POPULATIONBASED SCREENING FOR THYROID DYSFUNCTION

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POPULATION-BASED SCREENING FOR THYROID DYSFUNCTION

• Prof.Dr.Ioana Zosin
• University of Medicine and Pharmacy Victor
  Babes Timisoara
• Romania

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INTRODUCTION

• The population-based screening for thyroid
  dysfunction represents an actual topic, which
  elicits a lot of controversies and unsolved
  aspects.

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PLAN OF THE LECTURE

• Definition of Screening
• Thyroid Screening Classification
• Thyroid Screening Recommendations
• Thyroid Screening Tools
• Thyroid Universal Screening
• Thyroid Screening of High-Risk Groups
• Thyroid Screening during Pregnancy

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WHAT A SCREENING MEANS

• The application of a test to detect a potential
  disease or condition in a person who has no known
  signs or symptoms, with the goal of improving
  health outcomes.

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THYROID SCREENING CLASSIFICATION

• I. Universal (routine) screening
• for congenital hypothyroidism (CH)
• II. Screening of high risk groups
• (targeted, aggressive case finding)
  
  
• Screening in pregnancy has not yet a clear
  settled statute

?
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THYROID SCREENING RECOMMENDATIONS OF DIFFERENT
ORGANIZATIONS
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THYROID SCREENING RECOMMENDATIONS OF DIFFERENT
ORGANIZATIONS

• No organization recommends routine screening for
  thyroid disease in the general population, except
  screening of newborns for CH.
• The majority opts for a screening at the level
  of a populational segment.
• Some consider screening unjustified, because of
  insufficient evidence.

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SCREENING TOOLS, SCREENING STRATEGIES

• Tools and strategies are related to the type of
  screening (CH, targeted screening, screening
  during pregnancy)

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NEWBORN SCREENING FOR CH

• Significance
• CH induces various degrees of neurological, motor
  and growth deficits, including irreversible
  mental retardation the most worrisome aspect.
• Goal
• Newborn screening and thyroid substitution
  started within 2 weeks of age can normalize
  cognitive development.

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THE ORGANIZATION OF THE SCREENING SYSTEM

Pediatric Endocrinology
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COMPONENTS OF THE SYSTEM FOR THE SCREENING OF
NEWBORNS

• I. Education
• (health professionals, parents and policy
  makers)
• II. Screening
• (specimen collection, laboratory testing
• III. Early follow-up
• IV. Diagnosis
• V. Management
• VI. Evaluation

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SCREENING- COLLECTION ACTIVITIES

• Specimen collection capillary blood collected
  from a heel stick and absorbed onto filter paper
  (heel stick procedure)
• Timing the infant should be tested
• - before discharge
• - optimally by 2-4 days of age
• - independent of gestational age

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CHANGES in TSH and T4 in NEWBORN AT TERM
Fisher D, Klein A N Engl J Med, 1981
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SCREENINGLABORATORY TESTING in CH

• a primary TSH/backup T4 method
• a primary T4/backup TSH method
• a combined approach

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SCREENING METHODS
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INTERPRETATION OF SCREENING RESULTS
Each laboratory needs age-appropriate normative
values
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SCREENING RESULTS FURTHER ATTITUDE

• ?Newborns with an abnormal level of both T4 and
  TSH are presumed to be positive for CH and are
  close followed-up until the screening results are
  resolved.
• ?Those with either an abnormal T4 or TSH need a
  repeat specimen to clarify the discrepant
  findings.

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THE VALUE OF SCREENING STRATEGY

• -each strategy has advantages and disadvantages,
  both approaches appearing to be equivalent in
  the detection of CH
• -TSH is the most specific test for primary CH,
  but it does not detect cases with central
  (hypothalamic-pituitary) causes of CH

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• It is critical to remember that laboratory
  testing for screening purposes is different from
  diagnosing testing and screening is expected to
  produce some false positive results.

