Sep. 27, 2023
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Hypothyroidism can affect the central and peripheral nervous systems at multiple levels, producing a diverse array of neurologic symptoms and signs. Clinicians should be particularly aware of the diagnostic and management issues related to myxedema coma, dementia, myopathy, and polyneuropathy. Carpal tunnel syndrome may be the most common neurologic abnormality associated with hypothyroidism. The importance of hypothyroidism as a “reversible cause of dementia” remains unclear. The diverse manifestations of Hashimoto encephalopathy, a syndrome that appears to be inflammatory rather than a direct result of inadequate thyroid hormone levels, are important to recognize because the syndrome typically responds to high-dose steroid treatment.
• Hypothyroidism can affect practically every level of the central and peripheral nervous system.
• Although coma due to severe hypothyroidism (myxedema coma) is rare, it should always be considered in comatose patients without a clear cause because it requires rapid and specific treatment.
• Carpal tunnel syndrome is the most common peripheral nerve manifestation of hypothyroidism.
• An elevated thyrotropin level is the key diagnostic finding in primary hypothyroidism, which is the most common form of hypothyroidism.
Hypothyroidism is the clinical condition that results from inadequate synthesis of thyroid hormone. Myxedema is a state of severe hypothyroidism. William Gull published a detailed description of a patient with myxedema in 1874 and noted that the disorder resembled cretinism. In 1878 William Ord described five additional patients and proposed the designation "myxedema" because he was impressed with the nonpitting edema and gelatinous skin observed in these patients. In 1883 the Clinical Society of London named a committee to study myxedema, and in 1888 this committee published an analysis of 109 cases, noting a characteristic destruction of the thyroid gland in autopsied cases. The report also included the observation that a similar state could be produced in monkeys by removing the thyroid gland. An extract of sheep thyroid was first administered to a myxedematous patient by subcutaneous injection in 1891, and the first oral administration was attempted in 1892. Ground sheep thyroid is said to have been used as a common remedy for a condition resembling myxedema in fourth century China (185). The proposal that the Mona Lisa depicts a woman with postpartum hypothyroidism is probably impossible to prove (145).
Even the earliest descriptions of myxedema documented the frequent and prominent neurologic manifestations. With the identification of thyroxine in 1915 and triiodothyronine in 1952, it became possible to identify the neurologic consequences of less florid states of hypothyroidism.
There has been some inconsistency in the use of the term “myxedema.” Some use it as a synonym for hypothyroidism in general, others as a designation for severe hypothyroidism, and still others as a label for the doughy induration of the skin that occurs in severe hypothyroidism. Cretinism denotes a condition of abnormal development that results from congenital hypothyroidism.
The systemic manifestations of hypothyroidism include fatigue, lethargy, constipation, cold intolerance, menorrhagia, reduced appetite, weight gain, dry skin, dryness and thinning of the hair, and deepening of the voice. Patients with severe hypothyroidism have pale, cool skin that feels doughy, sparse hair, a large tongue, and periorbital puffiness. The heart is usually enlarged, and adynamic ileus can occur. Congenital hypothyroidism is associated with an increased risk of systemic malformations, especially cardiac and urogenital anomalies (201).
Hypothyroidism affects the central nervous system and the peripheral nervous system at multiple levels, resulting in a diverse set of neurologic symptoms and signs.
