Hypothyroidism by Douglas J Gelb MD Phd (Dr

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Hypothyroidism By Douglas J Gelb MD PhD (Dr. Gelb of the University of Michigan has no relevant financial relationships to disclose.) Originally released November 3, 1993; last updated July 9, 2017; expires July 9, 2020

Introduction

This article includes discussion of hypothyroidism, myxedema, steroid-responsive encephalopathy associated with autoimmune thyroiditis, SREAT, altered mental status, encephalopathy, coma, seizures, ataxia, cranial neuropathies, sleep disorders, peripheral neuropathies, and myopathies. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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.

Key points • 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.

Historical note and terminology

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 5 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 (Sanders 1962a).

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.

Clinical manifestations

Presentation and course

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 (Stoll et al 1999).

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. Because of newborn screening and early treatment, congenital hypothyroidism is less likely than in the past to cause severe mental retardation, but it still results in persistent, subtle, neurocognitive and motor deficits and abnormalities of brain imaging (Hong and Paneth 2008; Chen and Hetzel 2010; LaFranchi 2011; Skeaff 2011; Gilbert et al 2012; Bongers-Schokking et al 2013; Bas et al 2014; Rovet 2014; Samadi et al 2015). Transient hypothyroidism has also been implicated as a possible cause of cerebral palsy in premature infants (Hong and Paneth 2008). 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 (Bono et al 2004; Miller et al 2006; Miller et al 2007; Correia et al 2009; Samuels 2014). 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 (Volpato et al 2002; Bauer et al 2008; Biondi and Cooper 2008; Yamamoto et al 2012; Baumgartner et al 2014; Samuels 2014; Cappola et al 2015). Hypothyroidism is usually listed as 1 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 (Shetty and Duthie 1995; Dugbartey 1998; Locketz et al 2006; Bauer et al 2008; Tan et al 2008; Pasqualetti et al 2015). 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 (Van Osch et al 2004; Sampaolo et al 2005; de Jong et al 2006; de Jong et al 2009; Chaker et al 2016). Psychotic features occur in 3% to 5% of patients with severe hypothyroidism (Swanson et al 1981), giving rise to the term "myxedema madness" (Hynicka 2015).

Myxedema coma is the most severe expression of hypothyroidism (Jordan 1995; Fliers and Wiersinga 2003; Sarlis and Gourgiotis 2003; Wartofsky 2006; Kwaku and Burman 2007; Klubo-Gwiezdzinska and Wartofsky 2012; Gupta 2013; Chiong et al 2015; Ono et al 2017). 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 (Mallipedhi et al 2011).

Hashimoto encephalopathy is a rare, steroid-responsive syndrome characterized by various combinations of mental status changes, altered consciousness, stroke-like events, seizures, tremor, myoclonus, and opsoclonus in association with autoimmune thyroiditis (Chong et al 2003; Castillo et al 2006; Jacobs et al 2006; Marshall and Doyle 2006; Mocellin et al 2007; Mijajlovic et al 2010; Salazar et al 2012; Zhou et al 2017). 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 (Duffey et al 2003; Mocellin et al 2007). Spinal fluid protein is typically elevated and, in 1 published report, this was thought to be the cause of increased intracranial pressure (Frost et al 2004). 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 (Hussain et al 2005; Jacob and Rajabally 2005).

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 (Jellinek 1962). The seizures are typically generalized, but complex partial 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. Thus, hypothyroidism affects stroke risk factors in ways that could lead to an increased risk of stroke, but the relationship requires further study (Squizzato et al 2005; Chaker et al 2014; Yang et al 2015). Thyroid hormone levels may correlate with severity at presentation and early outcome in patients with acute ischemic stroke (Alevizaki et al 2006; Baek et al 2010; Akhoundi et al 2011; Bunevicius et al 2015; Forti et al 2015). The presence of thyroid autoantibodies may be associated with an unfavorable outcome in patients with acute ischemic stroke (Cho et al 2014).

Headaches. Many patients with hypothyroidism report headaches. In 1 series, 14% of patients had this complaint (Sanders 1962b). 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 (Martin et al 2017).

Ataxia. Ataxia is present in 25% to 33% of patients with hypothyroidism (Cremer et al 1969). These patients all have an unsteady gait, and many of them also have limb incoordination. Dysarthria also occurs but is less common. There is 1 report of Hashimoto encephalopathy presenting with progressive ataxia (Nakagawa et al 2007).

Movement disorders. Some features of hypothyroidism, such as bradykinesia and voice abnormalities, mimic parkinsonism, but no association has been documented between hypothyroidism and Parkinson disease (Munhoz et al 2004). 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 (Hopkins et al 2007).

