Thyroid Flashcards
Describe the regulation of thyroid hormone production.
Hypothalamus > TRH --> Ant Pit > TSH --> Thyroid gland > T3/T4
T3/T4 inhibits secretion of TRH
T4 converted to T3 in liver
T3/T4 can be conjugated with glucuronide and sulfate in liver and excreted in the bile
What secretes TSH?
thyrotrope cells in the ant pit
Describe the structure of TSH
Glycoprotein with an alpha and beta subunit
Alpha subunit of TSH is identical to subunits for
hCG
LH
FSH
only variability is in glycosylation
What is unique to SH and determines its receptor specificity
beta subunit
what is the receptor for TSH
thyroid follicular cells
What are the steps in thyroid hormone biosynthesis?
NaCL symporter to absorb I-> Thyroglobulin secretion> exocytosis> Iodine gets oxidated> Iodination with TPO> conjugation> endocytosis> proteolysis to make tyroxine and triodothyronine> transported to blood
What percent of thyroid hormone is synthesized as T4 vs T3?
T4 90%
T3 9%
rT3 1 %
How is 80% of T3 made?
peripheral deiodination of T4
how is rT3 made?
periophaeral deiodination of T4
What % of T4 is bound to TBG/TTR/Alb?
TBG + T4 = 75%
T4-TTr = 10%
T4-albumine = 12%
What % of T3 is bound to TBG/TTR/Alb?
TBG + T3 = 80%
T3-TTr = 5%
T3-albumine = 15%
A 47 year old female presents to her primary care physician complaining of palpitations and diaphoresis.
What is the best test for screening for thyroid disease?
Thyrotropin(TSH) is the SINGLE BEST TEST for assessing thyroid function
– Very SMALL changes in free T4 induce large reciprocal changes in TSH
Why is it recommended to measure free T4, rather than total T4, total T3 or free T3 to initially assess active hormone levels?
• Measurement of T4 is preferred over T3 due to the excess of T4
– 100 times as much total T4 as total T3 – 10 times as much free T4 as free T3
• >99.9% of T4 is bound to protein and biologically inactive
– A variety of conditions can alter thyroid hormone‐ binding protein levels
– This causes changes in total T4 but free T4 remains the same
Is there a rationale for measuring total T3 or free T3? If you did want to measure T3 would it be preferable to order total or free T3?
In most cases of hyperthyroidism, patients have elevated T4 and T3, so free T4 measurement is sufficient
There are occasional patients who have T3 toxicosis:
– Low TSH, normal FT4, elevated free T3 and total T3
– Thought to represent early stages of hyperthyroidism or be due to an autonomous nodule
- If a patient appears hyperthyroid clinically, but FT4 is normal, consider assessing T3
Is total T3 preferred or FT3?
Total T3 is preferred over FT3, as assays for FT3 are less widely validated
However, if the patient has a known altered distribution of binding proteins that would affect total T3, free T3 should be measured instead
What are causes of hyperthyroidism with NORMAL or HIGH radioidodine uptake??
Graves Hashitoxicosis Toxic adenoma/toxic multinodular goiter Iodine induced Secondary to trophoblastic dz or GCT TSH producing pituitary adenoma
What are causes of hyperthyroidism with near ABSENT radioiodine uptake?
thyroiditis
exogenous hyperthyrodism
ectopic hyperthyroidism (struma ovarii, metatstic thryoid cancer)
What is the typical presentation of a
patient with hyperthyroidism?
Anxiety, emotional lability, tremor, palpitations, weakness, heat intolerance, diaphoresis, weight loss, hyperdefecation, urinary frequency, oligo‐ or amenorrhea
What features should one look for on physical exam to help with the differential diagnosis?
– Hyperactivity and rapid speech
– Lid retraction and lid lag from sympathetic hyperactivity
– Thyroid exam
– Look for evidence of Graves’:
• Exophthalmos (proptosis – forward displacement of eye)
• Periorbital/conjunctival edema
• Pretibial myxedema
What tests could be ordered next to determine the cause of hyperthyroidism?
- If patient has an enlarged thyroid, ophthalmopathy and severe hyperthyroidism, further evaluation is unnecessary (Graves)
- Thyroid uptake and scan
- Thyroid ultrasound
- Measurement of Graves’‐related autoantibodies
- Repeat TSH, free T4
What does the ATA/AACE recommend as the first line test if clinical presentation is not diagnostic of Graves?
Thyroid uptake
Thyroid scan can be added if nodularity
When should you measure graves related autoAbs
Only when uptake and scan are unavailable or contraindicated
What autoantibodies are found in patients with thyroid disease?
Anti‐thyroid peroxidase (Anti-TPO)
anti‐thyroglobulin antibodies (Anti-TG)
Auto‐antibodies to the TSH (thyrotropin) receptor (TRAb)
What, if any role, do autoAbs found in patients with thyroid disease play in the pathophysiology?
