Chief’s Morning ReportApril 10, 2012

Case Presentation

A 50-years-old woman presented to the ED with chest pain and dyspnea. On the day of admission she collapsed and was unresponsive for a short while. She had not suffered from any episodes of syncope before.

PMH: single kidney; no h/o DM or HTN

Physical examination revealed a well nourished woman with a blood pressure of 90/60 mmHg and a pulse rate of 100 beats per minutes. She had a puffy face and examination of the neck revealed no struma (a swelling in the neck due to an enlarged thyroid gland). The jugular venous pressure was normal. Cardiac auscultation was normal and the lungs were clear. Peripheral pulses of radial, femoral and dorsalis pedis were present. ECG was done and is shown.

She received magnesium and was transferred to the CCU.

Next ECG obtained from the patient revealed T wave inversion and prolongation of QT intervals of 0.71 S.The patient received phenytoin as treatment for prolongation of QT intervals. At the third day of admission the patient developed positional vertigo and her blood pressure dropped to 80mmHg. Diagnostic laboratories were drawn.

Thyroid function test revealed Total T4 0.71 μg/dL, free T4 (FT4) 0.1 ng/mL, total T3 74 μg/dL and thyroid stimulating hormone 36 μU/mL. Other laboratory data such as blood urea nitrogen (BUN), Creatinine and electrolytes were in normal range. The patient received levothyroxine 100 μg/day. Two months after treatment with levothyroxine, QT intervals normalized and ventricular tachycardia was abolished. Her periorbital edema had diminished and both TSH and free T4 had normalized.

HYPOTHYROIDISM

Objectives

• Identify Risk Factors for hypothyroidism• Discuss clinical presentation, signs and

symptoms of hypothyroidism• Diagnose and distinguish primary, secondary

and tertiary hypothyroidism• Discuss treatment of hypothyroidism

Risk Factors

• Personal history– Previous thyroid dysfunction– Goiter– Surgery or radiotherapy affecting the thyroid gland– DM– Vitiligo– Pernicious anemia– Leukotrichia (premature gray hair)– Medications and other compounds

• Family history– Thyroid disease– Pernicious anemia– DM– Primary adrenal insufficiency

Clinical Presentation

• Symptoms and signs of the disease – vary in relation to the magnitude of the thyroid hormone deficiency

and– acuteness with which the deficiency develops

• May be modified by factors such as coexisting nonthyroidal illness

• Hypothyroidism caused by hypothalamic-pituitary disease may have associated endocrine deficiencies masking the manifestations of hypothyroidism

• Hypothyroidism after treatment of Graves' hyperthyroidism, some manifestations may persist throughout the patient's life

• 5-8x more likely in women

Many of the manifestations of hypothyroidism reflect one of two changes induced by lack of thyroid hormone

1. A generalized slowing of metabolic processes.

– This can lead to abnormalities such as fatigue, slow movement and slow speech, cold intolerance, constipation, weight gain, delayed relaxation of deep tendon reflexes, and bradycardia.

2. Accumulation of matrix glycosaminoglycans in the interstitial spaces of many tissues

– This can lead to coarse hair and skin, puffy facies, enlargement of the tongue, and hoarseness. These changes are often more easily recognized in young patients, and they may be attributed to aging in older patients.

Common Signs and Symptoms of Thyroid Dysfunction

Hypothyroidism• Fatigue• Weight gain• Cold intolerance• Skin dryness• Hair dryness or loss• Depression• Dementia

• Muscle cramps and myalgias• Edema• Bradycardia

• Constipation• Menstrual irregularity (especially

menorrhagia)• Infertility

Hyperthyroidism• Fatigue• Weight loss• Heat intolerance• Hyperhydrosis

• Nervousness• Insomnia• Tremor• Muscle weakness• Dyspnea• Palpitations• Tachycardia and atrial

tachyarrhythmias• Hyperdefecation• Menstrual irregularity (especially

hypomenorrhea)

Pretibial Myxedema

DIAGNOSISPrimary vs. Secondary or Tertiary Hypothyroidism

Major causes of hypothyroidism

Primary hypothyroidism:• Chronic autoimmune

thyroiditis• Iatrogenic

• Thyroidectomy, radioiodine therapy or radiation

• Iodine deficiency or excess• Drugs

• Thionamides, lithium, amiodarone, INF α

• Infiltrative diseases• Transient hypothyroidism

• Painless thyroiditis, postpartum,

• Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis

Central hypothyroidism• TSH deficiency• TRH deficiency

• Pituitary mass lesions

• Radiation• Surgery • Infiltrative

disorders• Sarcoid, TB,

hemochromatosis, syphilis, fungal infections

Generalized thyroid hormone resistance

UpToDate

Primary Hypothyroidism

• 95% of cases of hypothyroidism• Caused by disease of the thyroid gland with

decreased secretion of thyroxine (T4) and triiodothyronine (T3) -> reduction in the serum concentrations of the two hormones -> compensatory increase in TSH secretion

