Title: INTERPRETING MEDICAL TESTS AND OUTCOMES
1INTERPRETING MEDICAL TESTS AND OUTCOMES
- SESSION 8 FEBRUARY 27, 2006
- SESSION PRODUCER
- Denise Liston, Vice-President
- Underwriting Products Services
- LifePlans, Inc.
2Our Panelists
- Dr. Robert Watson, Allianz Life
- Dr. Bruce Margolis, Genworth Financial
3 White Matter Lesions
- Robert Watson, MD, FLMI
- Vice President Chief Medical Director
- Allianz Life
4A 58 yo F with an MRI report in her APS
- Reason for MRI Change in headaches
- MRI sequences performed Sagittal T1-weighted,
axial T-2 - weighted, axial FLAIR, axial DWI, sagittal FLAIR.
- The radiologists interpretation
- There are a few small areas of
hyperintense T2 - signals in the periventricular and
subcortical white - matters (sic) bilaterally. They are
nonspecific in - etiology. Differential dx includes
demyelinating - disease, vasculitis, chronic small
vessel ischemic - disease, inflammatory or infectious
disease such as - Lyme disease, or post-traumatic
changes. Correlation - with the patients clinical
history is suggested.
5Those things in the brain.
- White matter lesions (WML)
- White matter hyperintensities (WMH)
- White matter changes (WMC)
- Small vessel disease
- Small vessel ischemic changes
- Chronic small vessel ischemic disease
- Subcortical atherosclerotic changes
- Unidentified bright objects (UBOs)
- Leukoaraiosis (CT scan)
6THE FEMALE BRAIN
7WML Talk Objectives
- What they are what causes them
- Importance of grading location
- Associated stroke risk
- Associated dementia risk
- Combination with infarcts and/or cerebral atrophy
- Migraines WML
- Underwriting the risk
8(No Transcript)
9What they are what causes them
- Pathology
- Demyelination glial rarefaction
- as opposed to the scar tissue
(gliosis) - cavitation seen with strokes.
- Causation
- ischemic demyelination
- hyaline arteriosclerosis (hyaline wall
thickening of the small arterioles)
10What they are what causes them (cont.)
- 2 major risk factors
- Hypertension
- Increasing age
11What they are what causes them (cont.)
- The variables of blood pressure strongly
associated with WML risk - Hypertension presence
- Hypertension duration
- Adequacy of control with Rx
- de Leeuw FE et al. The Rotterdam Study.
Brain. 2002125765-72. -
12What they are what causes them (cont.)
- A random sample of 1920 participants aged 55
- 72. Prevalence grade according to
- hypertension present or not.
-
- BP status mild WML mod WML
severe WML - Normotensives 53 24 7.6
- Hypertensives
- - Rx, good control 49 22 14
- - Rx, w/o control 39 23 24
-
Liao D et al. Atherosclerosis Risk in Communities
Study (ARIC). Stroke.
1996272262-2270.
13What they are what causes them (cont.)
- Subjects with a negative hx of hypertension
- Age severe WML
- 60-70 7.4
- 70-80 16.7
- 80-90 47.4
-
de Leeuw FE et al. The Rotterdam Scan Study.
Brain. 2002125765-72.
14What they are what causes them (cont.)
- Other causes
- ApoE e4 (subcortical WML)
- Other as yet unidentified genetic factors
- Severe COPD with hypoxemia
-
-
de Leeuw FE et al. The Rotterdam Scan Study.
Brain. 2002125765-72.
15What they are what causes them (cont.)
- CADASIL (cerebral autosomal dominant
- arteriopathy with subcortical infarcts and
leukoencephalopathy) - Binswangers disease (syndrome of WML
- dementia)
-
16What they are what causes them (cont.)
- Other cardiac risk factors?
- DM
- No.
- Lipids
- No.
- Smoking
- Yes, but only in African Americans. (ARIC study)
- No. Worsens it if already present, doesnt cause
it. -
(Cardiovascular Health Study) - Nope. (Rotterdam Scan Study)
-
17A Simple Desultory Philippic
High quality (at least somewhat credible) WML
studies The Rotterdam Scan Study The
Cardiovascular Health Study The Atherosclerosis
Risk in Communities (ARIC) Study Large,
community-based populations, prospective,
multivariate-controlled, longitudinal with medium
to long-term follow-up, published in journals
with documented high journalistic quality
standards.
