Newborn Screening Overview and Screening for Congenital Hypothyroidism Flashcards
1
Q
What is Screening?
A
- Screening is a process of identifying apparently healthy people who may be at increased risk of a disease or condition. They can then be offered information, further tests and/or treatment to reduce their risk and/or complications.
- Screening is never 100% sensitive or specific. In any screening programme there is a minimum of false positive and false negative results.
2
Q
What is the Wilson and Junger’s Criteria for a Screenable Disease?
A
- The condition sought should be an important health problem.
- There must be an accepted and effective treatment for patients with the disease.
- Facilities for diagnosis and treatment should be available.
- There must be an appropriate, acceptable, and reasonably accurate screening test.
- The natural history of the condition, including development from latent to manifest disease, should be adequately understood.
- The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
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3
Q
How is the Newborn Bloodspot Screening conducted?
A
- Babies are screened by testing a capillary sample of blood obtained by a heel-prick stab – this is collected on to a card to form dried blood spots.
- In the UK babies are tested at 5 days of age – in other countries the practice is to test earlier.
4
Q
What are advantages of testing on Day 5?
A
- Minimises false positives as a result of TSH surge that occurs at birth.
In US where babies are screened prior to discharge the practice of early discharge of otherwise healthy full term infants has led to an increase in the false positive rate.
5
Q
What are the features of Newborn Screening Laboratories?
A
- Screening laboratories test a population of 25,000 - >100,000.
- Organisation of screening into a limited number of laboratories serving a defined minimum population is cost-effective, concentrates experience and information, facilitates audit and promotes development of expertise for these relatively rare disorders.
- In addition to analysis and reporting, the screening lab provides an advisory service, conducts clinical audit and is involved in teaching and training of other health professionals involved in the service.
6
Q
What are guideliness for Blood Spots?
A
- Each spot must be large enough to punch two discs (each disc is 3.2mm diameter) from each spot.
- Cards with multi-spotted samples (i.e. using several small spots to fill one whole circle) or samples spotted on both sides of the card are rejected.
- Multi-spotted samples are not homogeneous – therefore results are dependent on the area of the sample punched. They have also been found to produce lower analyte results.
7
Q
What is Congenital Hypothyroidism?
A
- CHT is defined as defective function of the thyroid gland from birth.
- CHT is the most common treatable cause of intellectual disability
- Increase in cases of CHT with eutopic gland-in-situ.
- ?Increased incidence may be due to greater sensitivity of current screening methods and/or inclusion of infants with transient disease.
- Traditionally thought to be usually sporadic – but familial cases occur with a frequency that is 15-fold higher than by chance alone; the genetic basis of these familial cases has been established in some but not all pedigrees.
- Altered ethnicities of the screened population, increased multiple and premature births, iodine status and hither to uncharacterised factors may also contribute.
8
Q
What is the aetiology of Congenital Hypothyroidism?
A
Primary
- Thyroid dysgenesis (Absent gland, hypoplastic gland, Ectopic Gland)
- Thyroid Dyshormonogenesis
Secondary (Central CH)
9
Q
What is the result of TSH Receptor Mutations?
A
- Result in TSH resistance – phenotype dependent on both the mutation and number of mutated TSHR alleles.
- Inheritance may be either dominant or recessive.
- Complete TSH resistance manifests as severe CH with gland hypoplasia, at the milder end of the spectrum raised TSH may be associated with preserved thyroid hormone biosynthesis from a normal sized gland.
- Even severe TSHR with an undetectable gland on imaging is associated with a measurable thyroglobulin, confirming the presence of some thyroid tissue.
10
Q
Describe the thyroid hormone synthesis process?
A
- In the thyroid follicular cells, iodide is actively transported and concentrated by the sodium iodide transporter present in the baso-lateral membrane.
- It is then oxidised by hydrogen peroxide generation system (thyroperoxidase, Pendrin (transports iodine across the apical membrane) and bound to tyrosine residues in thyroglobulin to form iodotyrosine (iodide organification)
- Some of these iodotyrosine residues (monoiodotyrosine and diiodotyrosine) are combined to form T4 and T3.
- When needed thyroglobulin is hydrolysed and hormones are released into the blood.
- A small part of the iodotyrosines are hydrolysed in the gland and iodine is recovered by the action of dehalogenases.
- Thyroid hormone biosynthesis requires an intact synthesis pathway comprising all of the transporter molecules, enzymes, thyroglubulin (TG) and adequate iodine substrate.
11
Q
What are some Gene causing Defects In Thyroid Hormone Synthesis?
A
-
Sodium-iodide symporter (SLC5A5) (AR)
- Transports iodine across basal membrane
- Spectrum from euthyroidism to severe CH
-
Thyroperoxidase (TPO) (AR)
- Catalyses the oxidation, organification, and coupling reactions
- Can lead to either Severe CH or Sometimes mild CH with monoallelic variants
-
Dual oxidases (DUOX1 and DUOX2) (AR & AD)
- H2O2 generation in the follicle
- Usually leads to mild-moderate or transient CH
-
Dual oxidase maturation factor 2 (DUOXA2) (AR)
- Required to express DUOX2 enzymatic activity
- Can lead to Mild transient CH
-
Pendrin (SLC26A4) (AR)
- Transport iodine across apical membrane
- Can lead to Euthyroid/mild hypothyroidism
-
Thyroglobulin (TG) (AD & AR)
- Support for thyroid hormone synthesis
- Can cause Spectrum from euthyroidism to severe CH
-
Iodotyrosine deiodinase (IYD) (AR)
- Nitroreductase-related enzyme capable of deiodinating iodotyrosines
- Spectrum from euthyroidism to severe CH; later onset hypothyroidism reported
12
Q
What are screening strategies for Congenital Hypothyroidism?
A
- TSH only (Most countries worldwide)
- T4/TSH (some USA states, Italy, Japan, Netherlands & Israel)
13
Q
What are the features of TSH only screening?
A
- TSH-based programmes are more sensitive in detecting primary hypothyroidism and more specific.
- Hence will pick both overt and borderline/subclinical primary CH. Benefits to neurodevelopmental outcomes when treating infants with mild to moderately raised TSH and borderline free T4 concentrations is controversial
- TSH will not detect babies with secondary hypothyroidism due to pituitary failure
14
Q
What are the drawbacks for T4/TSH only screening?
A
- A disadvantage of this approach is the high false-positive rate. It would be a challenge to maintain high sensitivity for detecting primary CH and avoid too many false positives.
15
Q
What is the Measurement of Bloodspot TSH using DELFIA?
A
- The blood is first eluted from the blood spot and TSH is then measured in the eluate using DELFIA method.
- DELFIA – time resolved dissociation-enhanced lanthanide fluoroimmunoassay
- Sandwich type assay with two monoclonal antibodies, one of which is immobilised on the walls of a microtitre well, whilst the other antibody is in liquid form and is labelled with europium.
- After the sample is incubated with solid and liquid phase antibodies (TSH forms sandwich between the two Abs) the wells are washed and enhancement solution added.
- The europium ions dissociate into solution where they combine with components of the enhancement solution to form highly fluorescent chelates.
- The fluorescence in the wells is measured in time-resolved fluorimeter which overcomes much of problem of naturally occurring background fluorescence in biological samples by making use of the long fluorescent decay time for lanthanide chelates.
