Thyroid Dysfunction

Question 1

Major signs and symptoms of hyperthyroidism

Answer 1

• Nervousness, anxiousness, restlessness, hand tremor
• Irritability
• Heat intolerance
• Increased sweating
• Increased appetite
• Increased frequency of bowel movements
• Weight loss
• Muscle weakness
• Exophthalmos and rapid heart beat

Question 2

Disorders leading to hyperthyroidism

Answer 2

• Graves Disease - 0.5% of the population
• Iatrogenic
• Hot nodule / toxic adenoma
• Toxic / multinodular goiter
• Subacute thyroiditis
• Silent (postpartum) thyroiditis
• Pituitary TSH overproduction
• Other:
  
  • Struma ovarii
  • Jod Basedow
  • Molar pregnancy

Question 3

Graves Disease: etiology

Answer 3

• Most common form of hyperthyroidism - occurs in 0.5% of the population
• Etiology
  
  • Autoimmune disease (Type II hypersensitivity) - circulating IgG directed at TSH receptor –> IgG interact with TSH receptor, stimulate thyroidal function
  • Neonatal Graves: hyperthyroid infant born to mother with Graves disease; infant’s hyperthyroidism disappears over several months (disappearance of maternal IgG)

Question 4

Graves Disease: clinical presentation and lab tests

Answer 4

• Clinical triad often presents during stress:
  
  • Hyperthyroidism: diffuse hyperfunctional enlargement of thyroid (toxic diffuse goiter with bruit)
  • Infiltrative ophthalmopathy with resultant exophthalmos (bulging of eye anteriorly)
  • Localized, infiltrative dermopathy (pretibial myxedema) in a minority of patients
• Lab tests:
  
  • Increased T3/T4
  • Decreased TSH
  • Increased radioactive iodine uptake (RAIU)

Question 5

Factitious/iatrogenic thyrotoxicosis: etiology, clinical presentation, lab tests

Answer 5

• Etiology:
  
  • Exogenous TH shuts off pituitary TSH production/release –> causes thyroid gland to atrophy
• Clinical presentation:
  
  • Thyrotoxicosis (aka hyperthyroidism)
• Lab tests:
  
  • Increased T3/T4
  • Decreased TSH
  • Majorly decreased RAIU (may be zero)

Question 6

Toxic adenoma (hot nodule): etiology, clinical presentation, lab tests

Answer 6

• Etiology:
  
  • AKA autonomous adenoma
  • Cells are clonal expansion of single mutated cells
  • Ex. TSH receptor gain of function mutation –> constitutively active thyroid follicle cells
  • Mutated cells lead to increased growth and increased hormone production
  • Overproduction of TH by nodule suppresses pituitary TSH –> remainder of thyroid gland shrinks
• Clinical presentation:
  
  • Thyrotoxicosis (hyperthyroidism)
• Lab tests:
  
  • Increased T3/T4
  • Decreased TSH
  • Increased RAIU localized at area of nodule

Question 7

Toxic nodular goiter (toxic multinodular goiter): etiology, clinical presentation, lab tests

Answer 7

• Etiology:
  
  • Autonomous activation of the TSH receptor (due to TSH receptor mutation) on hot nodules
    
    • Focal patches –> hyperfunctioning follicular cells
  • Iodine is substrate for unregulated thyroid hormone synthesis
  • Multiple areas of autonomy may exist surrounded by non-functioning areas + suppressed normal thyroid tissue
• Clinical presentation:
  
  • Thyrotoxicosis which may develop slowly over a number of years
  • Goiter
  • Hyperthyroidism can be induced by injudicious administration of TH if areas of thyroid are autonomous, but not sufficiently active to produce toxicity
• Lab tests:
  
  • Increased T3/T4
  • Decreased TSH
  • Increased RAIU in some “hot areas”
  • Decreased RAIU in “cold areas”

Question 8

Subacute thyroiditis (giant cell thyroiditis, De Quervain’s thyroiditis): etiology