18A Simple Desultory Philippic (cont.)
- Regarding the interpretation of findings in the
- medical literature
- Most medical studies published in the world
- literature are flawed in numerous ways --
- due to major study design problems such as
- selection bias and ascertainment bias -- and
- their findings are unreliable.
- Most new medical findings published in
- the medical literature will eventually
be - proven to be false.
-
19A Simple Desultory Philippic (cont.)
When a medical study shows a dramatic new
result that was unknown and unexpected prior
to the publication of that new study.
.the likelihood of this finding representing a
true fact more often than not goes from being
highly improbable up to improbable.
20A Simple Desultory Philippic (cont.)
Regarding the interpretation of a medical test,
a general rule of thumb applicable to most
When the pretest probability of a certain
condition being present is low, a positive test
result does not usually raise that level of
probability to the range of high.
21Carbohydrate Deficient Transferrin (CDT) Test
Interpretation An Example of Truth vs. Illusion
0.1 - 0.2 - 0.5 - 1 - 2 - 5 - 10
- 20 - 30 - 40 - 50 - 60 - 70 - 80
- 90 - 99 -
- 99 - 90 - 80 - 70 - 60 - 50 - 40 -
30 - 20 - 10 - 5 - 2 - 1 - 0.5 - 0.2 - 0.1
- 1000 -
- 500 -
- 200 -
- 100 -
- 50 -
- 20 -
- 10 -
- 5 -
- 1-
illusory test line
- 0.5 - 0.2 - 0.1 - 0.05 - 0 .02 - 0
.01 - 0 005 - 0.002 - 0.001
true test line
Post-test probability
Pre-test probability
Likelihood ratio
22 23WML grading 1-9 (ARIC Study)
- grade 0 no white matter findings
- grade 1 discontinuous periventricular rim with
- minimal dots of subcortical
disease - grade 2 thin, continuous periventricular rim
with a few patches of subcortical disease - grade 3 thicker, continuous periventricular rim
with scattered patches of subcortical disease - grade 4 thicker, shaggier periventricular rim
with - mild subcortical disease, may have
minimal confluent periventricular lesions
24WML grading 1-9 (cont.)
- grade 5 mild periventricular confluence
- surrounding the frontal and
occipital horns - grade 6 moderate periventricular confluence
- surrounding the frontal and
occipital horns - grade 7 periventricular confluence with moderate
- involvement of the centrum
semiovale -
- grade 8 periventricular confluence involving
most - of the centrum semiovale
- grade 9 findings more remarkable than grade 8
25WML grading (cont.)
2
1
4
3
1
6
5
8
7
Liao D et al. Atherosclerosis Risk in Communities
Study, Stroke. 1996272262-70.
26WML grading (cont.)
- ARIC Study
- grade 1 mild
- grade 2 moderate
- grade 3-9 severe
- Rotterdam Scan Study
- Subcortical
- graded in tertiles by volume
- Periventricular
- grade 0-1 mild
- grade 1.5-3.0 moderate
- grade 3.5-9.0 severe
272 main WML risks
- Stroke risk
- Cognitive decline risk
28WML Stroke Risk
29WML stroke RR in the elderly
- 3973 CHS participants, mean age 75, mean 7-yr.
FU. Controlled for age, gender, race, SBP, DM,
CVD, AF, infarct(s) on MRI, LVH, creat., carotid
wall thickness. - WML grade Stroke RR Incidence
- 0 or 1 1.0 0.6/yr.
- 2 1.4 0.9/yr.
- 3 2.4 1.7/yr.
- 4 3.7 2.8/yr.
- gt 5 2.7 2.6/yr.
- Kuller LH et al.
Cardiovascular Health Study.
- Stroke.
200435(8)1821-5.
30WML symptomatic stroke risk
- Mean age 72 multivariate controlled mean
4.2-yr. follow-up - Location Stroke RR
- Subcortical
- tertile 1 1.0
- tertile 2 1.4
- tertile 3 1.4
- Periventricular
- grade 0-1 1.0
- grade 1.5-3.0 2.0
- grade 3.5-9.0 2.8
- (Silent infarct 3.3)
- (Subcortical periventricular risks are
additive.) - Vermeer SE et al. Rotterdam Scan Study.
