Disorders of Thyroid

Function: Hypo and

Hyperthyroidism

Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI
Chairman, Diabetes Steering Committee, AMG/NHP, Appleton, WI

www.endocrinology-online.com
Anatomy of the Thyroid Gland
Follicles: the Functional Units of
the Thyroid Gland

Follicles Are the Sites

Where Key Thyroid
Elements Function:
• Thyroglobulin (Tg)
• Tyrosine
• Iodine
• Thyroxine (T4)
• Triiodotyrosine (T3)
 The Thyroid Produces and
Secretes 2 Metabolic Hormones

• Two principal hormones

– Thyroxine (T4 ) and triiodothyronine (T3)
• Required for homeostasis of all cells
• Influence cell differentiation, growth, and
metabolism
• Considered the major metabolic hormones
because they target virtually every tissue
 Thyroid-Stimulating Hormone
(TSH)

• Regulates thyroid hormone

production, secretion, and growth
• Is regulated by the negative feedback
action of T4 and T3
Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism
 Production of T4 and T3
• T4 is the primary secretory product of the
thyroid gland, which is the only source of T4
• The thyroid secretes approximately 70-90 g
of T4 per day
• T3 is derived from 2 processes
– The total daily production rate of T3 is about
15-30 g
– About 80% of circulating T3 comes from
deiodination of T4 in peripheral tissues
– About 20% comes from direct thyroid secretion
 T4: A Prohormone for T3

• T4 is biologically inactive in target

tissues until converted to T3
– Activation occurs with 5' iodination of the
outer ring of T4
• T3 then becomes the biologically
active hormone responsible for the
majority of thyroid hormone effects
 Thyroid Hormones Stimulate
Metabolic Activities in Most Tissues

• Thyroid hormones (specifically T3) regulate

rate of overall body metabolism
– T3 increases basal metabolic rate
• Calorigenic effects
– T3 increases oxygen consumption by most
peripheral tissues
– Increases body heat production
 Metabolic Effects of T3

• Stimulates lipolysis and release of free fatty

acids and glycerol
• Induces expression of lipogenic enzymes
• Effects cholesterol metabolism
• Stimulates metabolism of cholesterol to bile
acids
• Facilitates rapid removal of LDL from plasma
• Generally stimulates all aspects of
carbohydrate metabolism and the pathway for
protein degradation
 Additional Effects of T3

• Initiates or sustains differentiation and growth

• Stimulates formation of proteins, which exert
trophic effects on tissues
• Essential for neural development and
maturation and function of the CNS
• Important for normal reproductive function
• T3 is considered the major regulator of
mitochondrial activity
Disorders of Thyroid Function
Overview of Thyroid Dysfunction

• Hypothyroidism

• Hyperthyroidism
Typical Thyroid Hormone Levels
in Thyroid Disease

TSH T4 T3
Hypothyroidism High Low Low

Hyperthyroidism Low High High

 Thyroid Disease Spectrum
Overt Hypothyroidism
TSH >4.7 IU/mL, Free T4 Low

Subclinical Hypothyroidism
TSH >4.7 IU/mL, Free T4 Normal

Euthyroid
TSH 0.5-4.7 IU/mL, Free T4 Normal

Hyperthyroidism
TSH <0.5 IU/mL, Free T3/T4 Normal or Elevated

0 5 10
TSH, IU/mL
Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.
Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.
Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.
 Prevalence of Abnormal Thyroid
Function
The Colorado Thyroid Disease Prevalence study
• Used thyroid stimulating hormone (TSH) levels as a
measure of thyroid function
• Prevalence of elevated TSH levels (hypothyroidism)
was 9.5% and the prevalence of decreased TSH
levels (hyperthyroidism) was 2.2%
• Lipid levels increased as thyroid function declined
• 40% of patients taking thyroid medications had
abnormal TSH levels

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

 Prevalence of Elevated Serum TSH
by Decade of Age and Gender
NHANES III Study (N=17 353)
• At <40 years of
18
Males age, prevalence is
16
relatively low and
Elevated TSH, %
Participants With

14 Females
12 similar between
10 males and
8 females
6
4 • At ≥40 years of
2 age, a higher
0 percentage of
13- 20- 30- 40- 50- 60- 70- >80 female patients
19 29 39 49 59 69 79 have elevated
Age, y TSH levels

Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

 Thyroid-Stimulating
Hormone (TSH) Assays
• Key test for diagnosis of hypothyroidism and
hyperthyroidism

