9.5 SYSTEMIC MANIFESTATIONS OF HYPOTHYROIDISM

The clinical expression of thyroid hormone deficiency varies considerably between individuals, depending on the cause, duration and severity of the hypothyroid state. Characteristically, there is a slowing of physical and mental activity, and of many organ functions.

9.5.1 ENERGY AND NUTRIENT METABOLISM

Thyroid hormone deficiency slows metabolism, resulting in a decrease of resting energy expenditure, oxygen consumption, and utilization of substrates. Reduced thermogenesis is related to the characteristic cold intolerance of hypothyroid patients. Measurement of the resting energy expenditure is rarely performed nowadays. In patients with complete athyreosis it falls between 35 and 45 percent below normal. In Addison's disease, the BMR may fall to -25 or -30 percent and, in hypopituitarism to below - 50 percent. The failure to find a metabolic rate as low as - 35 percent, when the clear-cut picture of myxedema is present is very unusual. The effect of thyroid hormone deficiency on appetite and energy intake is not precisely known but energy expenditure certainly decreases, leading to a slight net gain in energy stores. An increase of adipose tissue mass results in an increase of serum leptin, which mediates a decrease in energy intake while energy disposal increases, eventually leading to a reduction in adipose tissue mass. Interactions between leptin and thyroid hormone have thus attracted much interest , especially because prolonged fasting in rodents decreases leptin and inhibits the hypothalamic-pituitary-thyroid axis resulting in a fall of serum TSH and serum T4. In hypothyroid patients, an increase, no change, or a decrease in plasma leptin concentrations has been reported. In one study, leptin concentrations expressed as standard deviation scores (Z-scores) from the mean value of female controls matched for body mass index and age, were lower in hypothyroid and higher in thyrotoxic women, whereas Z-scores did not deviate from the expected values after restoration of the euthyroid state¹. Thyroid hormone apparently modulates serum leptin to a small extent.

Protein metabolism. The effect of hypothyroidism on protein metabolism is complex, and its effect on the concentration of a given protein difficult to predict. In general, both the synthesis and the degradation of proteins are reduced, but hypothyroid patients are in positive nitrogen balance. Despite both a decrease in the rate of albumin synthesis and degradation, the total exchangeable albumin pool increases in myxedema ². The albumin is distributed in a much larger volume, suggesting enhanced permeability of capillary walls. A synthesis of thyroid hormone-responsive proteins is clearly reduced in the hypothyroid state, whereas that of proteins such as TSH or glycosaminoglycans may be increased under the same circumstances ^3,4.

Comparative studies of protein translation by hepatic ribosomes from T3-treated hypothyroid rats show that the mRNA's from some proteins are increased and others are decreased. Most of these proteins have not been identified. Treatment of myxedema is accompanied by mobilization of extracellular protein and a marked but temporary negative nitrogen balance, reflecting the mobilization of extracellular protein ⁵. In a later phase there is an increase in urinary potassium and phosphorus together with nitrogen in amounts suggesting that cellular protein is also being metabolized ⁶.

Carbohydrate metabolism. Glucose is absorbed from the intestine at a slower rate than normal. Fasting plasma glucose values are on average lower than normal ^7,8. The oral glucose tolerance test usually produces a low peak value that remains elevated at 2 hours. This response does not resemble that encountered in diabetes mellitus and is probably related to slow gastric motility and delayed absorption.

However, the glucose disappearance rate is also prolonged when the sugar is given intravenously, although the peak value is normal in magnitude and in time of occurrence ⁹. Insulin release in response to an oral glucose load may be variable due to the absorptive abnormalities associated with hypothyroidism. The insulin response to intravenous glucose is blunted and slightly delayed ⁹. In contrast to adult-onset diabetes, there is no evidence of resistance to insulin. In fact, the prolonged hypoglycemic effect of exogenous insulin in hypothyroid patients suggests increased sensitivity to insulin action ^8,10. This response, as well as the decrease in appetite, accounts for the diminished insulin requirement for the control of hypothyroid diabetics.

Lipid metabolism. Biosynthesis of fatty acids and lipolysis are reduced. Changes in serum lipids are listed in Table 9-4. The free fatty acid concentration is usually normal, but can be higher than normal in some patients²³. The lipid changes bear in general a reciprocal relationship to the level of thyroid activity.

