Title: Implications of testing for LFTs and Alcohol Markers
1Implications of testing for LFTs and Alcohol
Markers
Dr. Peter Miller AMU/ASU 21 May, 2008
2History of LFTs and life insurance
- AIDS in early 80s created need for blood HIV
testing - Why not add other tests if youre already taking
blood,? - Blood chemistry profile (BCP) included glucose,
lipids, renal function, serum proteins and liver
function tests, plus urinalysis - The Milliman and Roberts report on HIV testing
and the BCP justified the benefits of testing - Now came the challenge as to how to underwrite
the abnormal results
3Early underwriting elevated LFTs
- Confusion due to ignorance on significance of
elevations - We had never heard of Bayes' theorem, named after
the Reverend Thomas Bayes (17021761),
sensitivity, specificity, prevalence, pre-test
probability and post-test probability - Elevated GGT became the marker of alcohol abuse,
so that we were rating or declining many cases - In fact, what was the extra mortality of elevated
LFTs? - Some simple solutions were needed
4Easy solutions to the problems of elevated LFTs
- Recognition of the causes of mild/moderate
elevation - Hepatic causes fatty liver, alcohol abuse,
chronic HBV HCV, haemochromatosis, autoimmune
hepatitis, Wilsons disease, a-1-antitrypsin
deficiency - Nonhepatic causes celiac disease, inherited
disorders of muscle metabolism, acquired muscle
diseases, strenuous exercise - The major extra mortality is associated with
fatty liver, chronic viral hepatitis and alcohol
abuse - Identifying alcohol abuse is very difficult, even
in clinical practice - The simple way would be to perform a reflex test
of the serum sample that insurance labs were soon
storing, e.g. HBV - Also led to introduction of haemoglobin
associated acetaldehyde (HAA) and carbohydrate
deficient transferrin (CDT) as reflex tests - Add an LFT calculator so the underwriter doesnt
have to think and the problem was solved!!
5What is the mortality of elevated LFTs?
- Mom, I cant believe it was so quick
- those liver function tests are killers!
6The AALE studyAlcohol abuse and liver enzyme
study
- AAIM, SOA, ALU study of 82,262 insured lives with
policies issued 1989-95 and exposed to 1997
mortality experience compared to the 1990-95
Select Basic Tables - MIB codes for alcohol criticism (use significant
to health and longevity), adverse driving record,
abnormalities of ALT /or AST and abnormalities
of GGTP - Males only (too few female deaths for meaningful
analysis) - Mortality did not vary significantly with age,
though numbers were not meaningful enough for age
stratification for alcohol abuse - Mortality rates were not significant higher in
substandard vs. standard issue, 147 vs. 175
Titcomb et al. Alcohol Abuse and Liver Enzymes
(AALE) Results of an Intercompany Study of
Mortality. J Insur Med 200133277289
7AALE - summary reportwith our without other
non-study impairment or test codes
Titcomb et al. Alcohol Abuse and Liver Enzymes
(AALE) Results of an Intercompany Study of
Mortality. J Insur Med 200133277289
8Prevalence of fatty liver or hepatic steatosis
- Most common of all liver disorders cause of
chronic liver disease - MRI detection
- US adults 31
- Potential liver donors 33
- Ultrasound detection
- Koreans 23.4
- Japan 14 (19 years ago) 29 (2002 study)
- China 15 (2005)
- Italy (non-obese, nondrinkers) 16.4
- Liver donors with normal aminotransferase 20
- Prevalence increases with age
- Children 2.6
- At ages 40-59, 26
- Diabetes and obesity up to 75
- Diabetes with morbid obesity almost 100
- How can you rate for a condition that 20 of the
population has?
