Endocrinology Basics
• Endocrine systems are dynamic. – Individual lab values outside the “normal” range may be entirely
appropriate depending on the clinical status
• Normal is a relative value– If a hormone is low, its regulating hormone should be elevated– If a hormone is elevated, its regulating hormone should be low
• Avoid the temptation to jump to imaging until you know the patient has a disease. – Imaging can be performed quicker than biochemical testing– Non-functioning, benign tumors are common in endocrine
organs– You may develop tunnel vision and misdiagnose
Diagnosis and Management of Thyroid Disorders
A. Keith Cryar, MD
Thyroid Evaluation
• Thyroid Stimulating Hormone (TSH)
• Free Thyroxine (Free T4 or FT4)
• Anti-TPO antibodies
• Thyroglobulin
• Thyroid ultrasound
• Thyroid scan and uptake
• Total thyroxine (T4)
– Triiodothyronine Uptake
– Free Thyroxine Index
• Total triiodothyronine (Total T3 or T3)
• Free triiodothyronine (Free T3 or FT3)
• Fine Needle Aspiration (FNA)
Total thyroxine (total T4
or T4)
• It is only the unbound fraction that results in the biological effects of T4
Most of the total
T4 is bound
to proteins
• Can result in values above or below the normal range in a patient without abnormal thyroid function
• Pregnancy and oral contraceptives
• Low albumin
Variation in
protein binding
Free Thyroxine (Free T4 or FT4)
Measurements of the unbound or free T4
Several methods are used
• Standard methods are efficient for batch runs and “less likely” to be affected by protein variations
• “Gold standard” is by dialysis through a semi-permeable, but is technician intensive
TSH
This is the workhorse of thyroid tests
• It is readily available, reliable, and the most sensitive assessment of thyroid function (with a few exceptions)
Sensitive
• Changes logarithmically in response to changes in thyroid hormone levels
• Can be suppressed or elevated while the thyroid hormone levels are still in the “normal range for a population”
Not effected by proteins that often influence thyroid hormone levels
• Thyroid binding globulin (TBG)
• Pregnancy or oral contraceptives
• Hypoalbuminemia
When is TSH not useful?
• By definition, secretion is sub-normal and does not reflect actual thyroid status
Hypothalamic or pituitary disease
• Once suppressed, TSH does not reliably discriminate between subclinical, moderate, or severe hyperthyroidism
Suppressed TSH
• After radioactive iodine or surgical treatment of hyperthyroidism, TSH remains low for several weeks
• After treatment of prolonged or severe hypothyroidism, TSH may not return to normal for several weeks
Rapid changes in thyroid hormone levels, especially after prolonged abnormal states
Subclinical Thyroid Disease
• TSH is often used as a screening test or to follow patients on thyroid hormone replacement
• A FT4 is needed to clarify severity of thyroid dysfunction
Refers to patients with an abnormal TSH and normal thyroid hormone
levels
• Subclinical hyperthyroidism
• Subclinical hypothyroidism
“Subclinical” indicates that the typical signs and
symptoms are not evident to the
patient or clinician
• A suppressed TSH in elderly patients is associated with atrial fibrillation
• For other patient populations there is controversy over who will benefit from treatment
Subclinical is not necessarily the
same as irrelevant
Autoimmune Thyroid Disease
• Anti-thyroid peroxidase (anti-TPO) antibodies
Chronic lymphocytic thyroiditis
(Hashimoto’s thyroiditis)
• Thyroid receptor antibodies (TRAB)
• Thyroid Stimulating Immunoglobulin (TSIG)
Graves’ disease
Thyroglobulin
Co-released with thyroxine
• Low in exogenous thyroid ingestion
• High in hyperthyroidism
Primarily used is as a marker for recurrent thyroid cancer
• Most thyroid cancers retain ability to release
• Presence indicates residual normal thyroid tissue or cancer
Antibodies to thyroglobulin
• Presence of anti-thyroglobulin Ab can nullify the result of the thyroglobulin
• Liquid chromatography assays
• Not affected by antibodies
• Expensive and only performed in select national labs
Misc. Thyroid
Tests
• Radioactive iodine (I131 or I123)
• Scan - configuration
• Uptake - function
Nuclear
• Provides the most structural detail
• May provides clues if a nodule is benign or malignant
Ultrasound
• Thyroid nodules are common
• Most are benign
• FNA is the the most efficient method for differentiation
Fine Needle
Aspiration (FNA)
Hyperthyroidism
Etiologies of Hyperthyroidism
Grave's Disease
Toxic Nodular Goiter
Toxic Nodule
Thyroiditis
Exogenous
• Usually iatrogenic
• Occasionally surreptitious or inadvertent
Signs and Symptoms of Hyperthyroidism
• Nervousness
• Heat intolerance
• Palpitations
• Tremulousness
• Weight loss
• Weakness
• Diarrhea
• Enlarged thyroid
• Ophthalmopathy
• Warm, smooth skin
• Fine tremor
• Brisk reflexes
• Proximal weakness
• Tachycardia
Grave's Disease
• Due to immunoglobulin stimulation of the TSH receptor
• Produces a diffuse goiterHyperthyroidism
• An inflammatory condition of the periorbital tissue secondary to an autoimmune process
Ophthalmopathy
• Rare
• An inflammatory condition of the subcutaneous tissue of the lower extremity
• Also called pretibial myxedema, but is not true edema
Dermopathy(pretibial
myxedema)
Diagnosis of Graves’
Disease