The increased serum cholesterol may represent an alteration in a substrate steady-state level caused by a transient proportionally greater retardation in degradation than in synthesis ^11,12,13. The increase of serum cholesterol is largely accounted for by an increase of LDL-cholesterol, which is cleared less efficiently from the circulation due to a decreased T3-dependent gene expressing of the hepatic LDL-receptor ^14-16.

Interestingly, the LDL particles of hypothyroid patients are also susceptible to increased oxidizability ¹⁸. The increase of HDL2- but not of HDL3-cholesterol ^18,19 is due to a diminished activity of cholesteryl ester transfer protein ^20,21 and hepatic lipase (which is involved in the conversion of HDL2 to HDL3). The changes in plasma LDL-and HDL-cholesterol are related to changes in free thyroxine, not to polymorphisms in LDL receptor or cholesteryl ester transfer protein genes²². The sometimes present modest increase of serum triglycerides has been related to a decreased lipoprotein lipase activity in post-heparin plasma. Lipoprotein(a) is increased in hypothyroidism in some but not all studies. Remnant particles in serum (reflecting chylomicron and VLDL remnants) are less effectively cleared in hypothyroidism^24,25. Taken together, the changes in plasma lipids in hypothyroidism result in an atherogenic lipid profile²⁶.

9.5.2 FACIES AND INTEGUMENT

In the Report on Myxedema there is a detailed analysis of the symptoms of 109 patients described as "cretinoid," "expressionless," "heavy," "apathetic," "masklike," "vacant," "stolid," "good-tempered," "blunted," and "large-featured." The face is expression less when at rest, but it is not masklike, as in Parkinson's disease. When spoken to, the person with myxedema usually responds with a smile, which spreads after a latent period very slowly over the face. The patient is good-tempered but not entirely apathetic. The face is not vacant, as that of psychopathic patient may be. The features (except for the tongue) are not large, as in acromegaly. The face is expressionless at rest, puffy, pale, and often with a yellowish or old ivory tint. It is seldom as puffy as the classic facies of chronic renal failure. The skin of the face is parchment-like. In spite of the swelling it may be traced with fine wrinkles, particularly in pituitary myxedema. The swelling sometimes gives it a round or moonlike appearance (Fig. 9-3).

Figure 9-3. (A) The classic torpid facies of severe myxedema in a man. The face appears puffy, and the eyelids are edematous. The skin is thickened and dry. (B) The facies in pituitary myxedema is often characterized by skin of normal thickness, covered by fine wrinkles. Puffiness is usually less than in primary myxedema. The eyelids are often edematous. The palpebral fissure may be narrwowed because of blepharoptosis, due to diminished tone of the sympathetic nervous fibers to Müller's levator palpebral superious muscle and is the opposite of the lid retraction seen in thyrotoxicosis. The modest measurable exophthalmos seen in some patients with myxedema is presumably related to accumulation of the same mucous edema in the orbit as is seen elsewhere. It is not progressive and carries no threat to vision, as in the ophthalmopathy of Graves' disease. The tongue is usually large, occasionally to the point of clumsiness. Sometimes a patient will complain of this problem. Sometimes it is smooth, as in pernicious anemia (of course, pernicious anemia may coexist). Patients do not usually complain of soreness of the tongue, as they may in pernicious anemia. When anemia is marked, the tongue may be pale, but more often it is red, in contrast to the pallid face.

The voice is husky, low-pitched, and coarse. The speech is deliberate and slow. Often there is difficulty in articulation. Certain words are stumbled over and slurred, much as they are during alcoholic intoxication. The enlargement of the tongue, and possibly some thickness of the lips, may be responsible. The hair, both of the head and elsewhere, is dry, brittle, and sparse, and lacks shine. It varies in texture from coarse to normal. Its growth is retarded and it falls out readily. The eyebrows often are practically gone. Their disappearance begins at the lateral margin, giving rise to Queen Anne's sign. It should be noted, however, that this sign is not uncommon in elderly euthyroid women. In men the beard becomes sparse, and its rate of growth becomes greatly retarded. Haircuts are necessary only at long intervals. A shave a week is sufficient. The scalp is dry and scaly. The skin is cool as a result of decreased metabolism as well as cutaneous vasoconstriction. It is dry due to reduced secretion by sweat and sebaceous glands.

