HYPOTHYROIDISM Hypothyroidism Hypothyroidism is a clinical

HYPOTHYROIDISM

Hypothyroidism

Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormones.

There is a generalized slowing down of metabolic processes.

In newborn infants – Cretinism In adolescents – short stature, mental

retardation, precocious puberty In adults – symptoms largely reversible after

therapy

Interpretation for Thyroid Function Test

High T4 Normal T4 Low T4

High TSH

In vivo or in vitro artefact

Pituitary hyperthyroidism

Thyroid hormone resistance

Subclinical hypothyroidism Primary hypothyroidism

Normal TSH

As above

Sampling within 6 h of thyroxine dose

Normal Pituitary or hypothalamic hypothyroidism

Severe non-thyroidal illness

Low TSH

Hyperthyroidism Subclinical hyperthyroidism

Subtle thyroxine overreplacement

Autonomous functioning thyroid nodule

Non-thyroidal illness

Pituitary or hypothalamic hypothyroidism

Severe non-thyroidal illness

Etiology of Hypothyroidism

Primary – thyroid failure Secondary – pituitary TSH deficit (Hypopituitarism

due to pituitary adenoma, apoplexy, infiltrative disease-sarcoidosis)

Tertiary – hypothalamic deficiency of TRH (rare)

Peripheral resistance to the action of thyroid hormone

Hashimoto’s Thyroiditis Chronic lymphocytic thyroiditis Probably the most common cause of hypot

hyroidism With (younger patients) or without goiter (older pati

ents – atrophy gland after destruction by immunologic process)

High titer of autoantibodies to thyroidal antigens (Thyroglobulin Ab, Thyroperoxidase Ab = TPO Ab = Antimicrosomal Ab = AMA)

Pathogenesis of Hypothyroidism

Characteristic finding: accumulation of glycosaminoglycans – mostly hyaluronic acid (玻尿酸 ) – in interstitial tissues

The accumalation is due not to excessive synthesis but to decreased destruction of glycosaminoglycans.

Accumulation of this hydrophilic substance and increased capillary permeability to albumin account for this interstitial edema that is particularly evident in the skin, heart muscle, and striated muscle.

Clinical Manifestations of Hypothyroidism

Symptoms and signs vary in relation to the magnitude of the thyroid hormone deficiency, and the acuteness with which the deficiency develops. Less prominent clinically and better tolerated

when gradual loss of thyroid function (as in most cases of primary hypothyroidism)

Symptoms develop acutely after thyroidectomy or abrupt withdrawal of exogenous thyroid hormone

Clinical Manifestations of Hypothyroidism -- Skin

Cool and pale skin blood flow Dry roughness of skin the epidermis has a

n atrophied cellular layer and hyperkeratosis Decreased sweating calorigenesis and aci

nar gland secretion Generalized nonpitting edema (myxedema) in

severe hypothyroidism infiltration of the skin with glycosaminoglycans and associated water retention

Clinical Manifestations of Hypothyroidism -- Eyes

Periorbital edema -- as a manifestation of generalized nonpitting edema or Graves' ophthalmopathy.

Graves' ophthalmopathy may persist or worsen when hypothyroidism develops after treatment of Graves' hyperthyroidism. Patients will have variable degrees of stare, protrusion of the eyes, and extraocular muscle weakness.


-- Cardiovascular System

Bradycardia reductions in heart rate Impaired muscular contractility Reduced cardiac output decreased exercise capacity

and shortness of breath during exercise ECG: low voltage of QRS complexes and P and T wave

s CXR: cardiomegaly interstitial edema, myofibrillary s

welling, LV dilatation, pericardial effusion

Clinical Manifestations of Hypothyroidism -- Cardiovascular System

Myxedema induces coronary artery disease ?? CAD more common in p’ts with hypothyroidism Symptoms and signs of congestive heart failure

are usually absent in patients who have no other cardiac disease

Congestive heart failure or angina may worsen when hypothyroidism develops in patients with heart disease

Clinical Manifestations of Hypothyroidism -- Cardiovascular System

Hypertension peripheral vascular resistance In normotensive patients, BP increases are s

mall (<150/100 mmHg). The BP of patients with established hypertensi

on may increase further with the development of hypothyroidism.


-- Respiratory System

Fatigue, shortness of breath on exertion, and decreased exercise capacity impaired respiratory function + cardiovascular disease

Hypoventilation (shallow and slow respirations) respiratory muscle weakness + reduced pulmonary responses to hypoxia and hypercapnia

Obstructive sleep apnea macroglossia


-- Gastrointestinal Disorders

Constipation, even ileus gut motility Decreased taste sensation Gastric atrophy presence of antiparietal cell antibo

dies. Pernicious anemia occurs in 10% of patients with hypothyroidism caused by chronic autoimmune thyroiditis.

