GI Workshop Case Studies Cliff Titcomb MD Hannover Re AAIM Annual Meeting San Diego, October, 2012 5 Tests Commonly Known as Liver Function Tests Alanine Aminotransferase (ALT, SGPT) Aspartate Aminotransferase (AST, SGOT) Gamma-Glutamyltransferase (GGT) Alkaline Phosphatase (ALP) Bilirubin 2
Two Problems with the Liver Function Tests Don t Measure Liver Function Not Specific for the Liver LFTs Actually Measure: Hepatocellular injury (ALT, AST) Interruption of bile flow or cholestasis (ALP, GGT) Processing of hemoglobin (bilirubin) Actually comes closest to measuring a functional activity of the liver 4
True Measures of Liver Function Serum albumin Serum cholesterol Prothrombin time Measures coagulation factors produced in the liver 5 Transaminase (ALT/AST)Levels Correlate Poorly with Degree of Liver Pathology and Mortality Risk
The Ratio of AST:ALT is an Important Prognostic Marker A Ratio > 1 is Suggestive of Alcoholic Disease or Fibrosis Regardless of the Cause Levels and Pathology Type of damage affects degree of elevation Apoptosis - programmed cell death Decreased cell activity before death Common form of pathology in hepatitis C Damage may occur more extensively in one portion of cell Alcohol affects mitochondria more than cytoplasm Reason for greater elevation of AST 8
Levels and Pathology Toxic agent may affect substrate for synthesis of transaminases differently Pyridoxine (vitamin B 6 ) is needed to synthesize ALT Alcohol reduces pyridoxine and amount of ALT production Combined with mitochondria effects leads to AST > ALT Need viable hepatocytes to produce enzymes With severe cirrhosis there are not enough liver cells left to produce significant transaminase elevations AST:ALT ratio is commonly > 1 with cirrhosis 9 Measures of Cholestasis Alkaline Phosphatase (ALP) Gamma Glutamyl Transpeptidase (GGT)
Alkaline Phosphatase 80% originates from bone or liver normal individuals Most of the rest from the intestine May be increased in normal situations Pregnant women (placental origin) Growing children and adolescents (bone) Blood group B or O (intestinal - after fatty meal) Age (increases between 40-65, especially in women) 11 Obstruction of Bile Ducts Leads to Increased Synthesis of ALP Site of Obstruction Varies
Pathologic Elevations ALP Site of Obstruction Diffusely in liver hepatitis or drug reactions Locally in liver tumors, granulomatous disease Extrahepatic gallstones, tumors Isolated elevations < 1.5 x normal usually resolve spontaneously Persistent elevations > 1.5 x normal suggest more severe pathology 13 GGT Most sensitive marker for biliary tract disease Problem is poor specificity re liver disease Found in a variety of tissues Heart, brain, pancreas, kidney, spleen, seminal vesicles Induced by a variety of agents Alcohol, barbiturates, Dilantin Increases with age, male sex and obesity Appears to be a marker for cardiovascular disease Indicative of oxidative stress Associated with fatty liver and metabolic syndrome 14
An Isolated GGT Elevation Does Not Indicate Significant Liver Disease May be Associated with Mortality but Cause is Usually Other than Liver Bilirubin Results from enzymatic breakdown of heme Processed in liver for excretion in bile Conjugated with glucuronic acid to make soluble Direct bilirubin = conjugated Indirect bilirubin = unconjugated 16
Elevations of Bilirubin Most common is indirect values usually < 3 mg/dl Gilbert s disease - benign defect in conjugating enzymes Hemolysis Overwhelms the liver with too much bilirubin to be processed Direct hyperbilirubinemia = significant liver disease Loss of half of functional capacity 17 Major Causes of Chronic LFT Elevation Non-alcoholic steatosis (Fatty Liver) Steatohepatitis Alcohol related liver disease Viral hepatitis 18
Prevalence of These Diagnoses Varies with the Pattern and Degree of Enzyme Elevations Different Patterns Have a Different Mix of Underlying Diseases What You Do in Underwriting is Assess the Composite Risk of the Group of Individuals with a Given Pattern of Elevated LFTs Overall Risk Depends on the Mix of Serious and Benign Illnesses Within the Group Being Evaluated