Scaling is common but rarely assumes the appearance characteristic of ichthyosis. The tissues beneath it seem thick, but usually do not pit on pressure. In the lower extremities, pitting edema is not uncommon. Subcutaneous fat may be increased, with the formation of definite fat pads, especially above the clavicles, but is conspicuously absent in the more advanced form of the disease (myxedematous cachexia).

Retardation in the rate of healing of surgical wounds and of ulcerations, such as leg ulcers, has been described in myxedema. The nails are thickened and brittle. These changes are probably dependent, as are those of skin and hair, on retardation in growth. Nails require paring only at greatly lengthened intervals.

The hands and feet have a broad appearance, due to thickening of subcutaneous tissue. However, there is no bony overgrowth, so that they bear no resemblance to the extremities in acromegaly. Unusual coldness of the arms and legs is sometimes a subject of complaint. The palms are cool and dry. The characteristic skin changes are due to an increased amount of normal glycosaminoglycans and protein. The glycosaminoglycans are demonstrated by metachromasia after staining with toluidine blue. An increased concentration of glycosaminoglycans, composed principally of hyaluronic acid and chondroitin sulfuric acid, occurs in histologically similar skin lesions found in hyperthyroidism (pretibial myxedema). This excess accumulation of normal intercellular material represents not only an alteration in steady-state equilibrium but an actual increase in the synthesis and accumulation of glycosaminoglycan ¹.

The glycosaminoglycans are long-chain polymers of D-glucuronic acid and N-acetyl-D-glucosamine, forming hyaluronic acid, or of L-iduronic acid and N-acetyl-D-galactosamine sulfate, forming chondroitin sulfate B. They exist free and in ionic or covalent linkage to protein. These mucoproteins comprise part of the normal nonfibrillar intercellular matrix, the ground substance holding cells together. As they are characteristically hygroscopic, they presumably hold in bound form the nonpitting water comprising the mucous edema. The total amount of exchangeable sodium is increased in myxedema despite a slight reduction in its plasma concentration ².

The sodium is extravascular and probably in the interstitial spaces. The diuresis seen after giving thyroid hormone to a hypothyroid subject occurs coincidentally with a decrease in tissue metachromasia and a temporary negative nitrogen balance ³, and with this condition the extravascular sodium is mobilized and excreted. Studies with human skin fibroblasts have suggested that thyroid hormone inhibits the synthesis of hyaluronate. The mechanism for this effect has not been identified, but the thyroid hormone levels required to produce it in vitro are in the physiologic range ^1,4. Although similar deposits of mucopolysaccharides are found in the orbits of patients with the ophthalmopathy of Graves' disease and in the areas of localized myxedema, this striking observation has unfortunately not provided any basic understanding of the phenomenon, either in this condition or in primary myxedema.

9.5.3 NERVOUS SYSTEM

Recent studies using 31P nuclear magnetic resonance spectroscopy of the frontal lobe of adult hypothyroid patients report reversible alterations in phosphate metabolism, suggesting impairment of mitochondrial metabolism ¹. Thyroid hormone receptors are present in human brain. These and other findings indicate the adult human brain as a thyroid hormone responsive organ, and provide a biologic basis for the very prevalent neurologic and neurobehavioral symptoms in adult hypothyroid patients ² (Table 9-5).

Table 9-5 lists the numerous symptoms suggesting either neurologic or psychiatric disorders in patients with moderate to severe hypothyroidism. We are aware of no characteristic motor phenomena other than those due to weakness and to syndromes that seem to represent cerebellar dysfunction. A tendency to poor coordination was noted originally by the Myxoedema Commission. Jellinek and Kelly ³ described a series of myxedematous patients with ataxia, intention tremor, nystagmus, and dysdiadochokinesia. Ataxia has been noted in 8 percent of a large series of hypothyroid patients ⁴. The delayed relaxation phase of the deep tendon reflexes is a well-known manifestation. Patients may have intention tremor, nystagmus, and an inability to make rapid alternating movements. In fact, this inability has long been used as a test for myxedema. The cause of this syndrome is not apparent, although deposition of mucinous material in the cerebellar tissue may be of pathogenetic importance. Whatever the cause is, it is important that these symptoms show a prompt and definite decrease after replacement therapy with thyroid hormone ⁵.