Altered mental status. Cretinism, a condition consisting of marked developmental abnormalities due to severe congenital hypothyroidism, is most common in iodine-deficient environments. Two principal syndromes are recognized. One is characterized by dry, swollen, or thickened skin; sparseness of hair and nails; impaired bowel function; growth retardation; delayed sexual development; deep, hoarse voice; slow relaxation phase of deep tendon reflexes; psychomotor defects; and cognitive defects. These children often have incomplete maturation of the face, with wide-set eyes, saddle-nose deformity, mandibular atrophy, and thickened lips. The other syndrome consists of features that are primarily neurologic, including impaired cognition, defects of hearing and speech, squint, spastic paraparesis, and ataxia (78). Because of newborn screening and early treatment, congenital hypothyroidism is less likely than in the past to cause severe mental retardation, but it still occurs, and it is endemic in some parts of the world (36; 124; 11). Even prenatal maternal hypothyroidism or iodine deficiency can result in persistent, subtle, neurocognitive and motor deficits and abnormalities of brain imaging (93; 195; 78; 177; 182; 121; 06; 12; 96; 155; 115). Transient hypothyroidism has also been implicated as a possible cause of cerebral palsy in premature infants (93). In older children and adults, even mild hypothyroidism is associated with altered mental status, typically characterized as slowness, inattention, apathy, lethargy, and depression, and these symptoms improve after treatment with thyroxine (24; 149; 150; 44; 184; 64). In the elderly, cognitive measures may correlate with thyroid hormone levels, even in subjects who appear to be clinically euthyroid and whose thyroxine and thyrotropin levels are within the normal range, but the evidence for this correlation is inconclusive (219; 13; 20; 225; 14; 184; 30). Hypothyroidism is usually listed as one of the potentially reversible causes of dementia, but the literature on this topic suffers from inadequate criteria for diagnosing dementia and a failure to demonstrate complete and sustained recovery of cognitive function after thyroid hormone replacement (192; 56; 133; 13; 207; 164; 223). No association between Alzheimer disease and clinical hypothyroidism has been demonstrated, although abnormal levels of thyroid hormones in the serum and cerebrospinal fluid have been reported (218; 183; 49; 50; 34). Estimates of the prevalence of psychotic features among patients with hypothyroidism range from 3% to 15% (205; 116), giving rise to the term "myxedema madness" (98). Hypothyroidism is associated with an increased risk of clinical depression, but the effect size is modest (23; 160).
Myxedema coma is the most severe expression of hypothyroidism (110; 70; 186; 221; 123; 118; 80; 37; 161; 227). It occurs in less than 1% of patients with hypothyroidism, usually in patients with longstanding disease that often has not been treated or even diagnosed. It is most common in elderly women in winter. In addition to a depressed level of consciousness and the systemic features of hypothyroidism, the classic findings are hypothermia, hypoventilation, bradycardia, and distant heart sounds. Hyponatremia and hypoglycemia are common, and seizures may occur. One case report describes a patient with mild hypothyroidism who developed a syndrome very suggestive of myxedema coma; the patient improved after intensive intravenous thyroid supplementation (136).
Hashimoto encephalopathy is a rare, steroid-responsive syndrome characterized by various combinations of mental status changes, altered consciousness, stroke-like events, seizures, status epilepticus, tremor, myoclonus, and opsoclonus in association with autoimmune thyroiditis (40; 32; 103; 139; 151; 148; 181; 231; 41; 63). It is not a direct result of hypothyroidism, as it occurs even in euthyroid subjects. This condition has also been called SREAT (steroid-responsive encephalopathy associated with autoimmune thyroiditis), or NAIM (nonvasculitic autoimmune meningoencephalitis). Pathologic material is scarce but suggests an inflammatory component (55; 151). Spinal fluid protein is typically elevated and, in one published report, this was thought to be the cause of increased intracranial pressure (73). Most patients improve about 4 to 6 weeks after starting prednisone, 50 to 150 mg per day, but controlled trials have not been conducted. Steroid treatment is generally maintained for 4 months to 2 years, and most patients continue to do well after steroids are withdrawn. Clinical response to intravenous immunoglobulin, plasma exchange, and other immunomodulatory therapies has also been reported (97; 101). Some authors have questioned this syndrome’s validity because it is so protean and the response to steroids is unpredictable, with no clinical or laboratory features that correlate with steroid-responsiveness identified to date (40; 141; 216).
Seizures. Seizures are most common in myxedema coma but can occur with less severe disease. In a series of 56 patients with adult myxedema, 10 patients (18%) presented with seizures or syncope (106). The seizures are typically generalized, but focal seizures have also been reported.