For the Most Part This Relates to the Mix of Liver Disease One Exception GGT For GGT the Mortality Risk is Primarily to Non- Liver Related Causes Epidemiology of LFTs Insured Lives Distribution of GGT By Level - Single Enzyme 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ 22
Epidemiology of LFTs Insured Lives Distribution of ALT By Level - Single Enzyme 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ 23 Epidemiology of LFTs Insured Lives Distribution of AST By Level - Single Enzyme 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ 24
LFT Reflex Test Patterns Insured Lives Reflex Test Positives By Enzyme Level Single Enzyme - GGT % Positive 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL>70 Multiple of Normal 25 LFT Reflex Test Patterns Insured Lives Reflex Test Positive By Enzyme Level Single Enzyme - ALT % Positive 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 Multiple of Normal CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 26
LFT Reflex Test Patterns Insured Lives Reflex Positive Tests By Enzyme Level Single Enzyme - AST % Positive 100.00% 80.00% 60.00% 40.00% 20.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 27 LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level GGT+ALT - GGT Trigger 20.00% % Positive 15.00% 10.00% 5.00% CDT/HDL< 70 Hep B 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ Hep C CDT/HDL> 70 Multiple of Normal 28
LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level GGT+ALT - ALT Trigger % Positive 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 Multiple of Normal CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 29 LFT Reflex Test Patterns Insured Lives Reflex Tests Positive By Enzyme Level ALT+AST - ALT Trigger 40.00% % Positive 30.00% 20.00% 10.00% CDT/HDL< 70 Hep B 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ Hep C CDT/HDL> 70 Multiple of Normal 30
LFT Reflex Test Patterns Insured Lives Positive Reflex Tests ByEnzyme Level ALT+AST - AST Trigger % Positive 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 31 LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level GGT+AST - GGT Trigger % Positive 100.00% 80.00% 60.00% 40.00% 20.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 32
LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level GGT+AST - AST Trigger % Positive 120.00% 100.00% 80.00% 60.00% 40.00% 20.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 33 LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level All Elevated - GGT Trigger % Positive 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL< 70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 34
LFT Reflex Test Patterns Insured Lives Positive Reflex Tests By Enzyme Level All Elevated - ALT Trigger % Positive 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0+ CDT/HDL<70 Hep B Hep C CDT/HDL> 70 Multiple of Normal 35 Summary Epidemiology & Reflex Tests GGT shows a much wider dispersion of results than ALT or AST for most enzyme patterns Almost all isolated ALT elevations are less than 2x normal GGT does not scale possibility of reflex tests even for alcohol markers Reflex patterns remain the same regardless of degree of elevation Phenomenon is the same regardless of the number of enzymes elevated 36
Summary Epidemiology & Reflex Tests Percentage of positive reflex tests remains low regardless of degree of elevation for a single abnormal test For most patterns an elevated HDL significantly increases the positive hit rate for CDT and/or HAA Reflex test pattern for GGT+ALT is very similar to that for a single enzyme abnormal GGT+ALT is not an alcohol pattern More of an indicator of fatty liver/possible cardiovascular risk ALT+AST is primarily a hepatitis pattern Hepatitis B&C reflex test scale up with degree of elevation ALT scales risk better than AST It is not an alcohol pattern CDT/HAA rates remain low 37 Summary Epidemiology & Reflex Tests GGT+AST is primarily an alcohol pattern By definition AST>ALT Even in this group GGT does not scale probability of a positive alcohol marker GGT+ALT+AST is primarily a hepatitis pattern More hepatitis C than B Alcohol markers are have a higher positive rate but don t scale well The percentage of positive hepatitis B reflex tests in low in almost all patterns in the US Always lower than hepatitis C Reflects the very low prevalence in US population 38
