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”

Delayed relaxation of reflexes

Video

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