Strokes. No clear association is seen between hypothyroidism and strokes, but hypothyroidism is associated with diastolic hypertension and increased total and LDL cholesterol levels. It is also associated with elevated plasma homocysteine levels, and it may affect endothelial function and coagulation profiles. In a population-based study, both low and high free thyroxine levels were associated with lower retinal artery diameter and global brain perfusion than intermediate levels (66). Thus, hypothyroidism affects stroke risk factors in ways that could lead to an increased risk of stroke, but the relationship requires further study (200; 33; 226; 95). Thyroid hormone levels may correlate with severity at presentation and early outcome in patients with acute ischemic stroke (05; 09; 04; 26; 71; 229). The presence of thyroid autoantibodies may be associated with an unfavorable outcome in patients with acute ischemic stroke (39).
Headaches. Many patients with hypothyroidism or subclinical hypothyroidism report headaches, with a prevalence that is higher than in matched control groups in some series, but not all (178; 198). The headaches do not have any distinguishing characteristics; they are usually chronic, recurrent, and diffuse. One longitudinal retrospective cohort study suggests that headache disorders may be associated with an increased risk of developing new onset hypothyroidism (140).
Ataxia. Ataxia can be the presenting feature of hypothyroidism, or it can occur later in the course (46; 62). The ataxia manifests as unsteady gait in all cases, but this is accompanied by upper extremity coordination deficits in 61% of patients and dysarthria in 50% of patients. Ataxia has also been reported in patients with Hashimoto encephalopathy (156; 62).
Movement disorders. Some features of hypothyroidism, such as bradykinesia and voice abnormalities, mimic parkinsonism. One population-based cohort study reported an increased incidence of Parkinson disease in patients with hypothyroidism relative to euthyroid controls, but previous studies found no relationship; further study is necessary (154; 35). One case has been reported of a 12-year-old girl in whom titubation and paroxysmal dyskinesia were the presenting symptoms of hypothyroidism due to lymphocytic thyroiditis (94).
Cranial nerve abnormalities. Hypothyroid patients frequently report hearing loss, but it is thought to be due to fluid accumulation in the inner ear rather than neurologic dysfunction. It improves after hormone replacement. Tinnitus and vertigo are less common complaints, but compared with subjects without hypothyroidism, people with hypothyroidism have a higher incidence of Meniere disease (132). Ptosis occurs in 50% to 75% of hypothyroid patients, apparently due to decreased sympathetic tone. Patients with autoimmune thyroid disease can develop thyroid ophthalmopathy, a condition in which infiltration of the extraocular muscles with glycosaminoglycans and inflammatory edema cause diplopia, exophthalmos, pain behind the eyes, and blurred vision (86). In primary hypothyroidism, secondary pituitary enlargement can cause chiasmal compression leading to visual field defects. Distortions of taste and smell are common in patients with hypothyroidism, and they are largely reversed with hormone replacement (142). One study found that hypothyroidism was more prevalent in people with prolonged anosmia after COVID-19 than in controls (213). Hoarseness and articulation defects are also common, but they are probably a result of mucopolysaccharide deposition in the larynx, vocal cords, and tongue, rather than cranial nerve dysfunction (202; 122). Trigeminal neuralgia and facial palsy have been reported in patients with hypothyroidism but so rarely that the association may have been due to chance. A case report has been published of a patient with facial palsy, uvular deviation, and tongue deviation, all of which resolved after treatment for severe hypothyroidism (91). Another case report described a patient with hemifacial spasm that resolved with thyroid replacement, reappeared when treatment was stopped, and disappeared again when treatment was resumed (76). According to one group of investigators, Hashimoto thyroiditis is common among patients with benign paroxysmal positional vertigo, but the association is independent of thyroid status (163).
