The thyroid gland synthesizes and secretes tetraiodothyronine (T 4 ) and, in much smaller quantities, triiodothyronine (T3 ), which is at least two to four times more potent than T4 . Both of these hormones regulate tissue metabolism. Iodine is bound to tyrosine residues of thyroglobulin in the thyroid gland (organification), and these iodinated
residues are then coupled to form T4 and T3 . Both protein-bound (inactive) and unbound (active) thyroid hormone fractions exist in serum. In the periphery, T 4 is deiodinated to T3 , accounting for about 80 percent of T3 production^ ; otherwise it is converted into reverse T3 (rT3 ), a metabolically inactive product.
Pathogenesis and Pathophysiology. Hypothyroidism can be related to thyroid gland dysfunction (i.e., primary hypothyroidism), to a disturbance outside of the thyroid gland (i.e., central hypothyroidism), or to peripheral resistance to thyroid hormone. y Mechanisms of thyroid gland dysfunction include parenchymal destruction (viral or autoimmune), chronic inflammation with lymphocytic infiltration (Hashimoto's thyroiditis), cell death (radiation damage), or defective hormonogenesis. Defective hormonogenesis may occur due to inadequate iodine intake (i.e., endemic goiter), excessive ingestion of goitrogens (e.g., turnips), intrinsic defects in thyroid hormone production (e.g., rare enzymopathies), as well as medication-induced thyroid hormone synthesis disturbance (e.g., lithium, thionamides, amiodarone). In some patients, iodine loading may cause significant hypothyroidism (Wolff-Chaikoff effect).
Although the pathogenesis and pathophysiology of many of the peripheral neurological manifestations of the hypothyroid state are known, most of the CNS manifestations are unexplained. Although hypothyroid-induced seizures may be related to hyponatremia, coma likely represents a multifactorial process. y Direct metabolic effects or entrapment by adjacent tissue (e.g., myxedematous infiltration) may cause peripheral and cranial mononeuropathies. y , y Persistent percussion-induced local muscle contraction is referred to as myoedema and is caused by delayed Ca reuptake by the sarcoplasmic reticulum, thereby prolonging the contraction.y A reduction in myosin ATPase activity contributes to slowed contraction, and delayed reuptake of Ca by the sarcoplasmic reticulum contributes to delayed relaxation.^ Also, a shift in muscle fiber type distribution from fast twitch to slow twitch may contribute to slowed muscle contraction and relaxation. y In addition, a reduction in muscle mitochondrial oxidative capacity and beta-adrenergic receptors, as well as the induction of an insulin-resistant state, may contribute to weakness, fatigue, and exertional pain. y The pathophysiology of the muscle enlargement, a feature more commonly observed in children (Kocher-Debre-Semelaigne syndrome), is uncertain, although work hypertrophy related to prolonged contraction is suspected. y
Epidemiology and Risk Factors. The incidence of primary hypothyroidism is much greater in women than in men,y , y especially among women between the ages of 40 and 60 years. Central hypothyroidism (e.g., hypothalamic-and pituitary-related), on the other hand, is more commonly observed among the neurosurgical population.y Primary hypothyroidism is much more common than secondary hypothyroidism, and is usually caused by autoimmune destruction (e.g., Hashimoto's thyroiditis), irradiation, or surgically treated hyperthyroidism. Pituitary and hypothalamic disease contribute less than 10 percent of cases of hypothyroidism. y Myxedema coma is extremely rare, and its incidence is higher in elderly women, especially those over 60 years. y Risk factors for myxedema coma include noncompliance with levothyroxine therapy, infection, surgery, drugs, hyponatremia, and the winter months. y , y Although complex changes in thyroid function occur during pregnancy, the normal pregnant woman is euthyroid^ and the incidence of hypothyroidism is not influenced by pregnancy. y
Clinical Features and Associated Disorders. Clinically, the onset of hypothyroidism may range from subtle and insidious findings to florid psychosis. The general examination features of hypothyroidism are numerous (,,Table,38:7 ). cNs features include forgetfulness, inattention, apathy, and slowing of speech, movement and mentation. These features may mimic depression. Seizures, personality changes, psychotic states, coma, and dementia may also be clinically apparent. Cerebellar ataxia is seen in 5 to 10 percent of patients, y and may be the presenting sign (so-called myxedema staggers). A psychotic presentation (myxedema madness) characterized by agitation, disorientation, delusions, hallucinations, paranoia, and restlessness is observed in approximately 3 to 5 percent of patients. y Myxedema coma is extremely rare, and its characteristic features include extreme hypothermia, seizures (the presenting manifestation in nearly 20 percent of patients y ), respiratory depression, and areflexia. Death can occur when early recognition and prompt treatment are lacking. Dementia may develop when hypothyroidism is severe. Except for the marked increase in the number of hours these patients remain asleep or resting, the clinical features of the dementia are similar to those secondary to other causes. y
Peripheral neuromuscular features include cranial and peripheral neuropathies, prolonged reflex relaxation time (up to 85 percent of hypothyroid patients), y , y and myopathy. Visual field defects can occur when pituitary enlargement causes hypothyroidism with concomitant chiasmal compression. A facial mononeuropathy, due to nerve entrapment in the fallopian canal of the temporal bone, may rarely occur. y Although sensorineural hearing loss has been reported to correlate with the degree of hypothyroidism and has a high incidence among patients with congenital
_TABLE 38-7 -- GENERAL FEATURES OF HYPOTHYROIDISM_
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