9Liver Enzymes in NAFLD
- Diagnosis NAFLD requires the exclusion of alcohol
as cause 20 g/d for women and 30 g/d for men - Normal values in up to 79 at one time or other
may fluctuate - Typically mild elevation of ALT AST, 2 to 4
fold - ALT usually greater than AST ratio
- AST gt ALT may indicates cirrhosis
- May be elevations of GGT, alkaline phosphatase
ferritin - The diagnosis of NASH requires a liver biopsy,
but liver enzymes do not correlate with liver
histology - Full range of NAFLD may be seen with normal LFTs
10Mortality from NAFLD
- 420 patients at the Mayo Clinic from 1980-2000
- Imaging alone (348), imaging and biopsy (65),
biopsy alone (5) and cryptogenic cirrhosis with
metabolic syndrome (2) - Mean follow up 7.6 years (0.1-23.5)
- SMR all patients versus general population, 1.34
- SMR of those with at least 10 years follow up
1.55 - Liver disease 3rd leading cause of death v. 13th
in general Minnesota population - A 26 prevalence in the population makes it a
challenge to rate
The natural history of nonalcoholic fatty liver
disease a population-based cohort study. Adams
LA, Lymp JF, St Sauver J, Sanderson SO, Lindor
KD, Feldstein A, Angulo P. Gastroenterology.
2005 Jul129(1)113-21
11Chronic hepatitis B and C infection
- Low prevalence in the UK
- HBV lt0.3
- HCV 1 (Europe)
- HBV common in immigrants from areas of high
prevalence - Also IV drug abusers, frequent sexual partners
and male to male sex. - HCV mostly from contaminated blood or medical
equipment - HBV HCV easily identified as cause of LFT
elevation
12General Household Survey, 2002Alcohol
consumption in the last week
One unit of alcohol is obtained from half a pint
of normal strength beer, lager or cider, a single
measure of spirits, one glass of wine, or one
small glass of port, sherry or other fortified
wine.
13Average weekly alcohol consumption, by gross
weekly household income
Alcohol consumption General Household Survey, 2002
14Risk assessment of alcohol use
- Inconsistent taxonomy terminology of alcohol
usage - DSM IV alcohol abuse and dependence are based on
consequences and not usage - Wide range of alcohol consumption and mortality
patterns by gender, age, ethnicity, income level,
occupation, smoking status and socio-economic
status - Quantification of alcohol usage in research
studies and surveys relies almost entirely on
self-reporting - The beneficial effect on survival with some
levels of alcohol usage
15DSM-IV alcohol use disorders
16Alcohol consumption v. diagnosis of alcohol abuse
or dependence
- The DSM-IV categorical approach was used to
determine alcohol diagnoses for 435 highly
educated young adult men - Alcohol dependence group
- 4.5 mean drinks/day, max 15.5 drinks
- 16.5 mean drinking days/month, max 23.5 days
- Alcohol abuse group
- 3.4 mean drinks/day, max 12.5 drinks
- 15.6 mean drinking days/month, max 22.5 days
- No alcohol problem over 15 years
- 2.4 mean drinks/day, max 7.4 drinks
- 12.8 mean drinking days/month, max 14.4 days
Schuckit, M. A., T. L. Smith, et al. (2000). "The
5-year clinical course of high-functioning men
with DSM-IV alcohol abuse or dependence." Am J
Psychiatry 157(12) 2028-35.
17Relative risk of death according to alcohol use
18Relative risk of death from all causes and
various diagnoses
19Identifying excess alcohol use
- High level of suspicion
- Social and personal history
- Questionnaires, screening instruments
- Medical history
- Physical exam
- Laboratory assessment
20Social characteristics of alcohol misuse heavy,
binging
- Accident prone
- Driving criticism
- Cigarette smoker
- Frequent job changes or poor employment record
- Frequent mood shifts or violent behavior
- Jobs chosen to provide easy access to alcohol
- Marital instability
21Alcohol screening instruments
- National Institute on Alcohol Abuse and
Alcoholism (NIAAA) quality and frequency
questions - On average, how many days per week do you drink
alcohol? - On a typical day when you drink, how many drinks
do you have? - What is the maximum number of drinks you have had
on any given occasion during the last month? - CAGE, AUDIT, TWEAK, MAST, BMAST, RAPS4
- Single question screening (2005) When was the
last time you had more than X drinks in 1 day?