Sleep disorders. Hypothyroidism is associated with sleep apnea, even after adjustment for potential confounding variables (210). In particular, subclinical hypothyroidism is common among patients with obstructive sleep apnea, but newly diagnosed clinical hypothyroidism is rare (10; 147). Potential mechanisms by which hypothyroidism could cause sleep apnea (in addition to obesity, the most obvious confounder) include mucopolysaccharide deposition in the tongue and upper airway, altered regulatory control of pharyngeal dilator muscles, and depression of respiratory centers (114; 210). Central sleep apnea has also been reported. The symptoms of idiopathic hypersomnia have also been reported to improve after initiating treatment with thyroxine in patients with subclinical hypothyroidism (193). Restless legs syndrome is more prevalent in people with hypothyroidism than in people without hypothyroidism, and hypothyroidism is more prevalent in people with restless legs syndrome than in people who don’t have restless legs syndrome (03).
Spastic paraparesis. Paraplegia and extensor plantar responses have been reported in hypothyroid patients but so infrequently that the association may have been fortuitous. A single case has been reported of a patient with hypothyroidism of hypothalamic origin who had spastic paraplegia that resolved with physiologic doses of thyroid replacement (100). However, the patient also received a small physiologic dose of prednisone.
Peripheral nerve involvement. Hypothyroid patients commonly report limb paresthesias, but electrodiagnostic studies demonstrate a peripheral polyneuropathy in only a minority of patients (172; 59; 60; 162; 157). Elevated thermal thresholds have been described in patients with hypothyroidism and unexplained pain in the extremities, suggesting the possibility of small-fiber neuropathy (162). Severe neuropathy is rare. Hypothyroidism is present in 9% to 67% of patients with POEMS syndrome, but it is not the cause of the polyneuropathy; rather, both the polyneuropathy and the endocrinopathy of POEMS syndrome are manifestations of a paraneoplastic syndrome with poorly understood pathogenesis (53). The most common peripheral nerve manifestation of hypothyroidism is carpal tunnel syndrome, probably resulting from either obesity or mucopolysaccharide deposition within the nerve itself and in the surrounding tissue (07). In studies that control for confounding factors (such as obesity and rheumatoid arthritis), the association between carpal tunnel syndrome and hypothyroidism is only modest (194). Some hypothyroid patients have recurrent laryngeal nerve lesions as a result of prior thyroid surgery or because of compression by an enlarged thyroid gland. Thyroid enlargement can also compress the sympathetic chain in the neck to produce unilateral or bilateral Horner syndrome.
Neuromuscular junction dysfunction. A few hypothyroid patients with myasthenic syndromes that responded to thyroid replacement have been reported (159; 206). The neuromuscular transmission abnormality was different from that seen in myasthenia gravis. Autoimmune thyroiditis may be associated with a myasthenic syndrome, but this is presumably due to the autoimmune disorder rather than a direct manifestation of hypothyroidism (215; 197).
Muscle abnormalities. Proximal muscle weakness develops in about 25% of patients with hypothyroidism (172). The weakness is usually mild, and most of the patients complain of associated pain, slowness, or stiffness. The weakness is slowly progressive over months to years. Serum creatine kinase measurement cannot be used as an indication of myopathy in hypothyroidism because creatine kinase levels are increased in about 90% of hypothyroid patients, most of whom do not have overt myopathy (79; 69; 20). Conversely, markedly elevated creatine kinase levels do not exclude the diagnosis of hypothyroid myopathy (189).
Several abnormalities of muscle contraction are characteristic of hypothyroidism. Prolongation of both contraction and relaxation phases results in slow or "hung up" reflexes that normalize with thyroid hormone replacement. Measurement of reflex time was even used to assess adequacy of therapy before radioimmunoassays became readily available. Hypothyroidism can also lead to muscle enlargement, especially in children. The Kocher-Debre-Semelaigne syndrome refers to an "infant Hercules" appearance in some children with cretinism who manifest a striking increase in muscle bulk without an accompanying increase in muscle function (179; 58). Some hypothyroid adults have enlarged, firm muscles that become increasingly stiff and painful with exercise, forcing them to rest briefly before resuming activity, a condition known as Hoffman syndrome (48; 07). An adolescent with this syndrome has also been reported (191). Although this muscle activity bears a superficial resemblance to myotonia, it is not accompanied by electrical activity. Electrically silent contraction also occurs in myoedema, a local mound of contracting muscle induced by percussion or some other mechanical irritation of the muscle. Myoedema is present in about one third of hypothyroid patients.