Anti‐TPO and anti‐Tg are markers of autoimmune thyroid damage and not causative of disease, whereas TSI cause Graves’ disease pathology
Where are Anti-TPO and anti TG found?
– Found in autoimmune thyroid disorders ‐ Graves’ disease AND Hashimoto’s thyroiditis
– Thought to be secondary to the thyroid damage caused by infiltrating lymphocytes
How do auto Abs to the TSH receptor (TRAb) cause GRaves?
– Can be stimulating, neutral or blocking
– Stimulating Abs cause Graves’ disease by binding to TSH receptor, leading to thyroid hormone synthesis and secretion, as well as growth of the gland (diffuse goiter)
– Blocking antibodies can be found in patients with Hashimoto’s
but their causative role in hypothyroidism debated
What is the frequency of Ab detection in Graves vs Hashimotos thyroiditis?
Anti-TPO: 80% vs > 90%
Anti TG: 40-70% vs > 90%
Anti TRab: 100% (stimulating) vs 10-15% blocking
What tests are available to measure thyroid stimulating immunoglobulins?
– Quantitation of the amount of TSH receptor antibodies in patient serum
– Bioassay which measures the stimulatory effect of the antibodies on TSH‐responsive cells
What are the pros/cons of quantifying the amount of TSH receptor Abs?
• Pros: quick, less expensive
• Cons: Quantitates stimulating, blocking and neutral TSH
receptor antibodies
What are the pros and cons of hte bioassy?
- Incubate patient serum with the cells and normal control serum
- Reported as an index (or ratio)
- Pros: Specific for detection of stimulating antibodies only
- Cons: Expensive, time‐consuming assay
How does hte TSI bioassay work?
• ModifiedTSH receptor binds stimulating Abs but NOT blocking Abs
- Increases cAMP which activates a cAMP‐ responsive promoter
- Leads to production of LUCIFERASE
• Cells incubated with patient serum and normal control serum and an index TSI bioassay
or ratio is reported
Patient has the following:
• US: Borderline enlarged right lobe with 2.5 cm nodule
• Uptake and scan:
– Uptake measured at 24 hours: 63.1% (10‐30%)
– Diffuse increased uptake with decreased uptake in the right thyroid nodule
• TSI index: 5.4 (≤ 1.3)
• TSH: ≤ 0.02 mU/L (0.4 – 4 mU/L)
• FT4: 6.92 ng/dL (0.7 – 1.85 ng/dL)
• Anti‐TPO: 1927 IU/mL (< 35 IU/mL)
• Anti‐Tg: 50 IU/mL (< 40 IU/mL)
Diagnosis?
Graves’ disease:
– Elevated TSI index
– Increased diffuse uptake
How does reflex testing work?
What is the thyroid reflex testing algorithm here at the U of M?
Reflex testing triggers
the automatic ordering of a follow up test(s) if the initial test is abnormal
Most laboratories will offer reflex to FT4 if there is an abnormal TSH (4)
HOw do you interpret these lab results?
TSH: 9.68 mU/L (0.45 – 4.0 mU/mL)
FT4: 0.9 ng/dL (0.7 – 1.5 ng/dL)
Subclinical hypothyroidism
– Defined by a normal FT4 in the presence of an elevated TSH
– Prevalence ranges from 3‐8 %, increases with age
What are the causes of subclinical hypothyroidism?
Hashimoto’s thyroiditis (chronic autoimmune thyroiditis)
Subacute, postpartum or painless thyroiditis
Thyroid injury from surgery, radioactive iodine therapy, external radiotherapy to head or neck
Drugs impairing thyroid function
Inadequate replacement therapy for over hypothyroidism
Thyroid infiltration (i.e. amyloidosis, sarcoidosis, hemochromatosis, etc.) Central hypothyroidism with impaired TSH bioactivity
Toxic substances
TSH receptor gene mutations
What should be done for a pt withs subclinical hypothyroidism?
Expert panel recommendation:
– Comprised of endocrinologists and other specialists
– Do not treat patients with TSH between 4.5 and 10 mIU/L
– Monitor patients between 4.5‐10 mIU/L every 6‐12 months
• Also recommended measurement of anti‐TPO antibodies to predict risk of development of overt hypothyroidism or associated autoimmune disease
Ho do you interpret these Ab results? When are these tests considered most useful?
– Thyroid peroxidase antibody: 1749 (< 35 IU/mL) – Thyroglobulin antibody: 50 (< 40 IU/mL)
Hashimoto’s thyroiditis (chronic autoimmune thyroiditis)
in patients with subclinical hypothyroidism as they are at higher risk for progressing to permanent overt hypothyroidism
stored as a colloid and provides tyrosine residues for T3 and T4 synthesis
thyroglobulin
catalyzes iodination of tyrosine residues of thyroglobulin
TPO
Nearly all pts with Hashimoto thyroiditis have high serum concentrations of …
anti-TG and anti-TPO
What is the pathophysiology of Hashimoto thyroiditis?