• Characterized by a high serum TSH concentration and a low serum free T4 concentration

Forms of primary hypothyroidism

• Subclinical hypothyroidism – high serum TSH

concentration in the presence of normal serum free T4 and T3 concentrations

– few if any symptoms and signs of hypothyroidism

• Overt hypothyroidism – high serum TSH

concentration in the presence of a low serum free T4 concentration

– symptoms and signs of hypothyroidism

Hashimoto’s thyroiditis

• Chronic autoimmune (Hashimoto's) thyroiditis • Cell- and antibody-mediated destruction of

thyroid tissue:1. Cytotoxic T cells may directly destroy thyroid cells.2. More than 90 percent of patients have high serum

concentrations of autoantibodies to thyroglobulin, thyroid peroxidase, or the thyroid Na/I transporter

Nuclear accidents and thyroid

• French prophylaxis: In an individual with a healthy thyroid, taking 100 mg of stable iodine immediately before exposure to radioactive iodine reduces the dose to the thyroid by at least 95%– Distribute iodine around nuclear sites

• Chernobyl Accident: The 26 April 1986 accident at the Chernobyl nuclear power plant contaminated large areas of northern Ukraine as well as parts of Belarus and the Russian Federation. The environmental fallout included radionuclides of iodine, primarily iodine-131 (131I), which concentrates in the thyroid gland– increased prevalence of thyroid cancer and subclinical hypothyroidism– significant relationship between prevalence of hypothyroidism and

individual 131I thyroid doses due to environmental exposure

Central Hypothyroidism (Secondary and Tertiary)• Insufficient stimulation of the thyroid gland by TSH, by

either hypothalamic (tertiary) or pituitary (secondary) disease

• Low serum T4 concentration and a serum TSH concentration not appropriately elevated

• Suspect when:– Known hypothalamic or pituitary disease– Pituitary mass lesion is present– Symptoms and signs of hypothyroidism associated with

other hormonal deficiencies• <1% of patients with hypothyroidism

• Secondary hypothyroidism can be caused by any of the causes of hypopituitarism, most often a pituitary tumor

• Other causes include postpartum pituitary necrosis (Sheehan's syndrome), trauma, hypophysitis, nonpituitary tumors such as craniopharyngiomas, infiltrative diseases, and inactivating mutations in the gene for either TSH or the TSH receptor

• Tertiary hypothyroidism can be caused anything that damages the hypothalamus or interferes with hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary

• Can be caused by mutations in the gene for the TRH receptor• Like TSH deficiency, TRH deficiency can be isolated or occur in

combination with other hormonal deficiencies. Hypothalamic damage results from tumors, trauma, radiation therapy, or infiltrative diseases.

• TSH deficiency and TRH deficiency cannot be distinguished by biochemical tests and should undergo MRI

• Whether TSH or TRH deficient is of no practical importance to the patient's hypothyroidism

LABORATORY TESTING

Serum TSH

Serum fT4 Serum T3 Assessment

Normal Normal Normal EuthyroidNormal Normal to high Normal or

highEuthyroid hyperthyroxinemia

Normal Normal or low Normal or high

EuthyroidHypothyroxinemia

Normal Low Normal or low

Euthyroid: triiodothyronine therapy

Normal Low normal or low

Normal or high

Euthyroid: thyroid extract therapy

High Low Normal or low

Primary hypothyroidism

High Normal Normal Subclinical hypothyroidism

Low High or normal High HyperthyroidismLow Normal Normal Subclinical hyperthyroidism

Normal or high

High High TSH-mediated hyperthyroidism

Normal or low

Low to low-normal

Low or normal

Central hypothyroidism

Screening for Thyroid Dysfunction

• Serum TSH is accurate, widely available, safe and inexpensive diagnostic test for all common forms of hypothyroidism and hyperthyroidism