One report exists of a patient with necrotizing myopathy that resolved after treatment for central hypothyroidism (211). There are rare reports of patients with rhabdomyolysis that resolved after treatment for severe primary hypothyroidism (190; 187).
Even when untreated, hypothyroid patients can function without serious problems for many years. In the small percentage of patients who develop myxedema coma, however, mortality rates of 60% to 70% were the rule until advances in early recognition and treatment lowered the mortality rate to 15% to 25% (110; 118). More severe impairment of consciousness on presentation correlates with a poorer prognosis (175). Chronic over-replacement with thyroxine can increase bone turnover and can also lead to cardiac hypertrophy and arrhythmias. An increased metabolic rate can precipitate adrenocortical insufficiency, so patients with central hypothyroidism must be evaluated for adrenal insufficiency and, if it is present, hydrocortisone replacement must be initiated before starting thyroxine.
A 66-year-old woman reported progressive gait deterioration over the previous 3 months. Her husband wondered if she was simply depressed about her recent retirement, noting that over the past year she had grown increasingly lethargic and never wanted “to go anywhere or do anything.” She had lost her appetite and slept poorly.
Her examination was notable for psychomotor retardation without focal cognitive deficits. She had a mild ataxic dysarthria, and her speech was hoarse. Her cranial nerves were otherwise normal. Her gait and limb movements were ataxic with full strength throughout. She had normal reflexes, but slow relaxation was noted at the ankle.
She had a thyrotropin level of 95 mU/L (normal is less than 5) and a thyroxine level of 2.1 µg/dL (normal 4.7 to 12.4 µg/dL). Thyroxine replacement was initiated at a dose of 25 µg per day, gradually increasing until her thyrotropin level normalized at a dose of 75 µg per day. Her lethargy and depression improved within weeks of initiating treatment, and her ataxia gradually resolved over several months.
Hypothyroidism is classified as primary when it is caused by failure of the stimulated thyroid gland to release adequate amounts of thyroxine and triiodothyronine, secondary when it is caused by inadequate pituitary secretion of thyrotropin (thyroid-stimulating hormone), and tertiary when it is due to insufficient production of thyrotropin-releasing hormone by the hypothalamus. Secondary and tertiary hypothyroidism are also referred to as central hypothyroidism. Primary hypothyroidism is much more common than the other two forms. In the United States, primary hypothyroidism is most often the result of chronic autoimmune thyroiditis or of surgical or radioiodine ablation of an overactive thyroid gland (117; 209; 52; 42; 105; 85). Other causes include iodine deficiency, iodine excess, congenital conditions, infiltrative diseases, radiation, and drugs or environmental chemicals that impair hormone biosynthesis, such as lithium, amiodarone, sulfonamides, sulfonylureas, carbamazepine, oxcarbazepine, phenytoin, valproate, alemtuzumab, bexarotene, interleukins, sunitinib and other tyrosine kinase inhibitors, mitotane, propylthiouracil, methimazole, polychlorinated biphenyls, bisphenol-A, polybrominated diphenyl esters, and immune checkpoint inhibitors (43; 209; 52; 232; 20; 127; 84; 125; 131; 01; 228; 83; 113; 85; 87; 28; 75; 138; 168; 02; 174). Antineoplastic agents can cause hypothyroidism by a variety of mechanisms (84). Central hypothyroidism can result from genetic mutations, tumors, granulomatous and other autoimmune diseases, infection, irradiation, surgery, head trauma, hemorrhage, infarction, and medications (222; 167; 75; 135; 188; 214; 126; 153).
