Thyroid-pre class.ppt

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CONFIDENTIAL March 17 2004
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Thyroid hormones regulate biochemical
processes essential to growth and
development including:
 Energy production from carbohydrate
 Cardiovascular function
 Nervous system reactivity
 Digestive rate
Thyroid

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Thyroid Status
Euthyroidism - hormone production
and release is normal
Hypothyroidism - hormone production
and release is abnormally low
Hyperthyroidism - hormone production
and release is abnormally high

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Prevalence of Thyroid Disease
USA distribution
 Hypothyroidism - common
– 2 - 15% of population
 Hyperthyroidism - rare
– 0.3 - 0.6% of population
Distribution outside USA
 Variable

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Primary thyroid disease
 The defect is with the thyroid gland itself
Secondary thyroid disease
 The defect is with the pituitary gland
Tertiary thyroid disease
 The defect is with the hypothalamus
Thyroid Disease

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Hypothalamus and Pituitary

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Additional thyroid disorders with gland
involvement only, having little effect on
hormone production
 Goiter (enlargement)
 Thyroid cancer
 Thyroiditis (inflammation)
Thyroid Disease

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 98% of thyroid disease in the US is
hypothyroidism
 Most are female
 Most are primary
 Most cases involve autoimmunity
 This may be due to an abnormality in:
 Hypothalamus
 Pituitary gland
 Thyroid gland
Hypothyroidism

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Adults
 Early symptoms
– Weakness, nervousness, cold intolerance, headache,
fatigue, heavy menstruation
 Physical signs
– Thin brittle nails, thinning of hair, pale skin,
decreased reflexes
 Late symptoms
– Slow speech, excessive weight gain, constipation,
absence of sweating, limb swelling, hoarseness,
difficulty breathing, chest pain, deafness, absence of
menstruation
Hypothyroidism

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Hypothyroidism
Serious complications
 Heart failure
 Coronary artery atherosclerosis
 Anemia
 Infertility
 Increased susceptibility to infection
 Psychiatric disorders

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Hyperthyroidism
May be due to:
 Graves’ disease
– Autoantibodies against components or regions of
the thyroid plasma membrane, possibly including
the receptor for TSH leading, after a complex
series of events, to hypersecretion of hormone
 Toxic goiter
 Excessive intake of thyroid hormones
 Thyroiditis
 TSH-producing pituitary tumors

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Hyperthyroidism
Symptoms
 Restlessness, nervousness, irritability,
fatigability
 Unexplained weight loss despite a
ravenous appetite
 Excessive sweating, intolerance of heat
 Tremors
 Difficulty focusing eyes
 Diarrhea
 Rapid and irregular heartbeat

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Hyperthyroidism
 Complications - serious
 Heart failure
 Severe wasting of muscles and bones
 Eye damage
 Psychosis
 “Thyroid storm”
– Fever, heart failure, delirium
– Death ~2% of cases

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Thyroid Hormone Production
Thyroid hormone synthesis is controlled
by the hypothalamus through a
hormone called TRH (thyroid releasing
hormone)
Thyroid
Pituitary
Hypothalamus
TRH
TSH
T3/T4

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Thyroid/Pituitary Feedback Loop
Thyroid
Pituitary
Hypothalamus
TRH
TSH
T3/T4
Euthyroid Hypothyroid
TRH
TSH
T3/T4
Hyperthyroid
Low
High
TRH
TSH
T3/T4
Low
High

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Access System Thyroid Assays
 Hypersensitive TSH
 Total T4
 Free T4
 Total T3
 Free T3
 Thyroid Uptake
 Thyroglobulin*
 Thyroglobulin
Antibody*
* Used as a Tumor Marker Assay

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Thyroid Stimulating Hormone
TSH
Principal regulator of thyroid function
Released from the anterior pituitary
Glycoprotein hormone consisting of an
a and b chain
 The b chain is responsible for the
immunological and biological specificity

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TSH
TSH regulates the release of thyroid
hormones, thyroxine (T4) and
triiodothyronine (T3)
 Thyrotropin-releasing hormone (TRH) from
the hypothalamus controls the secretion of
TSH from the pituitary
 A negative feedback mechanism of the
hypothalamus monitors T3 and T4, adjusting
TRH secretion

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TSH Assay Sensitivity
Analytical sensitivity
 Lowest concentration that can be reliably
measured (detection limit)
– Determined as the dose on the curve which is 2 SD
from the RLU from the zero calibrator
Functional sensitivity
 The concentration that can be measured all the
time, at less than or equal to 20% CV

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TSH Assays
The first TSH assay was developed in
the 1950s
1st generation was developed in 1960
(detected hypo but not hyper)
2nd generation was developed in the
1980s using monoclonal antibodies

