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

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

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

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

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

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

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)

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

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

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