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. 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 (Hattori et al 2006). 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 (McConnell et al 1975). 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 (Stollberger et al 2001; Kovacs et al 2010). Trigeminal neuralgia and facial palsy have been reported in patients with hypothyroidism but so rarely that the association may have been due to chance. Genis and colleagues reported 1 case of a patient with hemifacial spasm that resolved with thyroid replacement, reappeared when treatment was stopped, and disappeared again when treatment was resumed (Genis et al 1993). 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 (Papi et al 2010).

Sleep disorders. Subclinical hypothyroidism is common among patients with obstructive sleep apnea, but newly diagnosed clinical hypothyroidism is rare (Bahammam et al 2011; Mete et al 2013). In contrast, obstructive sleep apnea was documented in 45% of successive hypothyroid patients in 1 prospective study (Hira and Sibal 1999). It can occur either on the basis of associated obesity or because of mucopolysaccharide deposition in the tongue and upper airway (Kaminski and Ruff 1989). 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 (Shinno et al 2009).

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 (Jackson et al 1978). 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 (Rao et al 1980; Duyff et al 2000; El-Salem and Ammari 2006; Orstavik et al 2006; Nebuchennykh et al 2010). Elevated thermal thresholds have been described in patients with hypothyroidism and unexplained pain in the extremities, suggesting the possibility of small-fiber neuropathy (Orstavik et al 2006). Severe neuropathy is rare. 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 (Anwar and Gibofsky 2010). In studies that control for confounding factors (such as obesity and rheumatoid arthritis), the association between carpal tunnel syndrome and hypothyroidism is only modest (Shiri 2014). 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 (Norris 1966; Takamori et al 1972). 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 (Turker et al 2008).

Muscle abnormalities. Proximal muscle weakness develops in about 25% of patients with hypothyroidism (Rao et al 1980). 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 (Graig and Smith 1965; Finsterer et al 1999; Biondi and Cooper 2008). Conversely, markedly elevated creatine kinase levels do not exclude the diagnosis of hypothyroid myopathy (Scott et al 2002).

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 (Salaria and Parmar 2004; Dursun et al 2011). 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 (Deepak et al 2004; Anwar and Gibofsky 2010). An adolescent with this syndrome has also been reported (Serranti et al 2013). 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.{embed="pagecomponents/media_embed" entry_id="18877"} One report exists of a patient with necrotizing myopathy that resolved after treatment for central hypothyroidism (Tiniakou and Mammen 2015).

Prognosis and complications

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% (Jordan 1995; Klubo- Gwiezdzinska and Wartofsky 2012). More severe impairment of consciousness on presentation correlates with a poorer prognosis (Rodriguez et al 2004). 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 secondary or tertiary hypothyroidism must be evaluated for adrenal insufficiency and, if it is present, hydrocortisone replacement must be initiated before starting thyroxine.

Clinical vignette 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.

Biological basis

Etiology and pathogenesis

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. Primary hypothyroidism is much more common than the other 2 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 (Kaplan 1999; Tews et al 2005; Devdhar et al 2007; Clemens et al 2011; Jayakumar 2011; Hanley et al 2016). Other causes include iodine deficiency, iodine excess, congenital conditions, infiltrative diseases, and drugs or environmental chemicals that impair hormone biosynthesis, such as lithium, amiodarone, sulfonamides, sulfonylureas, carbamazepine, oxcarbazepine, phenytoin, valproate, interleukins, sunitinib and other tyrosine kinase inhibitors, propylthiouracil, methimazole , polychlorinated biphenyls, bisphenol-A, and polybrominated diphenyl esters (Simko et al 2004; Vainionpaa et al 2004; Cooper 2005; Tews et al 2005; Devdhar et al 2007; Zoeller 2007; Biondi and Cooper 2008; Laurberg 2009; Lossius et al 2009; Hamnvik et al 2011; Lai et al 2013; Lele et al 2013; Agarwal et al 2014; Yilmaz et al 2014; Kafadar et al 2015; Hanley et al 2016). Antineoplastic agents can cause hypothyroidism by a variety of mechanisms (Hamnvik et al 2011). Secondary and tertiary hypothyroidism can result from tumors, granulomatous disease, irradiation, surgery, hemorrhage, and infarction.

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. Triiodothyronine acts on a family of nuclear receptors that bind to regulatory regions of genes and modify their expression (Brent 1994; Mendoza and Hollenberg 2017). 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 (Koromilas et al 2010). Most of the genes targeted by thyroid hormones in the brain remain to be identified (Warner and Mittag 2012).