• All patients with symptoms of hypothyroidism • Patients with laboratory or radiologic abnormalities that could be caused

by hypothyroidism, patients with risk factors for hypothyroidism, and patients taking drugs that may impair thyroid function – Substantial hyperlipidemia or a change in lipid pattern– Hyponatremia– High serum muscle enzyme concentrations– Macrocytic anemia– Pericardial or pleural effusions – Previous thyroid injury– Pituitary or hypothalamic disorders – History of autoimmune diseases

UpToDate

• ATA: all adults have their serum TSH concentration measured beginning at age 35 years and every 5 years thereafter

• American Academy of Family Physicians (AAFP) and the American Association of Clinical Endocrinologists (AACE): periodic assessment of thyroid function in older women

• American College of Physicians (ACP): office screening of women older than 50 years may be indicated

• United States Preventive Services Task Force: not recommended in children or adults

• Institute of Medicine: screening is not cost-effective in the (elderly) Medicare population

• Clinical consensus group (comprised of representatives from the Endocrine Society, ATA, and AACE) recommended against population-based screening. but suggested that aggressive case finding is reasonable in women older than 60 years and others at high risk for thyroid dysfunction (personal history of type 1 diabetes or other autoimmune disease, or a family history of thyroid disease)

Disorders that affect TSH

UpToDate

TREATMENT

http://www-thyroid.com/

Treatment

• Goal is restoration of euthyroid state• Treatment of choice is synthetic thyroxine (T4)• ~ 80% of a dose of T4 is absorbed • Plasma half-life of T4 is 7 days, daily treatment results in nearly

constant serum T4 and triiodothyronine (T3) concentrations when a steady state is reached

• T4 is a prohormone with very little intrinsic activity. It is deiodinated in peripheral tissues to form T3, the active thyroid hormone

• deiodination process accounts for about 80% of the total daily production of T3; as a result, serum T3 concentrations are within the normal range in hypothyroid patients receiving adequate T4 therapy

• The average replacement dose of T4 in adults is approximately 1.6 mcg/kg (range 50 to 200 mcg/day) body weight per day 

• T4 should be taken on an empty stomach, ideally an hour before breakfast

• Initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy patients, but older patients should be started on a lower dose (25 to 50 mcg daily)

• Those who have a history of coronary heart disease should initially be treated with 25 mcg/day

• Reevaluated and serum TSH measured in six weeks after initiation of therapy, T4 can be increased by 12 to 25 mcg/day if not within range (approximately 0.5 to 5.0 mU/L)

• Check TSH annually in patients on maintenance therapy

• Increases in dose may be required during pregnancy

• Small increases also may be required in patients in whom thyroid hormone absorption is diminished (patients with impaired acid secretion or other gastrointestinal disorders), excretion is increased (nephrotic syndrome), or the rate of metabolism is increased (therapy with rifampin, carbamazepine, phenytoin, or phenobarbital)

• In most trials, combination T4 -T3 therapy does not appear to be superior to T4 monotherapy for the management of hypothyroid symptoms. 

Central hypothyroidism

• T4 therapy needs to be monitored clinically and by measurements of serum T4; measurements of serum TSH are of no value. 

• Adjust dose according to the patient's symptoms and serum T4 values, aiming to maintain the serum T4 concentration in the upper part of the normal range

• May need more T4 to achieve serum T4 values in the upper half of the normal range than patients with primary hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy

• Pituitary-adrenal function should be assessed, usually by an ACTH stimulation test, before thyroxine (T4) therapy is begun in all patients with central hypothyroidism. If adrenal insufficiency is present, glucocorticoid therapy should be given concomitantly with T4

References• http://www.casesjournal.com/content/1/1/298• Schenck JB, Rizvi AA, Lin T: severe primary hypothyroidism manifesting with

torsades de pointes. Am J Med Sci 2006, 331:154-156.• Ladenson, Paul W., et al. American Thyroid Association Guidelines for

Detection of Thyroid Dysfunction. Arch Intern Med. 2000; 160:1573-1575.• UpToDate• B Le Guen, PY Hemidy, et al. French approach for the distribution of iodine

tablets in the vicinity of nuclear power plants. Health physics. 2002; 293-300.• Ostroumova, E., et al. Subclinical Hypothyroidism after Radioiodine

Exposure: Ukrainian–American Cohort Study of Thyroid Cancer and Other Thyroid Diseases after the Chornobyl Accident (1998–2000). Environ Health Perspect. 2009 May; 117(5): 745–750.

• Asvold BO, Bjøro T, Nilsen TI, Vatten LJ. Tobacco smoking and thyroid function: a population-based study. Arch Intern Med. 2007 Jul 9;167(13):1428-32.

Questions?