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HARMS OF SCREENING
False results
-induce parental stress nocebo effect -increase
significantly the costs of screening
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DIAGNOSIS

• 90 of those with initial positive results will
  remain positive, the remaining 10 cases are less
  severely affected and do not become detectable by
  TSH until age of 2-6 wks

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CURRENT ISSUES in SCREENING for CH

• there is not current consensus on the optimal
  screening method
• the usual programs miss many cases with central
  hypothyroidism
• a program using TSH,T4 and TBG was implemented
  since 1995 in the Netherlands and it improved
  significantly the diagnosis of central as well
  primary hypothyroidism
• Lanting
  CI et al., 2005

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TARGETED SCREENING FOR THYROID DYSFUNCTION
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TARGETED SCREENING FOR THYROID DYSFUNCTION

• It is performed when a provider believes there is
  a reason to screen thyroid function, based on
• - patients symptoms/signs
• - personal history
• - family history

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REASONS TO SCREEN FOR SUBCLINICAL THYROID
DYSFUNCTION (SCTD)

• The definition, complications, opportunity and
  the efficiency of treatment in SCTD are more or
  less controversial.
• The rationale for screening is to diagnose and
  treat SCTD

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DEFINITION OF SCTD

• SCTD represents an usual laboratory diagnosis,
  defined as an abnormal TSH level (reference range
  0.45-4.5 mU/L), associated with peripheral
  thyroid hormones values within their respective
  reference ranges.

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EPIDEMIOLOGY OF SCTD
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RISK CASES FOR SCTD
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SCREENING OF SCTDTOOLS
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SCREENING OF SCTDSTRATEGIES

• ?First line TSH cascading to TH measurements
• ?First line TSH and T4

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SCREENING OF SCTDSTRATEGIES
First line TSH-cascading to TH measurements when
TSH is abnormal

• TSH test has the ability to detect abnormalities
  before serum T4 and T3 levels are abnormal.
• It is critically important that the normal
  reference range for TSH be standardized

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REFERENCE RANGE FOR TSH
The present admitted reference for normal TSH is
0.45- 4.50 mU/L (ATA, AACE, ES, 2002)
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FIRST LINE TSH-CASCADING to TH
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SCREENING OF SCTDSTRATEGIES
First line TSH and T4, cascading to T3 if TSH is
low

• Provides the most satisfactory and sure method of
  assessing thyroid status

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PREFERRED STRATEGIES WHEN NO FINANCIAL OR OTHER
RESTRICTIONS(digivote response from RCPath
meeting in London)
TSH
TSH
TSHT4
TSH T4 T3
TSH T3
T4
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A TSH VALUE OUT OF REFERRENCE RANGE SCTD ?

• Serum TSH increase not associated with
  persistent S Hypo

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A TSH VALUE OUT OF REFERRENCE RANGE SCTD ?
Low Serum TSH not related to thyroid
overactivity
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NATURAL HISTORY OF SCTD

• Thyroid dysfunction is a graded phenomenon, which
  progresses from early to more advanced forms.

TSH
Euthyroidism
FT4
Ayala AR, et al,Endocrinologist, 1997
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NATURAL HISTORY OF SCTD

• may progress to overt disease
• may remain stable over time
• will spontaneously return to the reference
• range (recovery of thyroid function)

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S Hypo PROGRESSION TO OVERT DISEASE
it is estimated to 2-5 per year
Associated TPO Abs increase the risk by 80
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S HYPO SPONTANEOUS RECOVERY

• early or late
• Explanation transient expression of blocking TSH
  Abs
• TSH normalizes in 14.6 ? 42 ? (different
  follow-up periods)

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SPONTANEOUS NORMALIZATION OF TSH IN S Hypo
40/107 patients normalised TSH on follow-up (12 -
72 months)
Time for TSH normalization 6-60 months
Díez JJ et al, JCEM, 2005
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NATURAL HISTORY of S HYPER

• S Hyper may develop into overt disease at a rate
  of 1-5 per year
• the progression to overt disease depends on
• - initial TSH concentration
• - cause of endogenous S Hyper
• Prospective studies of patients with endogenous S
  Hyper show that TSH normalizes in almost 50 of
  cases, whereas overt hyperthyroidism develops at
  a rate of 5 per year.
• 
  Wiersinga WM, 1995

