INTERPRETING MEDICAL TESTS AND OUTCOMES

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INTERPRETING MEDICAL TESTS AND OUTCOMES

• SESSION 8 FEBRUARY 27, 2006
• SESSION PRODUCER
• Denise Liston, Vice-President
• Underwriting Products Services
• LifePlans, Inc.

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Our Panelists

• Dr. Robert Watson, Allianz Life
• Dr. Bruce Margolis, Genworth Financial

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White Matter Lesions

• Robert Watson, MD, FLMI
• Vice President Chief Medical Director
• Allianz Life

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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.

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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)

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THE FEMALE BRAIN
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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

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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)

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What they are what causes them (cont.)

• 2 major risk factors
• Hypertension
• Increasing age

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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.

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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.

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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.

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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.

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What they are what causes them (cont.)

• CADASIL (cerebral autosomal dominant
• arteriopathy with subcortical infarcts and
  leukoencephalopathy)
• Binswangers disease (syndrome of WML
• dementia)

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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)

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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.

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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.

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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.

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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.

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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
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• WML
• Severity Location

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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

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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

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

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2 main WML risks

• Stroke risk
• Cognitive decline risk

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WML Stroke Risk
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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.

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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.

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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.

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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.

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WML Dementia Risk

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

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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.

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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.

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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.

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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.
  

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WML Migraines
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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.

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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.

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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.

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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)

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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).

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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).
• .

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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.

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The End

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Liver Function Tests

• Evaluating Abnormal Values
• Bruce Margolis, DO, MBA
• Genworth Financial

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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

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Liver Anatomy
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143992-B411-43F4-8B25-AB3A460A3478/0/LiverFINALweb
.jpg
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Liver Function Tests

• Misnomer
• Proteins
• High Concentration in Liver Cells
• Present in Other Bodily Tissues
• Released with Liver Injury

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Liver Function Tests

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

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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)

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Hepatocellular Enzymes

• AST
• Hepatocyte
• Heart
• Brain
• Skeletal Muscle
• Kidney

• ALT
• Hepatocyte
• Liver
• Kidney
• Lung
• Pancreas
• Red Blood Cells
• Skeletal Muscle

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Cholestasis

• ALP
• Bile Duct Cells
• Bone
• Intestine
• Also Increased In
• Pregnancy
• Childhood

• GGT
• Biliary Tract Disease
• Heart
• Brain
• Pancreas
• Kidney Spleen
• Seminal Vesicles

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

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Non-Alcoholic Steatosis

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

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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

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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

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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

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Hepatitis B

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

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Hepatitis B
http//www.hon.ch/Library/Theme/HepB/hbvirus.GIF
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Hepatitis B
Acute Infection
Chronic Infection
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gif
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Hepatitis B
Adapted from http//www.cdc.gov/ncidod/diseases/h
epatitis/b/Bserology.htm
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Hepatitis B
Adapted from Lok SF, McMahon BJ. Hepatology
2004391
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Hepatitis B
Lau GKK, et al. NEJM 20053522682
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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

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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

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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

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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

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

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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

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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

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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

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Primary Biliary Cirrhosis

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

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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

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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

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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

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Questions?