Clinical Data Several studies have described biopsy findings of groups with chronic LFT elevation Can reconstruct diagnostic distribution from biopsy studies Use the relative risk of different conditions Estimate the overall risk of the group 39 Mortality Ratio Varies 184% - 208% in 3 Different Biopsy Groups Groups Represent Fairly Sick Populations at Tertiary Referral Centers
When Alcohol and Hepatitis Excluded Mortality Ratios Drop into 121-129% Range Insurance Experience Alcohol Abuse and Liver Enzymes (AALE) Study Intercompany study Based on MIB codes for abnormal liver enzymes and GGT Mortality ratios were modest when alcohol abuse and adverse driving were excluded Cases Issued Standard 87% Cases Issued Substandard 139% 42
Modeling the Risk Use different patterns and levels of elevation Determine the reflex test results for each combination Using the percentage of cases with each diagnosis and relative risk of each condition reconstruct the composite mortality risk of each group 43 Key Elements of Risk Assessment Reduction in mortality from use of reflex tests is derived from the diagnostic mix likely present in the group tested Reduction varies with enzyme pattern Mortality risk of the group is lower with a normal reflex test only if you exclude a major contributor to the deaths Generally a negative hepatitis C antigen lowers mortality more than a negative hepatitis B surface antigen Prevalence of hepatitis B in the US is very low ALT+AST group is the exception Clearly would NOT be the case in some geographic areas with a high prevalence of hepatitis B Elevated HDL increases risk in most groups Increases probability of alcohol abuse 44
Remember: Mortality Risk with GGT May be Independent of Reflex Patterns Pinkham CA, Krause KJ J Insur Med, 2009; 41:170-177.
The Value of a Reflex Test Depends on the Distribution of Diseases in the Group Only Credit if You are Likely Eliminating Some of the Risk in the Group Factors That Increase Risk Further Elevation of alkaline phosphatase Elevation of bilirubin Elevation of HDL level Increase probability of alcohol Abnormal measures of true liver function Prothrombin time Serum albumin Serum cholesterol 48
Factors That Increase Risk Further Indicators of a Specific Cause Iron, TIBC, ferritin hemochromatosis Ceruloplasmin, copper levels Wilson s disease Alpha 1-antitrypsin deficiency ANA, anti-smooth muscle antibody autoimmune hepatitis Anti-mitochondrial antibody primary biliary cirrhosis Abnormal CAT scan, MRI, ultrasound 49 Hepatitis B
Epidemiology Estimated 2 billion individuals infected worldwide 350-400 million chronically infected 10-30 million new infections per year 1 million deaths per year Estimated 12 million individuals infected in the US 800,000 to 1.4 million chronically infected 100,000 new infections per year 5,000 deaths per year 51 Stages of Hepatitis B Infection Immune tolerant phase Primarily occurs with infection at birth More common with genotype C Associated with a positive e antigen Seroconversion to e antibody may or may not occur and timing varies with genotype HBV DNA > 200,000 IU/ml, often in the millions ALT normal No or minimal inflammation or fibrosis on biopsy Immune active phase Phase of active virus clearance ALT levels are elevated and reflect immune damage to the hepatocytes HBV DNA > 20,000 IU/ml High risk of cirrhosis and HCC Seroconversion from e antigen to e antibody may occur 10% to 40% revert to e antigen positive, often with a flare of hepatitis 20% remain in immune active phase High HBV DNA usually >20,000 IU/ml Elevated ALT with active hepatitis or fibrosis Remainder go to Inactive Phase