• Profuse lymphocytic infiltration, lymphoid germinal centers and destruction of thyroid follicles
– Both T and B lymphocytes involved
• Central pathological phenomenon is thyroid‐cell death by cytotoxic T cells
• Therefore the antibodies are considered secondary to the thyroid damage inflicted by T cells
How would you interpret the following lab results?
TSH: 2.8 mU/L (0.45 – 2.5 mU/mL) FT4: 0.9 ng/dL (0.7 – 1.5 ng/dL)
• Did you notice that the upper limit of TSH was changed from 4.0 to 2.5? Did this affect your instinctual interpretation of the result?
• There is considerable debate about the upper limit of the reference range for TSH
• NHANES III study showed that after excluding individuals with diseases or factors known to affect thyroid hormone levels, 95% of the reference population had TSH levels between 0.3‐2.5 mIU/L
– In 2002 the National Academy of Clinical Biochemistry recommended the upper limit be lowered from 4‐5 mIU/L to 2.5 mIU/L
– In 2003 the AACE recommmended the upper limit be lowered from 4‐5 mIU/L to 3.0 mIU/L
What are arguments for lowering the upper limit?
– Higher rate of thyroid autoimmunity in patients with TSH > 3 mIU/L
– Higher rate of progression to overt thyroid disease in patients with TSH > 3 mIU/L
What are arguments against lowering the upper limit?
– Mild elevations of TSH are sometimes reversible
– Expense of therapy without proven benefit
– Additional 20 million Americans diagnosed with subclinical hypothyroidism
– Possibility of overtreatment by primary care physicians who see an abnormal lab value and react
What are the current recommendations for screening for hypothyroidism in nonpregnant adults?
No real concensus so…
One suggested approach is to screen those with:
– Symptoms of hypothyroidism
– Risk factors of hypothyroidism
– patients taking drugs which may impair thyroid function
A 47 yo F notices a bump on her neck and complains of diffiuclty swallowing. A thyroid nodule is palpable.
What testing should be ordered next?
TSH and thyroid US
What is the ddx for a thyroid nodule? Benign vs malignant?
Benign: Multinodular (sporadic) goiter (“colloid adenoma”) Hashimoto’s thyroiditis Cysts: Colloid, simple or hemorrhagic Follicular adenomas Hurthle‐cell adenomas
Malignant: Papillary carcinoma follicular medullary anaplastic primary thyroid lymphoma metastatic carcinoma (breast, renal cell, etc.)
If a thyroid US reveals a 2.1 cm left thyroid nodule but a normal TSH what should be done next?
FNA
What percent of thyroid nodules are found to be cancerous? What groups have a higher prevalence of cancerous nodules?
• 4 – 6.5 % of thyroid nodules are cancerous
• Cancer prevalence is higher in:
– Children
– Adults < 30 years old or > 60 years old
– Patients with a history of head and neck
irradiation
– Patients with a family history of thyroid cancer
What test(s) could be used to monitor the patient for residual or recurrent cancer?
Serum thyroglobulin has supplanted the uptake scan as a marker of tumor persistence or tumor recurrence for differentiated thyroid cancer
– For follicular, papillary and Hurthle cell cancer
– Synthesized only by the thyroid follicular cells so a specific marker of thyroid tissue
– Serum Tg concentration is dependent on the mass of thyroid tissue present
– Recommended to use the same assay/lab to monitor over time due to wide variability between assays
Why might this patient’s thyroglobulin be slightly above expected levels post‐thyroidectomy and ablation?
• Residual cancer
• Anti‐thyroglobulin antibodies
– Thyroglobulin antibodies can interfere with
measurement of thyroglobulin
– 20 – 25% of patients with differentiated thyroid cancer have anti‐Tg
– Results can vary differently depending on type of thyroglobulin assay used
– Radioimmunoassays can have falsely high or low thyroglobulin results
– Immunometric assays can have falsely low results
Why can RIA give you both a falsely high TG and falsely low TG?
– Falsely high Tg: if patient has anti‐Tg antibodies and little/no Tg, the anti‐ Tg antibodies will bind up radiolabeled Tg and decrease bound signal
Patient anti‐Tg
– Falsely low Tg: if patient has anti‐Tg and high Tg, anti‐Tg will bind patient Tg results in increase bound signal
Why may IMA give you a falsely low TG?
– Falsely low Tg: if patient has anti‐Tg antibodies, it will bind up the patient Tg
What should you do if a RIA assay shows that thyroglobulina nd anti-TG levels are declining?
continue to monitor every 6‐12 months and do occasional radiographic studies as clinically indicated
What should you do if thyroglobulina nd anti-TG levels are stable or rising?
consider imaging