Stroke. 2003341126-9. -
31Risk of WML/silent stroke combined
- WML grade WML only WML silent stroke
- 0 or 1 1.0 1.1
- 2 1.4 2.1
- 3 2.4 4.2
- 4 3.7 4.4
- gt 5 2.6 3.7
-
- Kuller LH et al. Cardiovascular Health Study.
Stroke. 200435(8)1821-5.
32WML stroke RR in the very old
- 1433 subjects aged gt75 yrs. with no stroke on
initial MRI. FU MRI done 5 yrs. later, showing
17.7 had 1 or more new strokes. - Severe WML was the single strongest predictor of
having a stroke out of 68 variables, including
all potential cardiovascular risk factors. -
- Longstreth WT et al. Cardiovascular Health
Study. Stroke. 2002332376-82. -
33WML Dementia Risk
- Small vessel disease
- is implicated in vascular dementia
- amplifies the effects of the
- pathologic changes of Alzheimers
34WML dementia risk
- Mean age 72 mean 5.2-yr. FU. Adjusted for age,
sex, education, BP, DM, smoking APOE genotype. - Location Dementia RR
- Subcortical
- tertile 1 1.0
- tertile 2 0.8 (NS)
- tertile 3 2.0 (NS)
- Periventricular
- grade 0-3 1.0
- grade gt3-6 2.0
- grade gt6-9 4.5
- (Dementia 76 AD, 13 VD, 11 other)
-
- Prins ND et al. Rotterdam Scan Study.
Arch Neurol. 20041531-4.
35WML dementia risk (cont.)
- 563 nondemented subjects aged 60-90, mean 7.3-yr
FU. Adjusted for age, sex, education, depression,
cerebral atrophy, cerebral infarcts. - Subjects with severe periventricular WML
experience cognitive decline nearly 3 times as
fast as the group average. - (0.28 MMSE points lost per yr. vs. 0.10 points
lost per yr.) - De Groot J et al. Rotterdam Scan
Study. Ann Neurol. 200252335-341.
36WML worsening dementia
- Subjects with worsening white matter grade
experience greater cognitive decline. - WML progression by 2 grades correlates with a
2-fold average rate of cognitive score drop
(i.e., average cognitive scores reach by 5 yrs.
the level reached by nonprogressors at 10 yrs.) -
- Longstreth WT et al. Cardiovascular Health Study,
Stroke. 20053656-61.
37WML, cerebral atrophy, post-stroke dementia
- 323 stroke pts. who underwent MRIs 3 mos.
post-stroke - The severity of WML is independently
- related to post-stroke cognitive decline.
- General cortical atrophy also predicts a range
- of cognitive deficits
- Infarct volume had less relevance.
- Jokinen H et al. . Helsinki
Stroke Aging Memory Study. J Neurol Neurosurg - Psychiatry. 2005761229-33.
-
38WML Migraines
39Migraines WML
- 295 migraineurs, mean age 48.5, half previously
undiagnosed from a community population (40 with
hypertension) cross-sectional study. Controlled
for age, sex, BP, smoking, BMI, BCP, chol, EtOH,
education, hx ergotamine use. - 38 of both migraineurs and controls had at
least 1 WML. So, no difference in overall WML
incidence. - Also no difference according to sex, migraine
frequency, or migraine type (with aura vs.
without). - Also no difference for periventricular WML.
- 1.9 OR for top quintile subcortical WML for
women with migraines - 2.4 OR for top quintile subcortical WML for
women - with high-frequency migraines (gt 1/mo.).
- Kruit MC et al. MRI CAMERA
Study. JAMA. 2004 291427.
40Migraines silent strokes
- Small subclinical posterior circulation
- strokes much more common in migraineurs,
- esp. in migraine with aura
- -- 0.7 in controls
- -- 2.2 in migraine without aura
- -- 7.5 of migraine with aura
-
-
- Kruit MC et al. MRI CAMERA Study. Brain. 2005
1282068-77.
41Migraines WML summary
- The Jury is still out. Need a medium to long-term
prospective community-based study of a larger
number of migraineurs to find the truth. - Tentative working inferences
- WMLs somewhat more common in
- migraineurs than in the general population.
- Nature of association uncertain.
- No good evidence to date that WMLs in
migraineurs - increase risk of future symptomatic stroke or
other - adverse outcome long-term.