Stages of Hepatitis B Infection Inactive phase E antigen negative ALT normal HBV DNA < 2,000 IU/ml, often undetectable Liver inflammation improves over time Fibrosis may revert over time May only slowly change on biopsy 20% may revert to immune active phase with recurrent liver damage Remain at risk for cirrhosis and HCC About 0.5%-0.8 % will clear the surface antigen and develop the surface antibody Resolution phase Clearance of surface antigen Risk of cirrhosis remains very low Risk of HCC is reduced but remains elevated relative to the general population. Risk Factors for Developing HCC and Cirrhosis E antigen positive Elevated ALT level, especially higher values Higher HBV DNA/viral load Genotypes C and F Basal core promoter (BCP) mutation Co-infection with other viruses (hepatitis C, D or HIV) Male sex (3 to 4:1 risk) Higher for HCC than cirrhosis Age increases significantly after 40 Family history of HCC Heavy alcohol use Smoking Steatosis does not increase risk for either HCC or cirrhosis Coffee intake decreases risk
Mutations Associated with Hepatitis B Basal Core Promoter (BCP) Associated with increased risk of HCC and cirrhosis Relative risk 1.7-3.2 for HCC RR 1.9 for cirrhosis Pre-Core (PC) Prevents the production of the e antigen Common in the Mediterranean region Does not occur with genotype A Tip off is the presence of high viral DNA level with absent e antigen More common in individuals with active liver inflammation Not clearly associated with an increased risk of HCC Risk of cirrhosis appears to be lower Treatment of Hepatitis B Immune tolerance phase generally not treated High viral load, normal ALT, e antigen positive Viral clearance only 10% May be useful in those > age 40 Most treatment occurs in immune clearance phase E antigen positive, elevated ALT, moderate viral load Clear reactivation also treated No evidence of benefit in the truly inactive carrier phase Normal ALT, low viral level 2 major types of therapy Interferon alfa Nucleos(t)ide analogs Entecavir (Baraclude) Tenofovir (Viread) Telbivudine (Tyzeka) Lamivudine (Epivir) Adefovir (Hepsera)
Interferon Therapy Advantages Limited duration of therapy (up to 12 months) No viral resistance Immunomodulatory and antiviral effects Greater chance of clearing hepatitis B surface antigen Disadvantages Requires subcutaneous injection Can t be used in decompensated cirrhosis Frequent side effects Nucleos(t)ide Analogs Advantages Oral use Strong antiviral activity Side effects are infrequent Can use in compensated and de-compensated cirrhosis Disadvantages Drug resistance can occur, affects other drugs in the class Especially lamivudine (Epivir) and telbivudine (Tyzeka) Needs to be used for an extended period of time Relapses may occur after drug is stopped
Iloeje UH et al., Clin Gastroenterol Hepatol, 2007; 5:921-931.
Iloeje UH et al., Clin Gastroenterol Hepatol, 2007; 5:921-931. Chen CJ et al., J Gastroenterol Hepatol, 2011; 26:628-638.
Hepatitis C Iloeje UH et al., Gastroenterology, 2006; 130:678-686.
Etiology Single-stranded RNA virus in the Flavivirus family 9,400 nucleotides organized into different functional regions 6 serotypes 50 subtypes Genotypes vary by region 70% of isolates in US are genotype 1a or 1b 65 Epidemiology 4.1 million U.S. individuals infected (1.6% of the population) Order of magnitude greater risk than hepatitis B in the U.S. 170 million infected individuals worldwide U.S. data 40% of chronic liver disease 30% of liver transplantations 10,000 annual deaths 66
HCV Testing Enzyme immunoassay (EIA) 3 rd generation Highly accurate Sensitivity 98%, specificity 99% Positive within 6-8 weeks of exposure Recombinant immunoblot assay (RIBA) Identifies the specific antigens to which antibodies are present Primarily used to confirm infection in low risk populations Test criteria: Reaction to 2 antigens = positive Reaction to 1 antigen = indeterminate Reaction to 0 antigens = negative HCV RNA assays Various technologies Qualitative and quantitative tests Both types of assays detect levels to 10 to 50 IU/ml 67 Clinical Aspects of Hepatitis C Chronic Infection Approximately 75% of acute cases progress to chronic hepatitis No specific characteristics to determine who will progress 30% have no symptoms and normal enzymes 50% have no symptoms but increased enzymes 20% have clinical liver disease with symptoms ALT(SGPT) > AST(SGOT) Waxing and waning course is common Liver enzymes frequently dip into normal range Average values 10 years after diagnosis are 1.5 times normal Degree of elevation of liver enzymes does not correlate with amount of liver damage Need a liver biopsy to assess severity 20% of chronic infections lead to cirrhosis in 20 years Can vary from 2%-50% depending upon genotype 68