Thyroxine, the primary secretory product of the thyroid, is relatively inactive. It is converted to the active hormone, triiodothyronine, by the enzymes type 1 deiodinase and type 2 deiodinase. A variety of other metabolites derived from thyroxine and triiodothyronine by deiodination occur endogenously, and their physiologic significance is still being elucidated (119). Triiodothyronine acts on a family of nuclear receptors that bind to regulatory regions of genes and modify their expression (25; 146). For example, triiodothyronine increases transcription of the genes for calcium ATPase in the sarcoplasmic reticulum of skeletal and cardiac muscle. Calcium ATPase mediates clearance of calcium from the cytoplasm after muscle contraction, so hypothyroidism results in prolonged muscle relaxation. As another example, thyroid hormones affect expression of myelin genes, and hypothyroidism causes a variety of structural and functional changes in the hippocampus, especially during development (120). Most of the genes targeted by thyroid hormones in the brain remain to be identified (220).
The genes that code triiodothyronine receptors are differentially expressed in various tissues, and the effects of triiodothyronine depend on the specific isoform of the receptor (173; 146; 180). The receptors are expressed in a developmentally specific pattern, especially in the brain (224). Many of the specific genes regulated by triiodothyronine in various tissues have not been identified, but the general metabolic effects of thyroid hormones are to stimulate oxygen consumption in almost all metabolically active tissues, increase absorption of carbohydrates from the intestine, and modulate lipid metabolism. Thyroid hormones mobilize mucopolysaccharides and prevent their deposition in skin and connective tissues. Thyroid hormones also interact with catecholamines. In addition, research has shown that triiodothyronine (and possibly thyroxine) has nongenomic actions, mediated by receptors in the plasma membrane, mitochondria, and cytoplasm (47; 146). The mechanisms underlying cognitive and affective manifestations of hypothyroidism are not fully understood (129). A variety of factors may be involved, including reduced responsiveness of the reticular activating system to catecholamines, impaired fluid and electrolyte regulation, and altered blood flow (13).
Depending on the population under study, between 3% and 18% of people have subclinical hypothyroidism, defined as an elevated serum thyrotropin level in a patient with a serum free thyroxine level that is within the population reference range (14; 166; 203). The incidence is higher in women than in men and increases with age. Many people in this category are asymptomatic, but some studies have reported increased rates of typical symptoms of hypothyroidism, such as fatigue, weight gain, cold intolerance, constipation, weakness, and memory problems.
The predominant causes of hypothyroidism worldwide are iodine deficiency and goitrogens. In areas of adequate iodine supply, like the United States, the most common cause of hypothyroidism is chronic autoimmune thyroiditis, which affects 3% of adults and 10% of postmenopausal women (212; 117). Transient thyroiditis occurs in about 4% to 9% of postpartum women, with chronic autoimmune thyroiditis developing in about 25% of those affected. Autoimmune thyroiditis can occur as a component of autoimmune polyglandular syndrome type 2, wherein Addison disease and diabetes are the most common accompanying endocrinopathies, or in association with other autoimmune manifestations including pernicious anemia, lupus, rheumatoid arthritis, Sjögren syndrome, chronic hepatitis, and myasthenia gravis.
The principal approach to prevention of hypothyroidism has been dietary iodine supplementation, especially with iodized salt. Precautions to protect the thyroid during surgery or radiation treatment should be taken when possible. Because the fetal thyroid is particularly susceptible to iodine-induced goiter, iodine should not be given in large doses during pregnancy, and pregnant women should not receive radioactive iodine.
The individual neurologic manifestations of hypothyroidism are not particularly distinctive. The differential diagnosis of hypothyroid myopathy, for example, is the same as the differential diagnosis of myopathy in general, and hypothyroidism is in the differential diagnosis of any patient with a gradually progressive dementia.
A few sources of diagnostic confusion deserve specific mention. The tissue changes of myxedema resemble the edema and facial puffiness that occur in nephrotic syndrome, and both hypothyroidism and nephrotic syndrome are associated with anemia and hypercholesterolemia. The mental slowing that occurs in hypothyroidism can easily be mistaken for depression. Myxedema coma is sometimes erroneously attributed to the accompanying hypothermia, leaving the underlying thyroid disorder unrecognized. For this reason, all hypothermic patients should be screened for hypothyroidism. Cretinism can sometimes be confused with Down syndrome, but the morphological abnormalities in these two conditions are usually distinctive enough to differentiate them.