-
-
-
42Underwriting WML
- Optimal rating system for WML considers
- WML severity
- Associated symptomatology
- Age
- Hypertension presence control
- Grade (especially for the periventricular WML)
- Coexistent silent infarct(s)
- Coexistent cerebral atrophy ( its severity)
- Stability on sequential MRIs (if done)
- Hx of migraine ( modestly favorable if mild/mod
subcortical WML present at a younger age)
43Underwriting WML Generalizations
- Mild
- Common finding, not much of a concern.
- Moderate
- Not a concern if isolated problem in older ages,
especially if subcortical only. - More of a concern at younger ages,
- especially if periventricular, and/or if
progressive or combined with BP not under
excellent control and/or combined with
mod-severe atrophy and/or with stroke(s).
44Underwriting WML Generalizations(cont.)
- Severe
- Major concern in younger age.
- Major concern in older age, especially if
periventricular, and/or if progressive or
combined with BP not under excellent control
and/or combined with mod-severe atrophy and/or
with stroke(s). - .
45Back to our 58 yo F with an MRI report in her
APS.
- Has grade 1 periventricular grade 1
- subcortical WML like approx. 50
- of people her age.
- This MRI finding no increased risk per se.
46The End
47Liver Function Tests
- Evaluating Abnormal Values
- Bruce Margolis, DO, MBA
- Genworth Financial
48Agenda
- Liver function tests (LFT)
- Causes of abnormal LFTs
- Non-alcoholic steatosis/steatohepatitis (NASH)
- Hepatitis A,B,C
- Gilberts Syndrome
- Primary Biliary Cirrhosis
- Underwriting Considerations
49Liver Anatomy
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143992-B411-43F4-8B25-AB3A460A3478/0/LiverFINALweb
.jpg
50Liver Function Tests
- Misnomer
- Proteins
- High Concentration in Liver Cells
- Present in Other Bodily Tissues
- Released with Liver Injury
51Liver Function Tests
- AST(SGOT) aspartate aminotransferase
- ALT(SGPT) alanine aminotransferase
- GGT gamma-glutamyltransferase
- ALP alkaline phosphatase
- Bilirubin
52Liver Function Tests
- Hepatocellular Enzymes
- AST/ALT
- Markers of Cholestasis
- ALP/GGT
- Tests of Liver Excretion
- Bilirubin
- Tests of Liver Synthetic Function
- Albumin/Prothrombin Time (PT)
53Hepatocellular Enzymes
- AST
- Hepatocyte
- Heart
- Brain
- Skeletal Muscle
- Kidney
- ALT
- Hepatocyte
- Liver
- Kidney
- Lung
- Pancreas
- Red Blood Cells
- Skeletal Muscle
54Cholestasis
- ALP
- Bile Duct Cells
- Bone
- Intestine
- Also Increased In
- Pregnancy
- Childhood
- GGT
- Biliary Tract Disease
- Heart
- Brain
- Pancreas
- Kidney Spleen
- Seminal Vesicles
55Bilirubin Metabolism
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iochem/coursenotes/blanchaer_tutorials/Frank_II/bi
liMetabMap.gif
56Elevated LFTs
- Non-alcoholic steatosis (fatty liver)
- Non-alcoholic steatohepatitis (fatty liver with
inflammation) - Chronic viral hepatitis
- Alcoholic liver disease
- Hemochromatosis
- Autoimmune hepatitis
- Granulomatous hepatitis
- Alpha-1-antitrypsin deficiency
- Primary biliary cirrhosis
- Wilsons disease
- Medications (phenytoin, statins)
57Non-Alcoholic Steatosis
- Most common liver biopsy finding
- Elevations in ALT, GGT
- Risk factors
- Obesity
- Diabetes
- Hyperlipidemia
- Female gender
- Generally benign
58Non-Alcoholic Steatohepatitis (NASH)
- Fatty infiltration with inflammation
- May see cell destruction /- fibrosis
- 10-20 progress to cirrhosis
- Risk factors for progression
- Evidence of fibrosis
- DM Type 2
- AST/ALT ratio gt1
59Hepatitis A
- RNA virus
- Transmission fecal-oral route
- Occurs sporadically or in outbreaks
- Most recover without sequelae
- Does not cause chronic liver disease
- Acute diagnosis IgM antibody historical
infection IgG antibody - Very good long-term prognosis
60Hepatitis B