Progression of Hepatitis C 4 Phases Phase I slow Progression curve flat Phase II increases slowly Curve begins to ramp up Phase III increasing rate Curve steeper Phase IV exponential increase Curve virtually straight up 69 4 Phases of Progression IV III I II 70
Progression of Hepatitis C Varies with Age Rates of progression differ between age groups Overall rate of progression is slower in younger individuals Duration in different phases varies with age Younger individuals have a long period in Phase I Phase I is very short in older individuals Rapidly go into Exponential Phase (IV) 71 Rate of Progression By Age Probability of Cirrhosis By Age and Duration Hepatitis C 100% 80% 60% 40% 20% 0% 5 10 15 20 25 30 35 38 Duration of Infection (Years) Age > 50 Age 41-50 Age 31-40 Age 21-30 Age < 21 Hepatology. 2002;36: S47-S56. 72
Factors Important in Progression Age Older > Younger Sex Males > Females Alcohol usage Even modest amounts of alcohol increase risk of progression Immune status Immunosuppression increases risk Viral factors Co-infection with hepatitis B or HIV HCV genotype and RNA levels are not correlated with progression Genotype is more important in assessing response to therapy 73 Predictors of Progression ALT level Higher levels have increased rate Biopsy results at baseline Greater degree of fibrosis Greater amount of inflammation Presence of steatosis Presence of fatty liver increases risk 74
Only Reliable Way to Assess Progression is with Liver Biopsy Types of Therapy Hepatitis C Interferon alpha alone Interferon alpha plus ribavirin Ribavirin does not induce remission when used alone Augments response to Interferon Reduces relapse rates PEG-Interferon alone PEG-Interferon plus ribavirin Current standard therapy Duration of therapy and response vary with genotype Genotypes 1, 4 48 weeks Genotypes 2, 3 24 weeks 76
Response to Therapy Rapid viral response (RVR) HCV RNA < 50 IU/ml at 4 weeks of therapy Chance of SVR 80%-90% Early viral response (EVR) HCV RNA < 50 IU/ml at 12 weeks of therapy SVR is rare (1%-3%) in those who fail to achieve EVR End of treatment response (ETR) HCV RNA < 50 IU/ml at end of therapy Sustained viral response (SVR) HCV RNA < 50 IU/ml 24 weeks after the end of therapy Relapse Detection of viral RNA after an ETR Non-response Failure to achieve a 2 log decrease in viral levels with treatment 77 Interferon Side Effects Flu-like syndrome 80% Neuropsychiatric symptoms 20% Especially depression Marrow suppression 5% 78
Ribavirin Synthetic nucleoside Active against several DNA and RNA viruses Used alone transiently decreases ALT Levels Not associated with decrease of viral RNA levels during or after therapy Augments response to Interferon or PEG-Interferon 79 PEG Interferon PolyEthylene Glycol is attached to Interferon Increases molecular weight Prolongs half-life 10 times Half-life increased from a few hours to several days Omits peaks and valleys in blood levels Permits treatment once per week Similar side effect profile to Interferon 80
Newer Oral Medications Protease inhibitors Telaprevir Boceprevir Block NS3/4A serine protease Inhibit virus production Added to the traditional PEG interferon/ribavirin combination Benefit demonstrated in multiple studies Improve SVR in Genotype 1 Including relapsers and non-responders Allows a shorter course with better compliance in many patients 81 Guiltinan AM et al., Am J Epidemiol, 2008; 1670:743=750. Neal KR et al., GUT, 2007; 56:1098-1104.
Ilyas JA, Clin Liver Dis, 2011; 15:515-536. Assis DN, Clin Pharmacol Ther, 2012; Pub Online.
Relapse Rate After A Sustained Viral Response is < 1% Treatment Alone Reduces Inflammation and Rate of Progression of Fibrosis Relapsers do Better than Non-Responders
Just Getting Treatment Improves Survival Hep C Mortality By Response to Treatment 25 Year Markov Model Select Mortality Ratio 500 400 300 200 100 0 20 30 40 50 60 Age No Treatment Non-Responder Relapser 87