Sensory phenomena are common. Numbness, tingling, and painful paresthesias are frequent ⁶ and are especially common in hypothyroidism after surgery or 131I therapy. Paresthesias were present in 79 percent of one series of 109 patients. A metachromatic infiltrate has been found in the lateral femoral cutaneous nerve and sural nerve, together with axon cylinder degeneration ⁷. Nerve conduction time is usually normal. Murray and Simpson ⁸ found that in some hypothyroid patients signs of median nerve pressure were present, apparently because of encroachment on the nerve by myxedematous infiltrates in the carpal tunnel ^9,10. A recent study reports carpal tunnel syndrome in 29% and signs of sensorimotor axonal neuropathy in 42%²². Deafness is a very characteristic and troublesome symptom of hypothyroidism. Both nerve and conduction deafness and combinations of the two have been reported, and vestibular abnormalities have also been demonstrated. Serous otitis media is not uncommon. Two-thirds of patients complain of dizziness, vertigo, or tinnitus occasionally: these problems again suggest damage to the eighth nerve or labyrinth, or possibly to the cerebellum. Whatever type of deafness is present, there is marked improvement after thyroid therapy. Acute thyroxine depletion caused by total thyroidectomy has no deleterious effects on hearing up to 6 weeks¹¹. Acquired hearing loss in association with adult-onset hypothyroidism should be distinguished from the sensorineural deafness of Pendred's syndrome. In the latter, treatment of hypothyroidism does not correct the hearing defect.

Night blindness is not uncommon. It is caused by a deficiency in the pigment retinene, which is required for the adaptation to dark. Uncorrected deficiency of thyroid hormone during neonatal life causes not only more profound neurologic abnormalities but also irreversible damage (see Ch. 15). Hashimoto?s encephalopathy is a vaguely defined condition in which otherwise unexplained neurological manifestations of central nervous system dysfunction are linked to TPO-antibodies. The condition responds to glucocorticoids, but a causal relation to thyroid autoimmunity is unproven²⁶. Mental Symptoms. The mental picture usually is one of extreme complacency. Memory is undoubtedly impaired, and attention and the desire to think are reduced . The emotional level seems definitely low, and irritability is decreased. Except in the terminal stage, reasoning power is preserved. Questions are answered intelligently, but slowly and without enthusiasm, and often with evidence of amusement. In a minority of patients, nervousness and apprehension are present. Psychosis may occur in untreated myxedema or during the initiation of therapy. This problem is discussed below.

Depression is so often associated with hypothyroidism that thyroid function tests should be performed in the evaluation of any patient presenting with this symptom. Central 5-hydroxytryptamine activity is reduced in hypothyroid patients ¹², and T3 supplementation might increase the efficacy of antidepressant drugs ¹³. At times, this manifestation of hypothyroidism is more severe than are many of the other clinical manifestations of the disease. Because hypothyroidism is so readily treated, it is an especially important cause to eliminate. Cognitive tests of patients with moderate to severe hypothyroidism indicate difficulties in performing calculations, recent memory loss, reduced attention span, and slow reaction time ^14,27. Failing memory correlates inversely with serum T3 and T4²³. Hypothyroidism may give rise rarely to reversible dementia, associated with reversible cerebral hypoperfusion²⁴. EEG abnormalities are also present, again depending on the severity and duration of the hypothyroidism. There may be absence of a waves and presence of low-amplitude theta and delta waves. Visual and auditory evoked potentials may be delayed as a consequence of abnormal cerebral cortical metabolism. Sleep apnea is not uncommon ¹⁵. It has been difficult to assign a causal role for the myopathy versus the coexistent obesity in some of the reported cases. However, the muscular dysfunction may extend to the diaphragm and intercostal muscles, thus impairing the ventilatory mechanism.