• TSH assay sensitivity has improved with

subsequent test generations
– First generation: RIA
Sensitivity: 1.0 IU/mL
– Second generation: IRMA
Sensitivity: 0.1 IU/mL
– Third generation: ELISA
Sensitivity: 0.03 IU/mL
Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.
Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text.
8th ed. 2000.
Zophel K, et al. Nuklearmedizin. 1999;38:150-155.
 Additional Laboratory Tests for
Thyroid Function
Test Normal Levels When to Use
Serum total T4 5-11 µg/dL DO NOT USE total T4/T3

Free T4 0.7-1.8 ng/dL Use with TSH to

assess degree of
hypothyroidism

Free T3 2.77 – 5.27 ng/dL Use when FT4 does

not confirm to TSH

TPOAb, TgAb Negative In combination with TSH,

predictor of disease
progression

Endocr Pract. 2002;8:457-469.

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.
Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm.
Accessed July 1, 2003.
 Screening for Disorders of Thyroid
Function

Population Testing Frequency

Every 5 years beginning at
Men
35 years of age
Every 5 years beginning at
Women
35 years of age
As soon as possible after
Pregnant women conception; up to 3 months
after giving birth
Patients >60 years of age Once a year

The Endocrine Society Web site. Available at: http://www.endo-

society.org/pubrelations/pressReleases/archives/1999/hypothyroid.cfm. Accessed April 17, 2003.
Loyola University New Orleans Web site. Available at: http://www.loyno.edu/~msthomas/hypo.html.
Accessed April 17, 2003.
Hypothyroidism
 Hypothyroidism

• Hypothyroidism is a disorder with multiple

causes in which the thyroid fails to
secrete an adequate amount of thyroid
hormone
– The most common thyroid disorder
– Usually caused by primary thyroid gland failure
– Also may result from diminished stimulation of the
thyroid gland by TSH
 Clinical Features of
Hypothyroidism
Tiredness Puffy Eyes

Forgetfulness/Slower Thinking Enlarged Thyroid (Goiter)

Moodiness/ Irritability Hoarseness/
Deepening of Voice
Depression
Persistent Dry or Sore Throat
Inability to Concentrate
Thinning Hair/Hair Loss Difficulty Swallowing
Loss of Body Hair Slower Heartbeat

Dry, Patchy Skin Menstrual Irregularities/

Heavy Period
Weight Gain Infertility
Cold Intolerance
Elevated Cholesterol Constipation
Muscle Weakness/
Family History of Thyroid Cramps
Disease or Diabetes
 Hypothyroidism and Depression
Have Many Common Features
Depression Hypothyroidism

• Constipation
• Appetite decrease • Bradycardia
• Decreased concentration • Cardiac and lipid
• Sleep decrease • Decreased libido abnormalities
• Suicidal ideation • Delusions • Cold intolerance
• Weight loss • Depressed mood • Delayed reflexes
• Appetite increase/ • Diminished interest • Goiter
decrease • Sleep increase • Hair and skin
• Weight increase changes
• Fatigue

Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20.

 Populations at Risk for
Hypothyroidism
• Women
• Prior history of Graves
disease or postpartum
thyroid dysfunction
• Elderly
• Other autoimmune disease
• Family history of
– Thyroid disease
– Pernicious anemia
– Type 1 Diabetes mellitus
Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.
Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.
Perros P, et al. Diabetes Med. 1995;12:622-627.
 Hypothyroidism: Types
• Primary hypothyroidism
– From thyroid destruction
• Central or secondary hypothyroidism
– From deficient TSH secretion, generally due to sellar
lesions such as pituitary tumor or craniopharyngioma
– Infrequently is congenital
• Central or tertiary hypothyroidism
– From deficient TSH stimulation above level of pituitary—ie,
lesions of pituitary stalk or hypothalamus
– Is much less common than secondary hypothyroidism

Bravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid.
8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.
Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.
 Primary Hypothyroidism:
Underlying Causes
• Congenital hypothyroidism
– Agenesis of thyroid
– Defective thyroid hormone biosynthesis due to enzymatic defect
• Thyroid tissue destruction as a result of
– Chronic autoimmune (Hashimoto) thyroiditis
– Radiation (usually radioactive iodine treatment for thyrotoxicosis)
– Thyroidectomy
– Other infiltrative diseases of thyroid (eg, hemochromatosis)
• Drugs with antithyroid actions (eg, lithium, iodine, iodine-
containing drugs, radiographic contrast agents, interferon alpha)