Weight gain decreased metabolic rate + accumulation of fluid (nonpitting edema) that is rich in glycosaminoglycans

Ascites, rare

Clinical Manifestations of Hypothyroidism -- Renal Function

Decreased glomerular filtration rate (GFR ) Impaired ability to excrete a water load The drug clearance (ex, antiepileptic, anticoa

gulant, hypnotic and opioid drugs), is decreased. Drug toxicity may occur if drug dosage is not reduced.

During T4 replacement, drugs that are administered at effective doses in patients who are hypothyroid may become less effective.

Clinical Manifestations of Hypothyroidism -- Anemia

Impaired hemoglobin synthesis thyroxine deficiency

Iron deficiency increased iron loss with menorrhagia + impaired intestinal absorption of iron

Folate deficiency impaired intestinal absorption of folic acid

Pernicious anemia vitamin B12 -deficient megaloblastic anemia


-- Reproductive Abnormalities

Women with hypothyroidism may have either oligo- or amenorrhea or hypermenorrhea-menorrhagia.

Decreased fertility Increased likelihood for early abortion Hyperprolactinemia may occur, and is occasionally s

ufficiently severe to cause amenorrhea or galactorrhea

The serum sex hormone-binding globulin concentration may be low in hypothyroidism. This will lower serum total but not free sex hormone concentrations.


-- Neurological Dysfunction

General depression of central nervous system function

Sleepiness, inability to concentrate Sluggish thought processes

Respond slowly to questions Less able to retrieve information from memory

Agitated psychosis, rare (“myxedema madness”) PET: 23% reduction in cerebral blood flow and a 12%

reduction in cerebral glucose metabolism


-- Neuromuscular Abnormalities

A delay in the relaxation phase of deep tendon reflexes

Carpal tunnel syndrome Paresthesia Asymptomatic elevation in serum CPK level t

o muscle hypertrophy (which may be accompanied by muscle cramps) to proximal muscle weakness to, in rare cases, rhabdomyolysis.


-- Metabolic Abnormalities

Hyponatremia may result from a reduction in free water clearance

Reversible increases in serum creatinine occur in 20 ~ 90% of hypothyroid patients

lipid clearance may be decreased, resulting in an elevation in the serum concentrations of free fatty acids and total and low-density lipoprotein cholesterol

Plasma homocysteine concentrations are increased in some hypothyroid patients,

Common Signs and Symptoms of Hypothyroidism

Sign or symptomWeakness

Skin changes (dry or coarse skin)

Lethargy

Slow speech

Eyelid edema

Cold sensation

Decreased sweating

Cold skin

Thick tongue

Facial edema

Coarse hair

Skin pallor

Forgetfulness

Constipation

Affected patients (%)99

97

91

91

90

89

89

83

82

79

76

67

66

61

Diagnosis of Hypothyroidism

Serum FT4, TSH

Normal FT4, TSH

TSH , FT4 FT4 , TSH normal or

Primary hypothyroidism

Euthyroid

Secondary hypothyroidism

TRH test

Excessive response

Normal type

response

No response

Pituitary lesion

Hypothalamic lesion

Primary hypothyroidism

Treatment of Hypothyroidism

Replacement of Triiodothyroxine (T3): unsatisfactory due to rapid absorption, short half-life, and transient effect

Levothyroxine (T4): Converted to T3 intracellularly Once daily, half-life: 7 days Well-absorbed Easily monitored by following serum TSH and

T4 levels

Treatment of Hypothyroidism

Replacement does of levothyroxine in adults range from 0.05 to 0.2 mg/d. It varies according to the patient’s age and body weight.

In young children: 4-5 ug/kg/d In adults: average 1.7 ug/kg/d In elders, start with lower dose, ex. 0.025mg daily, inc

rease the dose at 4- to 6-week intervals based on serum FT4 and TSH levels

Dose should be increased about 25% during pregnancy

Drugs Potentially Altering Thyroid Hormone Replacement Requirements

Increase replacement requirements

Drugs that reduce thyroid hormone production

Lithium

Iodine-containing medications

Amiodarone (Cordarone)

Drugs that reduce thyroid hormone absorption

Sucralfate (Carafate)

Ferrous sulfate (Slow Fe)

Cholestyramine (Questran)

Colestipol (Colestid)

Aluminum-containing antacids

Calcium products

Drugs that increase metabolism of thyroxine

Rifampin (Rifadin)

Phenobarbital

Carbamazepine (Tegretol)

Warfarin (Coumadin)

Oral hypoglycemic agents

Increase thyroxine availability and may decrease replacement requirements

Drugs that displace thyroid hormone from protein binding

Furosemide (Lasix)

Mefenamic acid (Ponstel)

Salicylates

Myxedema Coma

Myxedema coma may occur when severe hypothyroidism is complicated by trauma, surgery, infection, cold exposure, major medical illness, or inadvertent administration of hypnotics or opiates.