• Goiter, symptoms, ophthalmopathy, dermopathy
Clinical features
• Elevated FT4
• Undetectable TSH,
Laboratory data
• Diffuse, elevated radioiodine uptake
Nuclear
• Usually not necessary for the diagnosis
• Can be helpful in borderline cases
• Absence during treatment with anti-thyroid medications suggests remission
• Predicts recurrence for patients in remission
Positive TRAB or TSIG
Thyroid Associated Ophthalmopathy
• Lid lag, widened palpebral fissure (stare)
Due to hyperthyroidism of any etiology
• Conjunctival and peri-orbital edema
• Congestion of vessels in scleraInflammatory
• Proptosis, eye movement deficits, lid retraction
• Can compromise vascular supply to the optic nerve due to increased volume in a limited space
• ↑ tissue → ↑pressure → vascular compromise to nerve
Infiltrative
Treatment of Graves’
Disease
• May be the primary therapy for patients at high risk for problems from I131 or surgery
• Used to prepare patients for surgery or I131
• Increased surgical risk with hyperthyroidism
• Decrease radiation-induced thyroiditis
Antithyroid medications
• Results in hypothyroidism
• Takes several weeks for full effect
• Risk of temporary rise in T4 from radiation-induced thyroiditis
• May be more likely to exacerbate ophthalmopathy
Radioactive iodine (I131)
• Results in hypothyroidism
• Quick results
• Risks of hypoparathyroidism or recurrent laryngeal nerve damage
Surgery
Toxic Nodular Goiter
Usually occurs with known, long-standing nodular goiter
Patchy or inhomogeneous uptake of radioiodine
Less responsive to radioiodine than Graves’ disease
• Usually has a lower uptake than with Graves’ disease
• The thyroid is often larger in size
More often treated with surgery
Can be managed with anti-thyroid medications
Toxic Nodule
Solitary autonomous nodule
• May result in permanent hypothyroidism
• Suppression of the normal thyroid tissue can protect it from the I131 and patients can have normal thyroid function after treatment
I131
• Lobectomy leaves an normal lobe which can supply thyroxine needs (after hypertrophy)
Surgery
Types of Thyroiditis
• Bacterial, fungal, painful
Acute
• Viral, painful
Subacute granulomatous (de Quervain’s)
• Recovery to normal thyroid function expected
• Causes include autoimmune (Hashimoto’s), drugs, idiopathic
Silent (painless)
Course of thyroiditis
Thyrotoxicosis Secondary to
Thyroiditis
Self-limited illnesses only requiring symptomatic
treatment
Results in the release of pre-formed thyroid
hormones from the destructive process
• Symptoms are the identical
• Thyroid can be enlarged
• TSH is low, FT4 is elevated
May be clinicallyindistinguishable
from Grave's disease
However, the radioiodine uptake is
low
Chronic Lymphocytic Thyroiditis
(Hashimoto's thyroiditis)
Autoimmune disorder
20-30% of cases of thyrotoxicosis
• High prevalence in the postpartum period
In developed countries it is the most common cause of:
• Thyroid disease
• Enlarged thyroid (goiter)
High antibody titers in 90% of cases (neg in 10%)
Complications
• Hypothyroidism
• Thyrotoxicosis
Post-partum
thyroiditis
Post-partum thyroiditis is a
variant of Hashimoto’s
thyroiditis occurring after delivery
•Hyperthyroidism
•usually begins 1 to 4 months after delivery and lasts 2 to 8 weeks
•Hypothyroidism lasting from 2 weeks to 6 months
•Recovery
Classic clinical course
•Transient hyperthyroidism alone
•Transient hypothyroidism aloneOther possibilities
In both cases above, permanent
hypothyroidism may occur
Subacute Granulomatous
Thyroiditis
• Synonyms: nonsuppurative thyroiditis, giant cell thyroiditis, painful thyroiditis, and de Quervain's thyroiditis
• Cause: viral infection or a postviral inflammatory process
• Findings
– Painful thyroid
– Often preceded or associated with fever and URI
– Elevated ESR, C-reactive protein, thyroglobulin
– May cause thyrotoxicosis
– Follows classic thyroiditis course
• Treatment is symptomatic
– Aspirin or other nonsteroidals for pain
– Propanolol for tachycardia and tremor
– Occasional patients may need steroids
– Self-limited with a duration of 8 - 12 weeks
• Recurs in only 1.6 to 4% of patients
Exogenous Thyrotoxicosis
• Occasional surreptitious disorder
Common iatrogenic condition
• Suppressed TSH and elevated FTI
• Normal or small thyroid
• Low thyroglobulin
• Low I131 uptake
Clinically
Goiter
Types of Goiter
Endemic (in areas of iodine deficiency)
Sporadic (usually hereditary)
• Nodular is the most common (non-toxic nodular goiter)
Diffuse goiter may be chronic lymphocytic thyroiditis
Pemberton’s Sign
Patient experiences shortness of breath, red face and inability to swallow when raising arms above the head (like the signal
for a touchdown)
Indicates that the goiter is critically enlarged and
compromising the other structures in the neck
It is an indication for surgery
Pemberton’s sign
Hypothyroidism
• Autoimmune (Hashimoto's thyroiditis)
• Idiopathic or atrophic
• Radiation - I131 or external beam
• Surgery
Primary
• Hypothalamic
• PituitarySecondary
Clinical Features of Hypothyroidism
• Lethargy, fatigue
• Memory impairment
– dementia
• Cold intolerance
• Weight gain
• Hoarseness
• Paresthesias
• Irregular menses
• Dry, coarse cold skin
• Periorbital edema
• Coarse, thinned hair
• Pallor
• Thick tongue
• Delayed relaxation of reflexes
• Bradycardia
Keith Cryar, M.D.