• In the US, hypothyroidism is usually due to chronic

autoimmune (Hashimoto) thyroiditis
Chronic Autoimmune Thyroiditis
(Hashimoto Thyroiditis)
• Occurs when there is a severe defect in thyroid
hormone synthesis
– Is a chronic inflammatory autoimmune disease characterized
by destruction of the thyroid gland by autoantibodies against
thyroglobulin, thyroperoxidase, and other thyroid tissue
components
– Patients present with hypothyroidism, painless goiter, and
other overt signs
• Persons with autoimmune thyroid disease may have
other concomitant autoimmune disorders
– Most commonly associated with type 1 diabetes mellitus
• Will often have significantly elevated anti-TPO ab
What is a Normal TSH?
Treatment of Hypothyroidism
Hypothyroidism Treatment Goal
Euthyroidism

• The goal of hypothyroidism therapy is to

replace thyroxine to mimic normal,
physiologic levels and alleviate signs,
symptoms, and biochemical
abnormalities

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A

Fundamental and Clinical Text. 8th ed. 2000.
 Therapy Initiation and Titration
• Therapy with levothyroxine sodium products
requires individualized patient dosing
– Careful titration: use a formulation with consistent doses
– Clinical evaluation: symptoms resolve more slowly than
TSH response
– Laboratory monitoring: need consistent, sensitive TSH
measurements
• Individualized patient dosing is influenced by
– Age and weight
– Cardiovascular health
– Severity and duration of hypothyroidism
– Concomitant disease states and treatment

Endocr Pract. 2002;8:457-469.

Singer PA, et al. JAMA. 1995;273:808-812.
 Hypothyroidism Treatment

• Levothyroxine sodium is the treatment of choice for

the routine management of hypothyroidism
– Adults: about 1.7 g/kg of body weight/d
– Children up to 4.0 g/kg of body weight/d
– Elderly <1.0 g/kg of body weight/d
• Clinical and biochemical evaluations at 6- to 8-week
intervals until the serum TSH concentration is
normalized
• Given the narrow and precise treatment range for
levothyroxine therapy, it is preferable to maintain the
patient on the same brand throughout treatment

Singer PA, et al. JAMA. 1995;273:808-812.

Endocr Pract. 2002;8:457-469.
 AACE 2002 Position Statement on
the Management of Hypothyroidism
“Bioequivalence of levothyroxine preparations is
based on total T4 measurement and not TSH
levels; therefore, bioequivalence is not the
same as therapeutic equivalence.
Furthermore, various brands of levothyroxine
are not compared against a levothyroxine
standard.
Preferably, the patient should receive the same
brand of levothyroxine throughout treatment.”

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE

FOR THE EVALUATION AND TREATMENT OF HYPERTHYROIDISM AND HYPOTHYROIDISM. ENDOCRINE PRACTICE Vol 8 No. 6
November/December 2002
 Joint Position Statement on the Use and
Interchangeability of Thyroxine Products
According AACE, TES, and ATA:
“Patients should be maintained on the
same brand name levothyroxine product.”
“If the brand of levothyroxine medication is
changed, either from one brand to
another brand, from a brand to a generic
product, or from a generic product to
another generic product, patients should
be retested by measuring serum TSH in
six (6) weeks.”
2004 AACE, TES, and ATA Joint Position Statement on the Use and Interchangeability ofThyroxine Products
 Primary Hypothyroidism
Treatment Algorithm
Initial Levothyroxine Dose

6-8 Weeks

TSH >3.0 IU/mL Repeat TSH Test TSH <0.5 IU/mL

TSH 0.5- 2.0 IU/mL

Symptoms Resolved

Increase Continue Dose Decrease

Levothyroxine Levothyroxine
Dose by Dose by
12.5 to 25 g/d Measure TSH at 6 Months, 12.5 to 25 g/d
Then Annually or Singer PA, et al. JAMA. 1995;273:808-812.
When Symptomatic Demers LM, Spencer CA, eds. The National Academy of
Clinical Biochemistry Web site. Available at:
http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed
July 1, 2003.
 Therapy Monitoring
• Clinical and laboratory monitoring enable
– Evaluation of the clinical response
– Assessment of patient compliance
– Assessment of drug interactions, if applicable
– Adjustment of dosage, as needed