Clinical Features of Myxedema Coma

Decreased mental status Hypothermia Bradycardia Hyponatremia Hypoglycemia Hypotension Precipitating illness

Pathophysiology of Myxedema

Depressed ventilatory responses to CO2 retention and hypoxia

Weak respiratory muscle Decreased cardiac output Peripheral vasodilatation Hypotension Reduced cerebral blood flow with CNS depression Reduced renal perfusion and impaired free water clea

rance water intoxication Electrolyte imbalance Hyponatremia Hypothyermia

Treatment of Myxedema Coma

Active re-warming of the body is contraindicated, because it may induce vasodilatation and vascular collapse.

A rise in body temperature is a useful indication of therapeutic effectiveness of thyroxine.

Thyroid Function Tests in Nonthyroidal Illness

Low T3 level due to Inhibition of 5’-Deiodinase

The majority of hospitalized patients have low serum T3 concentrations, as do some outpatients.

80% of circulating T3 is produced by the peripheral 5'-deiodination of T4 to T3, a reaction catalyzed by 5'-deiodinases in organs such as the liver and kidney.

5'-deiodination decreases whenever caloric intake is low and in any nonthyroidal illness, even mild illness.

Inhibition of 5'-deiodination

High endogenous serum cortisol concentrations and exogenous glucocorticoid therapy

Circulating inhibitors of deiodinase activity, such as free (non-esterified) fatty acids

Treatment with drugs that inhibit 5‘-deiodinase activity such as amiodarone and high doses of propranolol

Cytokines (such as TNF-tumor necrosis factor, interferon-α, NF-kB, and IL-6)

Serum samples from patients with nonthyroidal illness impair uptake of T4 into cultured rat hepatocytes reducing the availability of substrate for conversion to T3

Increased Reverse T3 Level

Reverse T3 (rT3) is the product of 5-deiodination of T4

The clearance of rT3 to diiodothyronine (T2) is reduced in nonthyroidal illness because of inhibition of the 5'-deiodinase activity

Measurement of serum rT3 may be useful in hospitalized patients to distinguish between nonthyroidal illness (rT3) and secondary hypothyroidism (rT3). In patients with mild hypothyroidism, however, serum rT3 concentrations may be normal or even slightly high

Low T4 due to Reduced Protein-Binding

From 15~20% of hospitalized patients and up to 50% of patients in ICU have low serum T4 concentrations

There are reductions in the serum concentrations of one or more of the three thyroid hormone-binding proteins — thyroxine-binding globulin (TBG){major binding protein}, transthyretin (TTR, or thyroxine-binding prealbumin [TBPA]), and albumin

Low T4 due to Reduced Protein-Binding

Existance of thyroid hormone binding inhibitor, which decrease binding affinity of the binding protein to thyroid hormone causes further reduction in serum total T4 concentrations, and sometimes low serum free T4 concentrations

Unsaturated fatty acids, such as oleic acid, from anoxic or injured tissue, inhibits the binding of T4 to TBG.

Pituitary-Thyroid Axis

Patients with severe nonthyroidal illness may have acquired transient central hypothyroidism

In some critically ill patients serum: TSH concentrations fell coincident with decline

s serum T4 concentrations When recovering from nonthyroidal illness, the

re’s a rise in serum TSH concentration (which transiently reached supranormal values in some patients) preceded normalization of serum T4 concentrations

Thyroid Function in Ill Patients

Thyroid function should not be assessed in seriously ill patients unless there is a strong suspicion of thyroid dysfunction.

When thyroid dysfunction is suspected in critically ill patients, measurement of serum TSH alone is inadequate for the evaluation of thyroid function.

Thyroid Therapy in Ill Patients

In the absence of clinically apparent hypothyroidism, it is best to avoid thyroid hormone therapy and to re-evaluate later following recovery.

These changes in thyroid function may represent a protective adaptation for severe illness. For example, one effect would be to reduce oxygen and other metabolic demands.

Pharmacologic Use of Thyroid Hormone in Euthyroid Patients

Thyroid hormone, particularly T3, has been used in patients undergoing cardiac surgery in an attempt to assist in weaning from cardiopulmonary bypass or improve survival in high-risk patients. However, randomized clinical trials to date do not support its routine use in either instance

T3 has also been used in patients with refractory depression in an attempt to enhance the response to antidepressant drugs.

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HYPOTHYROIDISM Hypothyroidism Hypothyroidism is a clinical