The most extreme CNS manifestation of hypothyroidism is myxedema coma (see § 9.9). The typical somnolence of severe hypothyroidism may suggest the psychiatric diagnosis of depression or dementia ¹⁶. Patients are generally akinetic, though isolated case reports appear of patients who become hypomanic and agitated or garrulous (myxedema wit) as manifestations of this condition. Bipolar affective disorders and schizoid or paranoid ideations may also occur. These may so dominant the clinical picture that the signs of hypothyroidism may be obscured or pass unnoticed. Accordingly, it is critical to evaluate thyroid function in any patient presenting with such functional disorders before instituting other forms of therapy. If the condition is due to hypothyroidism, it will resolve with time and appropriate treatment ^17,18.

Cerebral blood flow, oxygen consumption, and glucose consumption have been reported to be diminished in proportion to the drop in metabolism in the rest of the body ¹⁹, but older studies found unaltered glucose and oxygen use by the brain in either hypo- or hyperthyroid animals or humans ²⁰. In one study, cerebral cortical perfusion was little changed with treatment, but there was a decided fall in cerebrovascular resistance ²¹. Recent studies indicate a generalized decrease in regional cerebral blood flow of 24% and in cerebral glucose metabolism of 12%, indicating that brain activity is globally reduced in severe hypothyroidism without the regional modifications usually observed in primary depression ²⁵.

9.5.4 CARDIOVASCULAR SYSTEM

Pulse rate and stroke volume are diminished in hypothyroidism, and cardiac output is accordingly decreased, often to one-half the normal value¹. Myocardial contractility is reduced, but there is also a steep decline in the circulatory load, so that the circulation rarely fails until very late in the disease². The speed of shortening is slowed, but the total force is not much modified.³. Myocardial adenyl cyclase levels are reduced⁴. The decrease in pulse rate occurs more or less in parallel with that of the metabolism. Stroke volume is reduced more than pulse rate at any given level, and is therefore the major determinant of the low cardiac output. Since the reduction in cardiac output is usually proportional to the decreased oxygen consumption by the tissues, the arteriovenous (AV) oxygen difference is normal or may be slightly increased. Slow peripheral circulation, and therefore more complete extraction of oxygen, as well as anemia, may be responsible for the increased AV oxygen difference. Myocardial oxygen consumption is decreased, usually more than blood supply to the myocardium, so that angina is infrequent. In some patients a reduction in cardiac output greater than the decline in oxygen consumption indicates specific cardiac damage from the myxedema ⁵.

Venous pressure is normal, but peripheral resistance is increased. Restoration of the euthyroid state normalizes peripheral vascular resistance. Changes in peripheral vascular resistance are not related to plasma adrenomedullin, but altered atrial natriuretic peptide secretion and adrenergic tone may contribute ²⁹. Central arterial stiffness is increased in hypothyroidism³⁰, and arterial blood pressure is often mildly increased. It varies widely, but diastolic hypertension is usually restored to normal after treatment ^6,7,31. The heart in hypothyroidism has been a focus of much controversy. The term Myxodemherz was introduced by Zondek in 1918 ⁸. It embraced dilatation of the left and right sides of the heart, slow, indolent heart action with normal blood pressure, and lowering of the P and T waves of the electrocardiogram. Zondek found that after treatment with thyroid hormone there was a return of the dilated heart to somewhere near normal size, a more rapid pulse without change in blood pressure, and gradual return of the P and T waves to normal. These findings have been confirmed and extended. Indeed, occasional severely hypothyroid patients without underlying heart disease have congestive heart failure or low cardiac output reversed by thyroid hormone administration ^7,9,10. Therefore, congestive heart failure or impaired cardiac output relative to metabolic needs can be caused by hypothyroidism. Microscopic examination discloses myxedematous changes of the myocardial fibers.

The cause of the cardiac enlargement has been disputed. Clearly, it is not due to hypertrophy alone, since it would not disappear so rapidly with treatment. One factor may be a decrease in contractility of the heart muscle. This decrease would require a lengthening of muscle fibers in order to perform the required work. Disappearance of interstitial fluid alone could account for only part of the observed schrinkage. Altered myosin synthesis is also important.