Keith Cryar, M.D.
Keith Cryar, M.D.
Y Iwasaki, K Fukaya. N Engl J Med 2018;379:e23.
Woltman’s Sign of Hypothyroidism“delayed relaxation of deep tendon reflex”
Diagnosis of Hypothyroidism
• Elevated TSH and low FT4 -diagnostic
Primary hypothyroidism
• Low hormone levels
• Inappropriately low TSH
• Normally, the TSH should be elevated if the FT4 is low
• May be undetectable, low or in the “normal” range when the FTI is low
Secondary hypothyroidism
Treatment of Hypothyroidism
Can usually start with full replacement
• Replacement Dose = 1.6 micrograms per kg per day of levothyroxine
Caution with elderly or those who may have compensated cardiac disease
Does the patient have Schmidt Syndrome?
How to take levothyroxine
Microgram doses
Narrow therapeutic window
Doses available:25, 50, 75, 88, 100, 112,
125, 137,150, 175, 200, 300
Absorption
Multiple medications, foods and multivalent cations can
bind levothyroxine and interfere with absorption
Strategy for administration
Take on an empty stomach with water
Remain NPO for 30-60 minutes
Need to wait 4 hours before Ca, Fe, Mg, etc.
Synthetic vs.
“natural thyroid”
Synthetic levothyroxine
• Levothyroxine is a simple molecule and easy to synthesize
• The product is 100% identical to that made by the thyroid with no contaminants
“Natural”, Pork, or Armour thyroid
• Slaughter house by-product
• Limited dosing strengths, variable potency
• Different ratios of T4 and T3
• Contaminated with other animal proteins
Replacement with T3
The thyroid produces both T4 and T3
T3 is the most active form of thyroid hormone
Vast majority of the T3 in the bloodstream comes from peripheral conversion of T4 to T3
Limited data suggests there may be individuals who do not fully convert T4 to T3
Rarely, if ever, need to treat with T3
Studies in which T3 supplementation have been added show minimal differences in symptoms except for increased cardiac arrhythmias
Thyroid Nodules
Approach to Thyroid Nodules
Hyperthyroid
First evaluate for possible toxic nodule with a thyroid scan
Euthyroid (normal function) or hypothyroid
It is important to rule out thyroid cancer
FNA is the method of choice
Hypothyroid or euthyroid patients
A thyroid scan not indicated
Thyroid cancer is usually a “cold nodule”
However, at least 80% of cold nodules are benign
Thyroid Ultrasound
Ultrasound provides the most accurate determination of size, number, growth, and characteristics of thyroid nodules
Nodules are more suspicious for malignancy if they have one or more of the following characteristics:
• Hypodensity
• Irregular margins
• Calcifications
• High grade vascular flow
However, only tissue sampling can reliably determine if a nodule is malignant or benign
FNA of thyroid nodules
Thyroid nodules are too common for all to be biopsied
or removed
Ultrasound-guided Fine Needle Aspiration aspiration (FNA) is
the evaluation of choice
Most nodules greater than 1.0-1.5 cm warrant consideration of
FNA
Nodules smaller than 1.0 cm with suspicious characteristics
should also be biopsied
U/S Guided Fine-Needle Aspiration
Thyroid Carcinoma
•Most common and most indolent
•Commonly has region lymph node metastases
Papillary
•Less common and more aggressive
•More likely to have distant metastases
Follicular
•One of the most aggressive of all cancersAnaplastic
•Sporadic or familial
•Associated with MEN II (A and B)Medullary
Thyroid cancer staging
Treatment of Thyroid
Cancer
Surgery is the primary treatment
• Total thyroidectomy
• Central lymph node dissection (en bloc removal)
• Lateral lymph node dissection (if abnormal lymph nodes detected by US or palpatition)
Depending on risk for recurrence
• May need I131 treatment to destroy residual cancer cells
Although cure rate is high, long term monitoring for recurrence is needed:
• Partial or complete suppression of TSH
• Serum thyroglobulin
• Neck ultrasound