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 (Ribeiro 2008; Mendoza and Hollenberg 2017). The receptors are expressed in a developmentally specific pattern, especially in the brain (Williams 2008). 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 (Davis et al 2016; Mendoza and Hollenberg 2017). The cognitive and affective manifestations of hypothyroidism are not fully understood (Leach and Gould 2015). 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 (Bauer et al 2008). Epidemiology"

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 (Toft 1994; Kaplan 1999). 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.

Prevention

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.

Differential diagnosis

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 2 conditions are usually distinctive enough to differentiate them.

Diagnostic workup

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. 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 (Peery and Meek 1998; Kaplan 1999; Beck-Peccoz et al 2006; Joshi 2011).

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 (Smith 1995; Umpierrez 2002; Emerson 2009; Mebis and Van den Berghe 2011). 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 (Spencer 1988; Peery and Meek 1998; Kaplan 1999; Fowler et al 2002; Umpierrez 2002). Moreover, a thyrotropin level above 20 µU/mL does not occur in nonthyroidal illness and is a reliable indicator of hypothyroidism.

In secondary hypothyroidism, thyrotropin and thyroxine levels are both low although in mild cases they may both lie at the low end of the normal range (Jostel et al 2009; Hepburn et al 2012). In tertiary hypothyroidism, the pituitary still produces thyrotropin despite the absence of hypothalamic stimulation, but the thyrotropin is less effective than normal. Thus, thyroxine levels are low, and thyrotropin levels are usually at the high end of the normal range. A thyroid-releasing hormone stimulation test can sometimes help to distinguish between secondary and tertiary hypothyroidism. Patients with secondary hypothyroidism frequently have low levels of other pituitary hormones, so 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 (Mocellin et al 2007).

Management

Although combination therapy with thyroxine and triiodothyronine has been advocated, the current standard treatment for hypothyroidism remains thyroxine replacement alone (Biondi and Wartofsky 2012; Jonklaas et al 2014). 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 (Toft 1994; Tandon 2011; Hanley et al 2016). 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 (Toft 1994; Devdhar et al 2007; Tandon 2011).

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). Alternative treatment regimens incorporating triiodothyronine either alone or in combination with thyroxine have been advocated, but the evidence remains inconclusive (Jordan 1995; Pittman and Zayed 1997; Bunevicius et al 1999; Fliers and Wiersinga 2003; Sarlis and Gourgiotis 2003; Rodriguez et al 2004; Tews et al 2005; Wartofsky 2006; Kwaku and Burman 2007; Klubo-Gwiezdzinska and Wartofsky 2012; Jonklaas et al 2014). 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. 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.

Outcomes

When hypothyroidism is adequately treated, no long-term consequences are experienced.

Special considerations

Pregnancy

Uncontrolled hypothyroidism during pregnancy is accompanied by an increased risk of fetal and maternal morbidity (Toft 1994; Drake and Wood 1998; Haddow et al 1999; Badawi et al 2000; LeBeau and Mandel 2006; Gartner 2009; Feldt-Rasmussen and Mathiesen 2011; Negro and Mestman 2011). In most women, thyroxine requirements increase by 30% to 50% during pregnancy, especially in the third trimester (Drake and Wood 1998; LeBeau and Mandel 2006; Negro and Mestman 2011). The serum thyrotropin level should be measured during each trimester, and the thyroxine dose adjusted accordingly. 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 (Gyamfi et al 2009; Behrooz et al 2011; Negro and Mestman 2011; Lazarus et al 2012; Henrichs et al 2013).

Anesthesia 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 (Bennett-Guerrero et al 1997).

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**References especially recommended by the author or editor for general reading.

ICD and OMIM codes

ICD codes

ICD-9: Unspecified acquired hypothyroidism: 244.9

ICD-10: Hypothyroidism, unspecified: E03.9

OMIM numbers

Hypothyroidism, congenital, nongoitrous, 2; CHNG2: #218700 Hypothyroidism, congenital, nongoitrous, 2; CHNG1: #275200

Profile

Age range of presentation

0-01 month 01-23 months 02-05 years 06-12 years 13-18 years 19-44 years 45-64 years 65+ years

Sex preponderance female>male,>2:1 female>male,>1:1

Family history family history may be obtained

Heredity heredity may be a factor

Population groups selectively affected none selectively affected

Occupation groups selectively affected none selectively affected

Differential diagnosis list myopathy progressive dementia nephrotic syndrome depression hypothermia Down syndrome

Associated disorders

Addison disease Altered mental status Autoimmune polyglandular syndrome type 2 Chronic hepatitis Cranial neuropathies Cretinism Diabetes mellitus Hoffman syndrome Horner syndrome Hyperthyroidism Hypothermia Hypothyroid myopathy Lupus Myasthenia gravis Myxedema coma Pernicious anemia Rheumatoid arthritis Sjögren syndrome The Kocher-Debre-Semelaigne syndrome