(X5 for men, 4 for women)
22Medical history with excessive alcohol use
- Trauma recurrent injuries, accidents
- Cardiovascular hypertension, atrial
fibrillation - Gastrointestinal gastritis, bleeding
- Psychiatric depression, anxiety
- Neurologic single seizure, peripheral
neuropathy - Pulmonary frequent, recurrent infections, TB
- Falls in elderly - impaired judgment,
hypotension, myopathy, neuropathy
23Laboratory findings with excess alcohol use
- Liver function test elevations AST, ALT, GGT
- Positive alcohol markers CDT, HAA
- Complete blood count high MCV, low hemoglobin,
platelets, and white blood count - Lipid profile high HDL-C, high triglycerides
- High uric acid, and high serum ferritin
- Low BUN, low blood glucose, low albumin, low
magnesium, and low phosphorus - Blood alcohol concentration (BAC)
- Biologic markers less sensitive specific than
questionnaires
24LFTs and excess alcohol use
- LFT elevations in 14.5 insurance applicants and
53 alcohol rehabilitation patients (Stout, 1998) - AST and ALT both may be elevated with alcohol
use. Sensitivity AST 60-80, ALT 50, specificity
low - AST/ALT ratio gt 2 suggests excess alcohol use
- GGT may be elevated with 4-5 drinks daily for gt4
weeks, decreases after 4-5 weeks abstinence.
Sensitivity 40-60, specificity 80. May not
identify low levels of consumption or binge
drinking. Poor screening test for alcohol. - Combined elevation of AST and GGT is more
suggestive of excess alcohol use
25Alcohol markers
- Carbohydrate-deficient transferrin (CDT) -
elevated by gt 4 drinks/day over 1-2 weeks,
normalizes with cessation in 1-3 weeks - CDT sensitivity 60-90, lower in women,
specificity 90-100, for regular chronic moderate
to heavy drinking, but not to binge drinking - Hemoglobin-associated acetaldehyde (HAA) -
combination of Hgb with acetaldehyde, elevated
with gt 5 drinks daily, or in the presence of
blood alcohol - Mean corpuscular volume (MCV) gt 100 - index of
red blood cell size, sensitivity low (30-60),
higher in alcohol dependent women, specificity
gt90, detects earlier drinking after a long
period of abstinence (Mundle et al, 2000)
26Abnormal laboratory values and CDT in insurance
applicants
- Positive CDT in 0.5 in 396 random applicants
- Elevated liver enzymes 11,477/123,513 applicants
- ALT 8.6, AST 2.9, GGT 8.3
- Reflexed to CDT
- Reflex CDT pos in 293/11,477 (2.6 ) with
elevated LFTs - GGT elevated in 70
- GGT and/or AST elevation in 97 of positive CDTs
- ALT alone elevated in only 2.7 of CDT positive
applicants - CDT positive in 2 with HDL gt 75 (n100), and in
5 of positive tobacco applicants (n101)
Stout, J Insur Med, 1998
27Reflex CDT in insurance applicants
- Reflex CDT positive in 1.96 of 33,082 applicants
with positive BAC, elevated LFTs or HDL - 31/132 applicants with positive blood alcohol
(23.5) - 493/29,091w/LFT elevations, mostly GGT(1.7)
- 127/3,979 with HDL gt 70 mg/dL (3.2)
- CDT correlates with smoking, BAC, GGT, AST HDL
- Recommend reflex testing with
- positive BAC, elevated GGT and/or AST with HDL gt
50 mg/dL, BUN lt 7.6 mg/dL, HDL gt 70 mg/dL, and
for cause
Stout, CRL News Views, 2000
28Reflex CDT and HAA in insurance applicants
- 50,000 HAA and CDT, reflexed, increased positive
rates in smokers, sensitivity 50-60, specificity
95-98, postulate CDT and HAA act differently,
occur independently - Reflex alcohol markers in 9,935 samples, 81.4