• Clinical and laboratory evaluations should be performed

– At 6- to 8-week intervals while titrating
– Every 6 – 12 months once a euthyroid state is established

Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds.
Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site.
Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.
Caution in Patients With Underlying
Cardiac Disease
• Using LT4 in those with ischemic heart disease increases
the risk of MI, aggravation of angina, or cardiac
arrhythmias
• For patients <50 years of age with underlying cardiac
disease, initiate LT4 at 25-50 g/d with gradual dose
increments at 6- to 8-week intervals
• For elderly patients with cardiac disease, start LT4 at
12.5-25 g/d, with gradual dose increments at 4- to 6-week
intervals
• The LT4 dose is generally adjusted in 12.5-25 g
increments

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A

Fundamental and Clinical Text. 8th ed. 2000.
Kohno A, et al. Endocr J. 2001;48:565-572.
Synthroid® [package insert]. Abbott Laboratories; 2003.
Impact of Maternal Hypothyroidism on Subsequent
Neuropsychological Development of Offspring

• Undiagnosed hypothyroidism in pregnant

women may adversely affect fetuses
• Treating maternal hypothyroidism during
pregnancy appears to be beneficial, even
when treatment falls short of euthyroid status
• Screening for hypothyroidism before or very
early in pregnancy may be warranted

Haddow JE, et al. N Engl J Med. 1999;341:549-555.

Treating Hypothyroidism Before and
During Pregnancy
• Encourage adherence with levothyroxine replacement
therapy before conception
• Monitor TSH levels before conception and during first
trimester
• Monitor TSH levels every 6 weeks throughout
pregnancy
• Remember, that during first trimester in a euthyroid
pregnancy, TSH will normally fall slightly.
• A goal TSH of 0.1 to 0.5 is acceptable for most
pregnant patients.
• Also, may use FT4/FT3 to confirm appropriate thyroid
status.
Gharib H, et al. Endocr Pract. 1999;5:367-368.
Mandel SJ, et al. N Engl J Med. 1990;323:91-96.
 Factors That May Reduce
Levothyroxine Effectiveness
• Malabsorption Syndromes • Drugs That Increase
– Postjejunoileal bypass Clearance
surgery – Rifampin
– Short bowel syndrome – Carbamazepine
– Celiac disease – Phenytoin
• Reduced Absorption • Factors That Reduced T4
– Colestipol hydrochloride to T3 Clearance
– Sucralfate – Amiodarone
– Ferrous sulfate – Selenium deficiency
– Food (eg, soybean formula) • Other Mechanisms
– Aluminum hydroxide – Lovastatin
– Cholestyramine – Sertraline
– Sodium polystyrene
sulfonate
Braverman LE, Utiger RD, eds. The Thyroid: A
Fundamental and Clinical Text. 8th ed. 2000.
Synthroid® [package insert]. Abbott Laboratories; 2003.
 Iron Ingestion and
Levothyroxine Therapy
Ferrous Sulfate Effect on TSH Levels in
Patients With Hypothyroidism

6 P<.001
TSH Level, IU/mL

0
Before Ingestion After Ingestion
Campbell NR, et al. Ann Intern Med. 1992;117:1010-1013.
Is there any role for T3
supplementation in the
management of
hypothyroidism?
NO!
Disorders Characterized by
Hyperthyroidism
Thyrotoxicosis and Hyperthyroidism
Definitions
• Thyrotoxicosis
–The clinical syndrome of hypermetabolism that
results when the serum concentrations of free
T4, T3, or both are increased
• Hyperthyroidism
–Sustained increases in thyroid hormone
biosynthesis and secretion by the thyroid gland

The 2 terms are not synonymous

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A
Fundamental and Clinical Text. 8th ed. 2000.
 Hyperthyroidism
Underlying Causes
• Signs and symptoms can be caused by any
disorder that results in an increase in circulation
of thyroid hormone
– Toxic diffuse goiter (Graves disease)
– Toxic uninodular or multinodular goiter
– Painful subacute thyroiditis
– Silent thyroiditis
– Toxic adenoma
– Iodine and iodine-containing drugs and radiographic
contrast agents
– Trophoblastic disease, including hydatidiform mole
– Exogenous thyroid hormone ingestion
 Signs and Symptoms of
Hyperthyroidism
Hoarseness/
Nervousness/Tremor Deepening of Voice