Gordon ¹¹ long ago called attention to the occurrence of pericardial effusion in myxedema and explained the increase in the transverse diameter of the heart shadow on this basis. Effusion must frequently play a role in the increase in the size of the heart shadow, but it has amazingly little effect on cardiodynamics. The presence of fluid may be reflected in the right ventricular pressure contour, but tamponade, although reported, is rare ^12,13. Effusions of the pericardium, pleura, and peritoneum are common findings in hypothyroidism ¹⁴. The protein of the effusion may be high or in the range of transudates. In 11 patients with tamponade studied, pericardial fluid protein ranged from 2.2 to 7.6 g/dl ¹². Occasionally, the fluid is high in cholesterol, with a "gold paint" appearance ¹³. The hypothyroid heart responds normally to exercise ^5,7. Graettinger et al. ¹ found that after exercise the low resting cardiac output increased normally with an increase of stroke volume and usually, of pulse rate. Their patients had slightly elevated resting pulmonary artery and right ventricular pressures and a diastolic dip in right ventricular pressure, all compatible with pericardial effusion. They doubt that myxedema alone can ever produce congestive heart failure, and believe that the recorded abnormalities represent not myocardial disease but pericardial effusion. The heart, in experimental hypothyroidism, also responds to norepinephrine with a rise in cAMP, but less so than does the normal heart, although the response in contractility is the same.

Plasma catecholamines in hypothyroid patients are elevated rather than reduced, even though circulating cyclic AMP is lower ⁷. This may be explained by a decrease in cyclic AMP generation in response to catecholamines only in certain tissues. There is a decrease in the number of ß-adrenergic receptors in the myocardium of hypothyroid rats, but there are no data with respect to human myocardium.

Since the treatment of myxedema restores the hypothyroid heart to normal, there is apparently little permanent structural damage ^9,10. Cardiac glycosides will not improve the function of the heart in uncomplicated myxedema. Although the drug is efficacious if heart failure has been produced by coincident organic disease, myxedematous patients with coincident heart disease and congestive heart failure may tolerated digoxin poorly, just as they do morphine. This poor tolerance probably represents delayed metabolism, rather than myocardial sensitivity to the drug. The plasma concentration of digoxin is higher than in the normal subject at the same dose level, and smaller doses are required. When the heart in myxedema does not return to a normal size under thyroid hormone administration, hypertrophy due to some other disease is present as a complication. The return in size to normal under treatment is slow and progressive, requiring between 3 weeks and 10 months for completion. This decrease in size, like the progressive elevation of the T waves (described below), is of diagnostic value.

The electrocardiogram reveals characteristic changes ^5,7,10,15-19. The rate is slow and the voltage is low. The T waves are flattened or inverted. Axis deviation, an increased P-R interval, and widened QRS complexes and prolonged QT interval are seen, but these signs are not diagnostic of myxedema. The pattern reverts toward normal with treatment, but the final pattern depends on the presence or absence of intrinsic myocardial disease. The rare occurrence of complete heart block complicated by Adams-Stokes attacks, with reversion to sinus rhythm after treatment with thyroid hormone, has been reported as has ventricular tachycardia ^18,19.

Changes resembling those of ischemic heart disease may be found during exercise: they may indicate an intrinsic anoxia rather than organic narrowing of the coronary vessels ^5,7,10,17.

The ECG changes have usually been attributed to the histologic changes in the myocardium. However, removal of pericardial fluid may immediately reverse the pattern toward normal suggesting that the effusion may in part be responsible for the abnormalities.

The systolic time intervals are prolonged in hypothyroidism ^5,7,10,20. They can be measured by several techniques and have been expressed as the ratio of the pre-jection period and the left ventricular ejection time or the interval between the onset of the QRS complex of the ECG and the onset of the Korotkoff sound ^21,22. The most obvious effect of thyroid hormone deficiency on the heart is a lengthening of both systolic and early diastolic time characteristics. As evaluated by equilibrium radionuclide angiography, the time to peak emptying rate and the time to peak filling rate are longer in hypothyroid patients than in controls²³; the time intervals are negatively related to serum FT4 in the hypothyroid patients. The subtle decrease in early active relaxation and prolongation of contraction without major changes in global systolic function of hypothyroid patients is reversible upon thyroid hormone replacement therapy²⁴.