The key laboratory finding in primary hypothyroidism is an elevated thyrotropin level, resulting from reduced inhibitory feedback from the thyroid gland to the hypothalamus and anterior pituitary. The reference range for thyrotopin levels may need to be adjusted upward in elderly patients (29; 57; 143; 137). Elevated thyrotropin levels can also result from thyrotropin-producing pituitary tumors, but these are rare. Another uncommon cause of elevated thyrotropin levels is the generalized thyroid hormone resistance syndrome. Free thyroxine levels are high in both of these conditions, whereas free thyroxine levels are normal or low in primary hypothyroidism (165; 117; 15; 111).
A more difficult diagnostic distinction can arise in patients with severe systemic illness, which can substantially alter thyroid hormone levels in patients without intrinsic thyroid disease. A variety of labels have been applied to this phenomenon, including the sick euthyroid syndrome and the nonthyroidal illness syndrome. It is probably at least as common as intrinsic thyroid disease. The potential for confusion is greatest in the subgroup of patients who have low thyroxine and triiodothyronine levels: although thyrotropin levels are usually low, they may be slightly elevated during recovery from acute illness (196; 217; 61; 144). Fortunately, thyroxine levels are often increasing during this phase of a systemic illness, so it is unusual for the nonthyroidal illness syndrome to result in a high thyrotropin level and a low thyroxine level at the same time (199; 165; 117; 72; 217). Moreover, a thyrotropin level above 20 µU/mL does not occur in nonthyroidal illness and is a reliable indicator of hypothyroidism.
In central (ie, secondary or tertiary) hypothyroidism, thyrotropin and thyroxine levels are both low, although in mild cases they may both lie at the low end of the normal range (112; 90; 167; 143). In some patients with tertiary hypothyroidism, the pituitary still produces thyrotropin despite the absence of hypothalamic stimulation, but the thyrotropin is less effective than normal, so that thyroxine levels are low and thyrotropin levels are at the high end of the normal range, leading to potential confusion with primary hypothyroidism. A thyroid-releasing hormone stimulation test can sometimes help to distinguish between secondary and tertiary hypothyroidism. Patients with central hypothyroidism frequently have low levels of other pituitary hormones; therefore, measurement of these hormones can also be helpful. Imaging studies can also help to distinguish hypothalamic from pituitary disease.
Anti-thyroid antibodies are the hallmark of Hashimoto encephalopathy. Although antibodies to the thyrotropin receptor may play a role in the disease, the most important antibodies are the antithyroid peroxidase antibodies (also referred to as antithyroid microsomal antibodies), present in nearly 100% of published cases, and the anti-thyroglobulin antibodies, present in about 70% of cases (151).
Although combination therapy with thyroxine and triiodothyronine has been advocated, the current standard treatment for hypothyroidism remains thyroxine replacement alone (22; 108; 88; 92; 21; 38; 65; 143; 109; 107). The average thyroxine replacement dose is 1.6 to 1.8 µg/kg per day in middle-aged adults, 1.4 µg/kg per day in the elderly, 10 to 15 µg/kg per day in infants, and 3 to 4 µg/kg per day in children between 5 and 10 years of age (212; 208; 108; 85; 222; 167; 21; 143). In healthy young adults, treatment can be initiated at the full dose of 1.6 µg/kg per day, with subsequent dose increases every 2 to 3 weeks until thyrotropin levels are normal (although it may take 8 weeks for the pituitary-thyroid axis to reach equilibrium after a change in dose). In elderly patients or patients with heart disease, a normal metabolic rate should be restored gradually because sudden increases in metabolic rate can tax cardiac reserve. In these patients, an initial thyroxine dose of 12.5 or 25 µg per day can be increased by 25 or 50 µg increments every 4 to 8 weeks until thyrotropin levels are normal (212; 52; 208; 108; 57; 143; 107).