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Definition of ‘Generation’
for TSH Assays
Generation limits
 1st: functional sensitivity of 1.0 mIU/mL
 2nd: functional sensitivity of 0.1 mIU/mL
 3rd: functional sensitivity of 0.01 mIU/mL
3rd generation TSH has ~ a 10 fold
greater assay functional sensitivity than
second generation

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TSH
Currently, the most effective measure of
thyroid activity is the hypersensitive 3rd
generation TSH assay
 Can discriminate hyperthyroid from euthyroid
 Less prone to interferences
 Responsive to subtle changes in thyroid status
 Very reliable, precise and consistent
throughout low end of measuring range

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Suspect Hypothyroidism Suspect Hyperthyroidism
Elevated Normal Subnormal Undetectable
Free T4 and Diagnose Free T4 Free T4
Thyroid Antibody Panel*
Normal Elevated Subnormal Elevated
Diagnose Diagnose Diagnose
Evaluate
Diagnose
for Hypopituitarism
or Hypoadrenalism
Thyroid Diagnosis Using 3rd Generation Access HYPERsensitive TSH
Suspect Thyroid Disease*

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Value of 3rd Gen in US Market
Challenge
 Differentiation of subnormal vs.
nondetectable TSH not always top priority
 Laboratories still using 2nd gen assay may
not see utility in reporting numeric values
<0.1

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Value of 3rd Gen in US Market
Analytical performance at borderline
 For 2nd gen assay, 0.1 is at lowest
detectable dose, where precision is poorest
 For 3rd gen assay, 0.1 is in a robust
portion of curve with good precision, thus
providing better resolution for borderline
cases
BCI does not charge more for 3rd
generation

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Thyroid Replacement Therapy
TSH is the most accurate indicator for
determination of the adequacy of
hormone replacement therapy
 Thyroid hormone dosage should be
adjusted at similar time intervals until TSH
values are within the normal range

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Thyroxine
Total T4
T4 is secreted from the thyroid gland
when stimulated by TSH
Total T4 is present in bound (99.97%)
and free (0.03%) forms
 No intrinsic biological activity until
converted to T3

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Total T4
 Elevated levels
 Hyperthyroidism
 pregnancy
 Decreased levels
 Hypothyroid diseases
such as Hashimoto’s
thyroiditis
Alone, does not provide a diagnosis for
hyperthyroidism or hypothyroidism

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Free T4
0.03% of T4 is not bound (Free T4)
Biologically active form of thyroxine
 Decrease is diagnostic for hypothyroidism
 Increase is diagnostic for hyperthyroidism
Normal range varies in pregnancy
 Especially useful when levels of binding
proteins have influenced the Total T4
result

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Triiodothyronine
Total T3
T3 has intrinsic biological activity
 20% comes from thyroid gland
 80% comes from de-iodination of T4
occurring in the cells
 Total T3 is present in bound (99.6 -
99.8%) and free (0.2 - 0.4%) forms

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 Used to assess patients with
hyperthyroid appearance, normal FT4
and decreased TSH
 The TSH negative feedback loop
responds more readily to T3 than to T4
Total T3

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Total T3
 Elevated levels
 Hyperthyroidism
 Pregnancy
 T3 toxicosis
(selective T3
production)
 Decreased levels
 Hypothyroid states
such as Hashimoto’s
thyroiditis, neonatal
hypothyroiditis
 Secondary
hypothyroid states

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Free T3
0.2 - 0.4% of T3 is not bound (Free T3)
Major biologically active thyroid hormone
 Decreased in hypothyroidism
 Increased in hyperthyroidism
– 5% have only free T3 elevated
 Especially useful when levels of binding
proteins have influenced the Total T3
result

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Thyroid Uptake
 Measures number of unbound sites on carrier
proteins, primarily Thyroid Binding Globulin
(TBG)
 TU expressed as the % of the T4 added to the
reaction mixture which is bound
 Used in FTI (free thyroxine index) calculation
 Method of estimating free thyroid hormone prior
to availability of direct free hormone assays

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Thyroid Uptake
 Decreased TU
(Relatively unsaturated
binding sites)
 Hypothyroidism
 Pregnancy
 Increased TBG
synthesis
 Oral contraceptives
 Elevated TU
(Highly saturated
binding sites)
 Hyperthyroidism
 Anabolic steroid
therapy
 Reduced TBG
synthesis
 Drug interactions

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Free Thyroxine Index
Method to estimate free thyroid hormone
(FT4) prior to development of direct free
hormone assays
FTI = T4 mg/dL x Thyroid Uptake %
Median of Reference Interval
Clinical significance
 Increased in hyperthyroidism
 Decreased in hypothyroidism