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CONSEQUENCES OF UNTREATED S Hypo
CARDIOVASCULAR FUNCTION AND LIPID PROFILE
1.
Systemic vascular resistance Arterial
stiffness Endothelial dysfunction
2.
Conflicting results
3.
Lipid profile
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S Hypo CORONARY HEART DISEASE, TOTAL MORTALITY
AND CARDIOVASCULAR DISEASE MORTALITY
Relative Risk End Point (95 CI)
P-Value CHD 1.20 (0.97-1.49) 0.140 Total
mortality 1.12 (0.99-1.26) 0.51 Cardiovascular
mortality 1.18 (0.98-1.42) 0.65
0.1
0
10
Lower Risk
Higher Risk
Ochs N, et al. Ann Intern Med. 2008
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ASSOCIATION OF S Hypo WITH RISK OF CORONARY HEART
DISEASE META-ANALYSIS RESULTS STRATIFIED BY MEAN
AGE
Ochs N, et al. Ann Intern Med. 2008
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CONSEQUENCES OF UNTREATED S Hyper
CARDIOVASCULAR RISK
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RELATIVE RISK of DEVELOPING ATRIAL FIBRILLATION
in S HYPER
(gt 60 years of age taking no thyroid
medications)
TSH 0.1 mIU/L
TSH 0.1-0.4 mIU/L
TSH 0.4 5.0 mIU/L
S Hyper was found to be an independent risk
factor for atrial fibrillation in patients with
other cardiac risk factors
Sawin CT, NEJM , 1994
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S Hyper AND ATRIAL FIBRILLATION
Mean age 66-68 yrs, prevalence of underlying CV
disease (57-65) similar in all 3 groups
TSHlt0.03mU/L
13.8
12.7
2.3
(n725)
(n613)
(n22,300)
Atrial Fibrillation
Auer J et al, Am Heart J, 2001
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S Hyper CORONARY HEART DISEASE, TOTAL MORTALITY
AND CARDIOVASCULAR DISEASE MORTALITY
Ochs N, et al. Ann Intern Med. 2008
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TO TREAT OR NOT SCTD ?
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ARGUMENTS FOR TREATMENT of S Hypo

• The strongest arguments for treatment
• the risk of progression to overt disease
• the possible improvement of quality of life
• the possibility that S Hypo represents a
  cardiovascular risk

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TREATMENT OF S Hypo
depends on TSH values
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ARE THERE BENEFITS OF SUBSTITUTION THERAPY IN S
Hypo ?

• -does not result in improved survival or
  decreased cardiovascular mortality
• -few data indicate that treatment improves some
  parameters of lipid profile and left ventricular
  function
• Vilar HCCE et al, Cochrane Database
  Syst.Rev.,2007

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RISKS AND DISADVANTAGES OF THYROXIN TREATMENT IN
S Hypo

• -Hyperthyroidism (one fifth of cases)
• -Reduced BMD ?
• -Risk of atrial fibrillation
• -Lifelong treatment
• -Costs of treatment

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WHAT SHOULD WE DO IN THE LIGHT OF THIS
UNCERTAINTY?

• -to treat cases with TSH gt10 mU/L
• -mild increases in TSH levels with some vague
  symptoms may justify a short trial of treatment
  of 3-6 mo
• -if not treated, cases should be monitored for
  TSH yearly

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THE MANAGEMENT of S HYPER
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SPECIAL ASPECTS of SCREENING in SCTD
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PITFALLS IN SCREENING and TREATMENT OF SCTD

• -inadequate strategy of screening
• -innacurate screening algorithm

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SCREENING OF THYROID DYSFUNCTION DURING PREGNANCY
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IS THYROID SCREENING DURING PREGNANCY NECESSARY ?

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EPIDEMIOLOGY OF THYROID DYSFUNCTION AND TPO Abs
INCIDENCE DURING PREGNANCY AND POSTPARTUM
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ADVERSE EVENTS FOR MOTHER AND FETUS IN THYROID
DYSFUNCTION
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MATERNAL UNTREATED Hypo AND AVERAGE CHILD IQ
SCORES TSH level elevated during the
midtrimesterIQ evaluated between 7-9 y
Control group
p0.005
7 p
Untreated
Average IQ Score
adapted from Haddow JE, N Engl J Med, 1999
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THE SIGNIFICANCE OF THYROID AUTOIMMUNITY (TAI)
IN PREGNANCY
TAI is associated with
incidence of PPTD

• rate of pregnancy loss,
• even in euthyroidism

incidence of gestational thyroid dysfunction by
worsening of a preexisting subtle thyroid
dysfunction (first trimester)
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THYROID SCREENING RECOMMENDATIONS DURING PREGNANCY

• ACOG Routine Screening not Recommended
• ENDOCRINE SOCIETY Middle position
• AACE Routine TSH before Pregnancy or during
  the First Trimester

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A) CASE-FINDING APPROACH for WOMEN at INCREASED
RISK for THYROID DYSFUNCTION

• family history of thyroid dysfunction
• personal history of thyroid dysfunction/thyroid
  surgery in the past
• goiter
• type I diabetes and other autoimmune disorders
• symptoms or clinical signs suggestive of a
  thyroid dysfunction
• previous therapeutic head or neck irradiation
• history of infertility, miscarriage or preterm
  delivery
• TPO Abs (when known)