Mental Disturbances/ Persistent Dry or Sore Throat

Irritability
Difficulty Swallowing
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/ Palpitations/
Vision Changes Tachycardia

Enlarged Thyroid (Goiter) Impaired Fertility

Weight Loss or Gain
Menstrual Irregularities/
Light Period Heat Intolerance
Increased Sweating
Frequent Bowel Movements
Sudden Paralysis
Warm, Moist Palms

Family History of
First-Trimester Miscarriage/
Thyroid Disease
Excessive Vomiting in Pregnancy
or Diabetes
Initial Evaluation of a Patient with
Hyperthyroidism

• TSH, FT4, FT3

• Thyroid uptake and scan
• Thyroid stimulating immunoglobulins (if
suspect Grave’s disease)
 Graves Disease
(Toxic Diffuse Goiter)
• The most common cause of
hyperthyroidism
– Accounts for 60% to 90% of cases
– Incidence in the United States
estimated at 0.02% to 0.4% of the
population
– Affects more females than males,
especially in the reproductive age
range
• Thyroid stimulating
immunoglobulins may be
positive in some patients and
helpful for diagnosis
 Toxic Multinodular Goiter

• More common in places with lower iodine

intake
– Accounts for less than 5% of thyrotoxicosis cases
in iodine-sufficient areas
• Evolution from sporadic diffuse goiter to toxic
multinodular goiter is gradual
• Thyrotropin receptor mutations and TSH
mutations have been found in some patients
with toxic multinodular goiters
• Surgery or 131I is recommended treatment
Braverman LE, et al. Werner & Ingbar’s The Thyroid. A
Fundamental and Clinical Text. 8th ed. 2000.
 Thyroiditis

• Different types: subacute, chronic, other

• RAI imaging will show decreased uptake
• In subacute thyroiditis: thyroid may be
exquisitely tender on exam
• Some may have + anti TPO ab, + anti-TG ab
and hESR
• Does not respond to anti-thyroid medication
or RAI treatment
• TOC is steroids and other adjunctive therapy
 Iodine Induced Hyperthyroidism

• RAI imaging will show decreased uptake

• Usual presentation is a patient with history of MNG
who receives IV contrast
• Other causes include amiodarone treatment or a
patient moving from a previously iodine deficient
area to one of high iodine intake
• Can be very difficult to treat, TOC is steroids and
adjunctive tx.
• If possible stop the offending agent (ie amiodarone).
• Often does not respond well to anti-thyroid
medications, but may try.
• There is no place for RAI treatment.
 Transient Thyroxicosis of
Pregnancy
• Occasionally a suppressed but detectable TSH and
normal or hFT4/FT3 is found early in pregnancy
• Due to structural homology between B-HCG and TSH
• More severe in twin pregnancies and hyperemesis
gravidum (higher B-HCG)
• Usually self limited and resolves on own
• May treat with PTU and B blockers if severe or
symptomatic
• Be aware of the possibility of a primary thyroid disorder
also occurring in pregnancy, this may be suggested by:
– Undetectable TSH
– Goiter
– History of pre-existing thyroid disease
 Should Subclinical
Hyperthyroidism be Treated?
Depends on the individual circumstances and
presentation of the patient:
• Usually will treat if TSH < 0.1
• If TSH between 0.1 and 0.5:
– May initially observe only and follow for development of
overt hyperthyroidism (especially if young and otherwise
healthy patient)
– Should consider treatment if evidence of potential
complications of hyperthyroidism (osteopenia or
osteoporosis, a-fib), if frail/elderly or (possibly) if
symptoms
Treatment of Hyperthyroidism
Treatment of Hyperthyroidism
• Antithyroid drugs
– Inhibit the synthesis of T4 and T3
• Radioactive iodine therapy
– Iodine 131 taken up by functioning thyroid tissue
can decrease thyroid hormone production
• Surgical resection
– Remove hyperplastic and adenomatous tissues
– Restore normal thyroid function and,
consequently, pituitary function

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A

Fundamental and Clinical Text. 8th ed. 2000.
 Adjunctive Therapy of
Hyperthyroidism

• Beta blockers
• Corticosteroid therapy
• Bile acid sequestrants
• Iodide
 Which Treatment to choose?

Depends on:
• Patient preference
• Severity of hyperthyroidism
• Evidence of complications of
hyperthyroidism
• Pregnancy
• The cause of hyperthyroidism