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INTERPRETING MEDICAL TESTS AND OUTCOMES

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Title: INTERPRETING MEDICAL TESTS AND OUTCOMES


1
INTERPRETING MEDICAL TESTS AND OUTCOMES
  • SESSION 8 FEBRUARY 27, 2006
  • SESSION PRODUCER
  • Denise Liston, Vice-President
  • Underwriting Products Services
  • LifePlans, Inc.

2
Our 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

4
A 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.

5
Those 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)

6
THE FEMALE BRAIN
7
WML 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)
9
What 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)

10
What they are what causes them (cont.)
  • 2 major risk factors
  • Hypertension
  • Increasing age

11
What 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.

12
What 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.

13
What 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.

14
What 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.

15
What they are what causes them (cont.)
  • CADASIL (cerebral autosomal dominant
  • arteriopathy with subcortical infarcts and
    leukoencephalopathy)
  • Binswangers disease (syndrome of WML
  • dementia)


16
What 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)


17
A 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.

18
A 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.


19
A 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.

20
A 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.

21
Carbohydrate 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
  • WML
  • Severity Location

23
WML 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

24
WML 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

25
WML grading (cont.)
2
1
4
3
1
6
5
8
7
Liao D et al. Atherosclerosis Risk in Communities
Study, Stroke. 1996272262-70.
26
WML 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

27
2 main WML risks
  • Stroke risk
  • Cognitive decline risk

28
WML Stroke Risk
29
WML 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.

30
WML 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.

31
Risk 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.

32
WML 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.

33
WML Dementia Risk
  • Small vessel disease
  • is implicated in vascular dementia
  • amplifies the effects of the
  • pathologic changes of Alzheimers

34
WML 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.

35
WML 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.

36
WML 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.

37
WML, 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.

38
WML Migraines
39
Migraines 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.

40
Migraines 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.

41
Migraines 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.

42
Underwriting 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)

43
Underwriting 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).

44
Underwriting 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).
  • .

45
Back 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.

46
The End

47
Liver Function Tests
  • Evaluating Abnormal Values
  • Bruce Margolis, DO, MBA
  • Genworth Financial

48
Agenda
  • Liver function tests (LFT)
  • Causes of abnormal LFTs
  • Non-alcoholic steatosis/steatohepatitis (NASH)
  • Hepatitis A,B,C
  • Gilberts Syndrome
  • Primary Biliary Cirrhosis
  • Underwriting Considerations

49
Liver Anatomy
http//www.cincinnatichildrens.org/NR/rdonlyres/32
143992-B411-43F4-8B25-AB3A460A3478/0/LiverFINALweb
.jpg
50
Liver Function Tests
  • Misnomer
  • Proteins
  • High Concentration in Liver Cells
  • Present in Other Bodily Tissues
  • Released with Liver Injury

51
Liver Function Tests
  • AST(SGOT) aspartate aminotransferase
  • ALT(SGPT) alanine aminotransferase
  • GGT gamma-glutamyltransferase
  • ALP alkaline phosphatase
  • Bilirubin

52
Liver 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)

53
Hepatocellular Enzymes
  • AST
  • Hepatocyte
  • Heart
  • Brain
  • Skeletal Muscle
  • Kidney
  • ALT
  • Hepatocyte
  • Liver
  • Kidney
  • Lung
  • Pancreas
  • Red Blood Cells
  • Skeletal Muscle

54
Cholestasis
  • ALP
  • Bile Duct Cells
  • Bone
  • Intestine
  • Also Increased In
  • Pregnancy
  • Childhood
  • GGT
  • Biliary Tract Disease
  • Heart
  • Brain
  • Pancreas
  • Kidney Spleen
  • Seminal Vesicles

55
Bilirubin Metabolism
http//www.umanitoba.ca/faculties/medicine/units/b
iochem/coursenotes/blanchaer_tutorials/Frank_II/bi
liMetabMap.gif
56
Elevated 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)

57
Non-Alcoholic Steatosis
  • Most common liver biopsy finding
  • Elevations in ALT, GGT
  • Risk factors
  • Obesity
  • Diabetes
  • Hyperlipidemia
  • Female gender
  • Generally benign

58
Non-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

59
Hepatitis 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

60
Hepatitis 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

61
Hepatitis B
  • Risk Groups
  • IV drug abuse
  • Sexual transmission
  • Household contacts chronically infected
  • Infants born to infected mothers
  • Healthcare workers
  • Dialysis patients

62
Hepatitis B
http//www.hon.ch/Library/Theme/HepB/hbvirus.GIF
63
Hepatitis B
Acute Infection
Chronic Infection
http//www.thebody.com/hepp/jun_jul01/images/fig2.
gif
64
Hepatitis B
Adapted from http//www.cdc.gov/ncidod/diseases/h
epatitis/b/Bserology.htm
65
Hepatitis B
Adapted from Lok SF, McMahon BJ. Hepatology
2004391
66
Hepatitis B
Lau GKK, et al. NEJM 20053522682
67
Hepatitis 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

68
Hepatitis 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

69
Hepatitis 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

70
Hepatitis 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

71
Hepatitis C
1986
2002
2001
1998
From Strader, DB, et al. Hepatology 2004391147
72
Hepatitis 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

73
Gilberts 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

74
Primary 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

75
Primary 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

76
Primary Biliary Cirrhosis
  • Laboratory findings (early)
  • Increased ALP/GGT
  • Anti-mitochondral antibodies
  • Signs/Symptoms
  • Fatigue
  • Pruritis
  • Jaundice
  • Hepatomegaly
  • Splenomegaly

77
Primary 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

78
Primary 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

79
Underwriting 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

80
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