male, CDT tested in 85, (n8,460), HAA in 28,
(n2,810), and both tested in 13.4, (n1,335) - Positive CDT in 474/8,460 (5.6), positive HAA in
129/2,810 (4.6), both positive in 22/1,335
(1.6) - Recommended testing GGT gt 65 U/L, AST/ALT gt 1,
AST gt 33 U/L, HDL gt 80 mg/dL, best results with
both CDT and HAA - High AST/ALT ration more likely to give positive
CDT
Daniel, OTR 1997
Lowden Wagner, OTR 2002
29Maximum screen positive rates of CDT for various
laboratory tests
- Test
- GGT
- ALT
- AST
- AST GGT
- AST/ALT gt2
- HDL
- Cotinine
- Blood alcohol
- Triglycerides (low)
- BUN (low)
- Maximum positive CDT
- 4
- 2
- 7
- 10
- 8
- 8
- 6
- 23
- 4
- 20
63 (17-90) screen tests (Bio-Rad) confirmed
positive with capillary electrophoresis
Stout RL, CRL News Views 1998 2000
30Problems with CDT
- Sensitivity 60-90 for heavy regular consumption
of gt5 drinks per day but low for binge drinkers - Outdated assays had high false positives and
there is still no standardised assay - False positives due to chronic active hepatitis,
liver cancer, iron deficiency anaemia,
haemochromatosis, congenital disorders of
glycosylation, specimen aging and genetic
variants of transferin (up to 3 of general
population) - In a low prevalence population, majority of
results will be false positives for detecting
alcohol abuse - Positive CDT ? alcohol abuse or dependence
- Conclusion poor screening test but may have use
as a confirmatory test where there is a high
index of suspicion
31Excessive detection of alcohol consumption (EDAC)
and alcohol markers
- 134 (7) of 1680 samples positive for EDAC, a
profile of 15 tests including liver enzymes,
lipids, proteins and blood sugar - 22/134 (16) positive for CDT and/or HAA. Suggest
EDAC may identify excess alcohol use in
applicants with normal liver enzymes (9/22) but
positive CDT and/or HAA (Bean et al, J Insur Med,
2001) - Similar study, EDAC-CDT vs. traditional
screening but this did not include GGT (On the
Risk, 2002) - 5774 samples, 810 positive for traditional screen
(with GGT), 22/810 (3) CDT 324 positive EDAC,
44/324 (14) CDT (On the Risk, 2005) - Is a proprietary product, so difficult to
peer-review or reproduce
32Alcohol markers in screening insurance applicants
- A good screening test should be reliable and
accurate, provide good sensitivity, specificity
and predictive value - It should be clinically available and practical
for widespread application - Clinical CDT studies conducted in
alcohol-dependent groups, sensitivity is not good
for heavy or risky drinking - Data limited on HAA and EDAC
- HAA alcohol 8 papers, 4 same author (last in
Feb 2003), EDAC alcohol 7 in 8 years (all same
authors) in PubMed - No studies of relationship between positive
markers and morbidity or mortality endpoints - Positive CDT ? alcohol abuse or dependence
- Conclusion CDT is a poor screening test but may
have use as a confirmatory test where there is a
high index of suspicion
33Alcohol risk assessment
- Risk varies and depends on many factors including
pattern, quantity and frequency of alcohol use,
individual susceptibility and characteristics,
and external factors - Quantity alone does not identify the mortality
risk as there are trade offs in the various
causes of death - Effective underwriting, that utilizes multiple
sources and factors, provides the best assessment
of risk