Answer 8

• Viral infection causes viral or thyroid antigen, released secondary to virus-induced host tissue damage
• Antigen stimulates cytotoxic T lymphocytes –> damage thyroid follicular cells
• In contrast to autoimmune disease: this immune response is virus-initiated, non-self-perpetuated –> process is limited
• Thyroid gland leaks T3, T4, and inactive iodinated compounds

Question 9

Subacute thyroiditis: clinical presentation and lab tests

Answer 9

• History of viral URI that spreads to thyroid –> externally sore throat (neck) & radiation of pain to neck and ears
• Swollen and tender thyroid gland, fever, hypermetabolism
• Course: initially hyperthyroidism, as it subsides –> euthyroidism, hypothyroidism, finally euthyroidism
  
  • May subside over months
• Course is important to know to not confuse with early Graves or late Hashimoto
• Lab tests:
  
  • Increased T3/T4 (during hyperTH phase)
  • Decreased TSH
  • Decreased RAIU
  • Increased ESR

Question 10

Silent thyroiditis: etiology, clinical presentation, lab tests

Answer 10

• Etiology:
  
  • Likely autoimmune –> lymphocytic thyroiditis and autoAbs present in 50-75% of cases
  • 5-8% of pregnancies followed by silent thyroiditis, especially in patients with other autoimmune disease like T1D
• Clinical presentation:
  
  • Mild hyperthyroidism, non-tender enlargement of thyroid gland
  • Hypothyroidism may follow before return to euthyroid state is achieved
  • Clinical course may be recurrent over a matter of years - predilection for postpartum occurrence of this entity
• Lab tests:
  
  • Increased T3/T4
  • Decreased TSH
  • Decreased RAIU
  • Normal ESR
  • Lymphocytic pathology

Question 11

Pituitary overproduction of TSH: etiology, clinical presentation, lab tests

Answer 11

• Etiology:
  
  • Pituitary tumor that secretes TSH or pituitary resistance to T3 –> relative excess of TSH & overproduction of thyroid hormones that cause hyperthyroidism
  • Very rare
  • Thyroid hormone resistance due to mutations in TRb receptor in ligand binding domain
• Clinical presentation:
  
  • Thyrotoxicity
• Lab tests:
  
  • Increased T3/T4
  • Increased TSH

Question 12

Other causes of hyperthyroidism (3)

Answer 12

• Struma ovarii
  
  • Hyperfunctioning thyroid tissue found in ovaries
  • Increased RAIU in pelvis
• Jod-Basedow
  
  • Iodide induced hyperthyroidism, particularly in areas of iodide deficiency
  • Recently noted with multinodular goiters as well
• Molar pregnancy
  
  • Hyperthyroidism
  • Possibly hCG stimulates thyroid (same a-subunit as TSH)

Question 13

Major signs/symptoms of hypothyroidism

Answer 13

• Metabolic pathways slow down
• Every organ system malfunctions
• Myxedema includes all hypothyroid symptoms
  
  • Fatigue
  • Somnolence
  • Decreased appetite
  • Weight gain
  • Dry skin
  • Brittle hair and anils
  • Cold intolerance
  • Constipation
  • Muscle cramps
  • Headaches
• Patients appear sluggish and puffy, with cool dry skin and slow heart rate
• Myxedema coma –> severe hypothyroidism leads to decreased mental status & hypothermia

Question 14

Lab tests for hypothyroidism

Answer 14

• ​Decreased T4 and decreased free T4
• RAIU and TSH used to narrow differential diagnosis

Question 15

Primary hypothyroidism: etiology

Answer 15

• Pathology interfering with thyroid gland function –> decreased release of thyroid gland
• Two most common causes:
  
  • Autoimmune lymphocytic thyroiditis (Hashimoto’s Disease)
    
    • Very common
    • Seen in 5-10% of the population, incidence increases with age
    • Patient has circulating autoantibodies against thyroglobulin and/or thyroid peroxidase
  • Radioactive iodine ablation of the thyroid
    