- DNA virus
- Declining incidence in US
- Highest rate of disease 20-49 year olds
- Estimated 1.25 million infected in US
- Less than 5 develop chronic infection
- Death from chronic liver disease 15-25 those
chronically infected - Increased risk hepatoma
61Hepatitis B
- Risk Groups
- IV drug abuse
- Sexual transmission
- Household contacts chronically infected
- Infants born to infected mothers
- Healthcare workers
- Dialysis patients
62Hepatitis B
http//www.hon.ch/Library/Theme/HepB/hbvirus.GIF
63Hepatitis B
Acute Infection
Chronic Infection
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64Hepatitis B
Adapted from http//www.cdc.gov/ncidod/diseases/h
epatitis/b/Bserology.htm
65Hepatitis B
Adapted from Lok SF, McMahon BJ. Hepatology
2004391
66Hepatitis B
Lau GKK, et al. NEJM 20053522682
67Hepatitis C
- Leading cause chronic liver disease US
- Leading cause death from liver disease US
- Leading indication for liver transplant
- Estimated 2.7 million in US infected
- 30,000 new infections 2003
- Most infections related to illegal injection drug
use
68Hepatitis C
- 80 have no signs or symptoms
- 55-85 go on to chronic infection
- 70 of chronically infected have chronic liver
disease - 5-20 develop cirrhosis over 20-25 years
- Hepatoma develops 1-2/yr in those with cirrhosis
- 1-5 die from chronic liver disease
69Hepatitis C
- Testing
- HCV antibodies (anti-HCV)
- Qualitative HCV RNA
- Confirm anti-HCV
- If negative
- Resolved HCV infection
- False positive anti-HCV
- Low/intermittent viral levels
- Quantitative HCV RNA
- Reporting ranges vary according to test
70Hepatitis C
- Genotyping
- 6 genotypes
- 1 70 of US infections
- Response rates 42-46
- 2/3 3 found Southeast Asia
- Response rates 76-82
- 4 Africa/Middle East
- 5 South Africa
- 6 Hong Kong/Vietnam
- Predicts likelihood of treatment response
71Hepatitis C
1986
2002
2001
1998
From Strader, DB, et al. Hepatology 2004391147
72Hepatitis C
- Indications for Treatment
- HCV RNA
- Portal-portal fibrosis
- Genotypes 2/3
- Presence of steatosis
- Increase risk of progression to cirrhosis
- Sustained response absence of HCV RNA 6 months
after treatment
73Gilberts Syndrome
- Inherited unconjugated hyperbilirubinemia
- Bilirubin levels usually lt3 mg/dl should be lt6
mg/dl - 3-7 population
- Increased levels precipitated by
- Dehydration
- Fasting
- Menstruation
- Stress
- Totally benign disorder
74Primary Biliary Cirrhosis
- Chronic cholestatic liver disease
- Progressive destruction of intrahepatic bile
ducts - Felt to be autoimmune
- Positive antimitochondral antibodies
- Prevalence 40.2/100,000
- Femalemale ratio 91
- Peak age presentation 35-60
75Primary Biliary Cirrhosis
- Asymptomatic
- Slowly progressive
- 40-67 develop symptomatic disease 5-7 years
- If untreated, median survival 16 years
- Symptomatic
- If untreated, median survival 7.5 years
- Untreated leads to cirrhosis
76Primary Biliary Cirrhosis
- Laboratory findings (early)
- Increased ALP/GGT
- Anti-mitochondral antibodies
- Signs/Symptoms
- Fatigue
- Pruritis
- Jaundice
- Hepatomegaly
- Splenomegaly
77Primary Biliary Cirrhosis
- Staging
- Stage 1 portal inflammation bile duct
abnormalities - Stage 2 periportal fibrosis /- inflammation
- Stage 3 septal fibrosis with inflammation
- Stage 4 nodules with inflammation
78Primary Biliary Cirrhosis
- Treatment
- Ursodeoxycholic acid (UDCA)
- Prognosis
- Variable
- Asymptomatic do better
- Stage12 - do better 25-30 complete response
- Studies suggest almost normal longevity in those
treated with Stage 1 2 disease
79Underwriting Considerations
- Which enzyme(s) elevated and trend
- Old vs. new
- BMI, ETOH, presence of DM, hepatitis, medications
- Results of laboratory evaluation
- Ultrasound
- Biopsy results
- Treatment/Response
80Questions?