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.
Clinical Manifestations of Hypothyroidism
-- 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.
Clinical Manifestations 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
Clinical Manifestations of Hypothyroidism
-- 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
Clinical Manifestations of Hypothyroidism
-- 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.
Clinical Manifestations of Hypothyroidism
-- 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
Clinical Manifestations of Hypothyroidism
-- 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.
Clinical Manifestations of Hypothyroidism
-- 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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