Patients in myxedema coma require rapid treatment with a single intravenous bolus of 200 to 400 µg of thyroxine followed by daily maintenance doses of 1.2 µg/kg intravenously (or 1.6 µg/kg enterally once the patient has recovered sufficiently for this to be feasible). In situations where intravenous levothyroxine is unavailable, enteral levothyroxine has been used successfully (171). Alternative treatment regimens incorporating triiodothyronine either alone or in combination with thyroxine have been advocated, but the evidence remains inconclusive (110; 169; 27; 70; 186; 175; 209; 221; 123; 118; 108; 102; 227; 107). Stress doses of hydrocortisone should be given along with the thyroid hormone replacement in case the patient has coexisting adrenal insufficiency. Before initiating this treatment, a baseline cortisol level should be drawn, and if it is elevated, the hydrocortisone can be discontinued. Also, broad spectrum antibiotics are often started. Hypothyroid patients being prepared for emergency surgery require a similar treatment regimen because of the extreme sensitivity to central nervous system depressants. Hypothermia should be treated with passive warming; active warming may result in hypotension due to peripheral vasodilation.
Studies have failed to prove that levothyroxine supplementation for treatment of subclinical hypothyroidism provides any clinical benefit (166; 203; 68; 17; 19; 38; 134; 152; 45; 51). This might suggest that when evaluating patients with neurologic conditions, such as dementia or polyneuropathy, it is pointless to check thyrotropin levels without also checking thyroxine levels, because an elevated thyrotropin level does not warrant treatment unless the thyroxine level is low. This conclusion is not justified, however, because the clinical trials did not explicitly select patients with neurologic symptoms, and the primary outcomes were not neurologic. Treatment of subclinical hypothyroidism is commonly recommended for individuals with thyrotropin levels of 10 mIU/L or higher, although even in this subgroup, the evidence of clinical benefit is limited (166; 68; 17; 19; 152; 107; 176). One metaanalysis found that treatment of older patients with subclinical hypothyroidism results in improved lipid profiles (230).
When hypothyroidism is adequately treated, no long-term consequences are experienced.
Thyroid hormones play a fundamental role in fetal development and tissue differentiation, particularly in the nervous system (170; 180; 77; 99). Uncontrolled hypothyroidism during pregnancy—especially early in pregnancy—is accompanied by an increased risk of fetal and maternal morbidity (212; 54; 82; 08; 130; 74; 67; 158; 104; 204). In most women, thyroxine requirements increase by 30% to 50% during pregnancy, especially in the third trimester (54; 130; 158; 134; 204; 12; 137). The traditional approach has been to measure the serum thyrotropin level during each trimester and adjust the thyroxine dose accordingly, although a randomized, prospective trial provided support for a single adjustment as soon as possible after pregnancy is confirmed (204). The dose of thyroxine that was used before pregnancy can be resumed immediately after delivery.
Some studies have found that women with subclinical hypothyroidism during pregnancy have children with lower IQ scores than women with normal thyroid function. However, the difference is very small, and thyroid replacement in this setting has not been shown to be beneficial, so there is no evidence to support the routine screening of pregnant women for hypothyroidism (81; 16; 158; 128; 89; 31; 121; 204; 06; 96; 143). The risk of adverse outcomes in pregnant women with subclinical hypothyroidism is higher in women who have antibodies to thyroid peroxidase than in those who are antibody-negative, but studies of the effect of thyroxine treatment on pregnancy outcome in antibody-positive women have yielded inconsistent results (134; 204; 96).
Hypothyroid patients are extremely sensitive to any medications that can suppress respiratory drive, notably sedatives, narcotics, and other anesthetic agents. When the use of these medications is unavoidable, postoperative ventilator dependence may be prolonged. The tissue swelling that occurs in hypothyroidism may also complicate the establishment and maintenance of a patent airway (18).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Douglas J Gelb MD PhD
Dr. Gelb of the University of Michigan has no relevant financial relationships to disclose.See Profile
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.See Profile
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