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Thyroid Hormones - Summary
>99+% T3 and T4 in circulation is
bound
 TBG (thyroid binding globulin)
 Albumin
 Pre-albumin

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Thyroid Hormones - Summary
T3/T4 concentration and activity
 T4 is 70 x higher in concentration than T3
 T3 is 4 x more active than T4
 T3 can be made from T4 by removing an
iodine molecule
 Both are only active in their “free” form
– Less than 1% is free in the healthy state
– Concentration of free forms is diagnostic

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Thyroid Testing
 Purpose
 Check overall
metabolic status
 Differentiate
between different
types of thyroid
disease
 Monitor/evaluate
therapy
TRH
TSH
T3/T4

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Suspect Thyroid Disease
Hypothyroidism Hyperthyroidism
Thyroid Diagnosis Using Free T4 Estimate (T4 and Thyroid Uptake)
Subnormal Marginal Normal Normal Marginal Elevated
(Interferences?)
2nd Gen 2nd Gen 2nd Gen 2nd Gen
TSH TSH TSH Total T3 TSH
Normal Elevated Elevated Normal Normal Elevated Normal Subnormal
or borderline
Diagnose Diagnose Diagnose Diagnose Diagnose
FT4 FT4 TSH 3rd Gen TSH
and and or TRH &FT4
Auto ABs Auto ABs
Normal Subnormal Subnormal Normal
Diagnose Diagnose Diagnose Diagnose Diagnose
Evaluate
for Hypopituitarism
or Hypoadrenalism

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Interpretation Difficulties
Results may be unreliable in the majority
of the candidate population
 Pregnant women
 Women on birth control
 Individuals with nonthyroid illness
 Individuals with malnutrition
 Individuals with disalbuminemia
 Persons with increased TBG

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Interpretation Difficulties
Pituitary lag is major cause of apparent
clinical discrepancy
 Development phase - TSH is sensitive, but
FT4 lags
 Early treatment phase - FT4 is reliable, but
TSH lags by 6-8 weeks
Drug effects
Pregnancy/general health effects

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Thyroid Hormones in Pregnancy
 TSH and hCG have structural similarity
 The a chains are similar to hCG (also FSH
and LH)
 hCG rises to extremely high
levels during pregnancy
– 1 in 500 pregnant women experience TSH
receptor stimulation, causing a temporary, non-
autoimmune Graves disease, demonstrated by
decreased levels of TSH and high levels of free
T4 and free T3
TSH
hCG

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When to Do Thyroid Testing in
Clinically Euthyroid Patients
 Newborns
 Goiter
 History of chronic thyroiditis
 History of radioiodine therapy
 History of head and neck irradiation
 Graves’ eye disease
 Monitoring thyroid replacement/suppressive therapy
 Atrial fibrillation or flutter
 Prior history of thyroid medications

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Other Circumstances When
Thyroid Testing May Be Appropriate
History of autoimmune disease
 Personal history of non-thyroid autoimmune disease
(diabetes)
 Familial history of thyroid or other autoimmune disease
 Neonate of mother with history of autoimmune thyroid
disease
Personal history of depression
Unexplained major weight loss or gain
All patients over the age of 50

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Testing ‘Well’ Patients
If the TSH level is normal, no further work-
up is needed, unless the patient becomes
symptomatic or suspicion for hypo is
strong
Medications do not affect TSH levels as
they do TT3 and TT4
If the TSH is high, it should be repeated
with a FT4 level

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Testing ‘Well’ Patients
If only 1 test can be performed, TSH
would be best (for ambulatory well
patients)
 Greater sensitivity for detecting thyroid
dysfunction
 Patients with early thyroid failure or mild
hyperthyroidism often will have abnormal
TSH values with FT4 estimates in the normal
range

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Suspect Thyroid Disease
It is recommended that patients
suspected of thyroid dysfunction on
clinical grounds have both FT4 and
TSH
If both the TSH and the FT4 are
normal thyroid disease is essentially
excluded

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Hospitalized or NTI
(Non-Thyroidal Illness)
TSH levels may be transiently
abnormal in patients under the acute
stress of illness
FT4 may be a more reliable indicator

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Pituitary Dysfunction
Due to Hypothalamic or Pituitary Disease
Normal TSH values, despite significant
reductions in FT4
 These inappropriate TSH values are
presumably due to a reduction in TSH
bioactivity, frequently observed in such cases
 A poor TSH response to TRH stimulation
testing will assist in confirmation of diagnosis

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Want More Information?
 Check out the
American
Thyroid
Association
web site
www.thyroid.org

Thyroid-pre class.ppt

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