    • Common treatment for Graves’ Disease, hot nodule, and multinodular goiter

Question 16

Primary hypothyroidism: clinical presentation

Answer 16

• Goiter:
  
  • When thyroid fails, pituitary increases production of TSH to compensate –> goiter
  • But if abnormality is destructive, goiter may not appear or may disappear in late course of disease
• Hypothyroidism/myxedema
• Onset of Hashimoto’s disease is gradual
  
  • May be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles w/ secondary release of thyroid hormones

Question 17

Primary hypothyroidism: lab tests

Answer 17

• Primary hypothyroidism:
  
  • Decreased T3/T4
  • Increased TSH
  • Decreased RAIU
• Transient thyrotoxicosis:
  
  • Increased T3/T4
  • Decreased TSH
  • Decreased RAIU

Question 18

Secondary (pituitary) hypothyroidism: etiology, clinical presentation, lab tests

Answer 18

• Etiology:
  
  • Pituitary insufficiency (due to a variety of causes)
• Clinical presentation:
  
  • Hypothyroidism/myxedema
  • Accompanied by multiple hormone deficiencies
  • Occasionally TSH deficiency may be isolated
• Lab tests:
  
  • Decreased T3/T4
  • Decreased TSH
    
    • Responds poorly to TRH stimulation
  • Decreased RAIU

Question 19

Tertiary (hypothalamic) hypothyroidism: etiology, clinical presentation, lab tests

Answer 19

• Etiology:
  
  • Hypothalamic failure (due to a variety of causes)
• Clinical presentation:
  
  • Hypothyroidism/myxedema accompanied by multiple trophic hormone failure
• Lab tests:
  
  • Decreased T3/T4
  • Decreased TSH
    
    • Responds well to TRH stimulation

Question 20

Distinction between primary and secondary hypothyroidism

Answer 20

• Critical
• 2ndary hypothyroidism:
  
  • Therapy with TH may unmask latent pituitary ACTH deficiency (accelerates cortisol metabolism) –> precipitate acute adrenal insufficiency
  • Always administer cortisol first (before TH)

Question 21

Tests used to evaluate thyroid function: serum thyroxine

Answer 21

• Total T4
• Major hormone produced by thyroid gland
• Important to remember that bound hormone comprises 99.975% of circulating hormone
  
  • Free hormone is metabolically active
• Normal: 4-12 ug/dL
• Influenced by thyroidal secretion and level of thyroxine binding proteins in circulation
  
  • Pregnancy: Increased TBG –> increased total T4
    
    • Patient is euthyroid because serum free T4 is normal
  • HyperTH: increased total T4 and increased free T4
  • Decreased TBG: decreased total T4 and normal free T4 –> euthyroid

Question 22

Tests used to evaluate thyroid function: free thyroxine

Answer 22

• Not really well measured due to low concentration
• Normal: 0.58 - 1.64 ng/dL

Question 23

Tests used to evaluate thyroid function: triiodothyroxine

Answer 23

• Levels measured by radioimmunoassay
• Active TH in circulation
• Normal: 90-190 ng/dL

Question 24

Tests used to evaluate thyroid function: serum TSH

Answer 24

• Accurate measurements are most valid and important assessments of thyroid function
• Normal: 0.5 - 5.0 ug/mL
  
  • 1ary hypoTH: increased TSH
  • 2ndary hypoTH: decreased TSH
• Increased TSH may be first sign of thyroid failure
• Increased TSH –> inadequate T3/T4 production
• HyperTH: decreased TSH
  
  • Unless pituitary in origin –> increased TSH

Question 25

Tests used to evaluate thyroid function: serum thyroglobulin (TG)

Answer 25

* Not a measure of thyroid hormones * Measure of thyroidal protein secretion * Used to follow thyroid cancer patients - TG is tissue-specific marker for thyroid disease * Reverse T3: recent data suggest conversion of T4 to T3 or rT3 is important branch point, under metabolic control * Starvation/steroid administration/severe illness: T4 preferentially inactivated to rT3 in lieu of active T3 * Euthyroid sick syndrome or non-thyroid illness