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B) UNIVERSAL or ROUTINE THYROID SCREENING in
PREGNANCY

• very rationale because it may reduce the
  incidence of peripartum maternal complications
  and fetal loss and may improve fetal neurological
  development
• there are now concrete arguments that targeted
  screening may miss many cases of thyroid
  dysfunction (1/3)
• indirect argument gestational diabetes is
  screened in all women at 24-26 wks
  hypothyroidism being nearly as common as
  gestational diabetes could have the same treatment

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WHY CAN NOT BE IMPLEMENTED NOW THE UNIVERSAL
SCREENING IN PREGNANCY? Unsolved issues

• necessary thyroid tests
• timing of the determinations
• definition of a functional abnormality
• adequate therapeutic intervention and monitoring

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SUGGESTED THYROID SCREENING TOOLS DURING
PREGNANCY
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WHEN TO SCREEN?

• -the optimal time of screening has not been
  determined because of the suppression of TSH at
  the end of first trimester and immune-related
  changes
• - it may be performed 12-20 wks

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INTERPRETATION of THYROID PARAMETERS DURING
PREGNANCY THE USE OF GESTATIONAL AGE-SPECIFIC
INTERVALS

• The interpretation of screening tests during
  pregnancy is not facile (physiologic changes of
  pregnancy on maternal thyroid function)
• The reference intervals throughout pregnancy
  can differ significantly from non-pregnant
  reference intervals and the use of non-pregnant
  reference intervals for TFT may induce a large
  percent of unclassified results
• It is recommended to use trimester-specific
  reference intervals for the interpretation of TFT
  in pregnancy
• 
  

US Nat Acad of Clin Biochem 2003
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GESTATIONAL AGE-SPECIFIC REFERENCE INTERVALS FOR
TSH (mU/L)
1
2
3
Stricker et al, Eur J Endoc, 2007
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GESTATIONAL AGE-SPECIFIC REFERENCE INTERVALS FOR
FT4 (pmol/L)
1
2
3
Stricker et al, Eur J Endoc, 2007
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BENEFITS OF MEDICAL INTERVENTION FOR THYROID
DYSFUNCTION
Selenium- a new therapeutical aquisition
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POSTPARTUM THYROID DYSFUNCTION (PPTD)
Issues
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SCREENING RECOMMENDATIONS

• ? targeted screening
• Previous episode of
  PPT
• Personal history of
  AITD (Hashimoto)
• Positive TPO Abs
• Diabetes type 1
• Recurrent
  miscarriages
• Goiter
• Family history
• ? universal screening

Risk cases
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SCREENING TOOLS

• TPO Abs during pregnancy first trimester
  (identify the women at risk to develop the
  disease)
• TSH measurement in the postpartum 6wk
  (identifies the women who have developed PPTD)

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COST EFFECTIVENESS OF THYROID SCREENING

• A) UNIVERSAL SCREENING FOR CH

The cost-benefits are based on an estimated
burden to society with institutional care of
mentally retarded children
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B) THYROID SCREENING IN THE GENERAL
POPULATIONCOST-EFFECTIVENESS OF TSH SCREENING
vs. OTHER PREVENTIVE MEDICAL PRACTICES
Smoking cessation
Exercise for CHD prevention
Breast cancer screening women aged 40 to 74 y
Women ?age of 35 y and every 5 y after, 9,200
/QALY
Hypertension screening men aged 40 y
Men ?age of 35 y and every 5 y after,
22,500/QALY
Hypertension screening women aged 40 y
Breast cancer screening women aged 65 to 74 y
Cholesterol screening of asymptomatic population
0 Most cost- effective
20
40
60
80
100 Least cost- effective
Dollars (1994, thousands)
Danese MD et al, JAMA, 1996
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C) THYROID SCREENING DURING PREGNANCY

• Screening all pregnant women for AITD in the
  first trimester is cost-effective compared with
  no screening, regarding the possibility of
  impaired neurodevelopment that is associated with
  treatment.
• Dosiou C et al.,
  EJE, 2008
• 
  Thung S et al., AJOG, 2009

The costs depend on the national assurance system
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THYROID SCREENINGUNSOLVED ASPECTS/FUTURE STUDIES

• - A consensus regarding different types of
  screening would be useful
• - Supplementary screening studies are necessary
• - The thyroid screening during pregnancy needs a
  special attention

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• THANK YOU