It is frequently suggested that accelerated atherosclerosis occurs in hypothyroidism³². Hypothyroidism accelerates atheromatous changes when these are induced experimentally in animals, but data in humans are not complete enough to justify this assertion. Most autopsied myxedematous subjects have severe atherosclerosis, but they are also usually 60 years or more of age. Arterial disease did not appear to be accelerated in patients rendered hypothyroid for therapy of angina pectoris or congestive heart failure ²², but they have been observed over a relatively short period. Increased coronary arteriosclerosis is found in myxedematous patients with hypertension, but not if they are normotensive ²⁵ (see further §9.8.4). Nevertheless, the atherogenic profile of serum lipids and increased levels of homocysteine in hypothyroidism might well contribute to a higher prevalence of atherosclerosis in hypothyroid patients. However, a 20-year follow-up study in the UK did not observe a higher incidence of ischemic heart disease in subjects with thyroid antibodies or hypothyroidism³⁵. Another population-based study from The Netherlands, in contrast, found subclinical hypothyroidism to be an independet risk factor for aortic atherosclerosis and myocardial infarction; the attributable risk was comparable to that of other known risk factors for coronary artery disease³⁶.

Occasionally angina pectoris is encountered in myxedema under two sets of circumstances. The less common is that in which angina or angina-like pain is present before treatment ^26,27,28. This generally indicates the presence of significant coronary artery compromise since there is inadequate myocardial oxygenation despite reduced cardiac output and O2 utilization. Although improvement sometimes occurs with therapy ²⁷, this should not be undertaken until angiographic evaluation of the coronary arteries has been performed (see below).

Angina may also appear for the first time after therapy has been initiated, indicating that coronary flow is inadequate for resumption of normal cardiac function ^26,27,28. Again, this may indicate the presence of a structural lesion.

9.5.5 RESPIRATORY SYSTEM

Dyspnea is a frequent complaint of myxedematous patients, but it is also a common symptom among well persons. Congestive heart failure of separate origin, pleural effusion, anemia, obesity, or pulmonary disease may be responsible. Some information on pulmonary function in hypothyroidism is available ^1-7. Wilson and Bedell ¹ found a normal vital capacity and arterial PCO2 and PO2 in 16 patients. They also found a decreased maximal breathing capacity, decreased diffusion capacity, and decreased ventilatory response to carbon dioxide. Decreased ventilatory drive is present in about one-third of hypothyroid patients, and the response to hypoxia returns rapidly within a week after beginning therapy ⁶.

The severity of hypothyroidism parallels the incidence of impaired ventilatory drive. Weakness of the respiratory muscles has also been implicated as a cause of alveolar hypoventilation. Patients with myxedema may develop carbon dioxide retention, and carbon dioxide narcosis may be a cause of myxedema coma ^3,4.

Myxedematous patients are more subject to respiratory infections. Obstructive sleep apnea has been documented in hypothyroidism in about 7% and is reversible with therapy ^5,7. The prevalence of hypothyroidism in patients seen for snoring or obstructive sleep apnea syndrome is, however, no greater than that seen in the general population⁸. The same authors report little or no improvement in apnea symptoms upon thyroid hormone replacement therapy in the hypothyroid patients.

9.5.6 MUSCULOSKELETAL SYSTEM

Muscles.Muscle symptoms like myalgia, muscle weakness, stiffness, cramps and easy fatiguability are very prevalent in hypothyroid patients^23,24. Weakness in one or more muscles groups is present in 38% as evident from manual muscle strength testing ²².The symptoms are aggravated by exposure to cold. They are also prominent during the rapid onset of hypothyroidism after surgery or 131I therapy. Impairment of mitochondrial oxidative metabolism provides a biochemical substrate for these complaints, as evident from a rise in the ratio of inorganic phosphate to ATP in resting muscle and an important decrease in phosphocreatine in working hypothyroid muscle with a greater fall in intracellular pH than in controls ^1,2. Transition from fast type II to slow type I muscle fibers is involved in the change of muscle bioenergetics ³, which is probably multifactorial. One patient with disabling muscle cramps was found to have reduced a-glucosidase activity in a muscle biopsy; after therapy with T4, the symptoms disappeared and the muscle enzyme activity returned to normal ⁴. The electromyogram in myxedema may be normal or may demonstrate abnormalities distinct from those seen in myotonia or other muscle disease ⁵. Polyphasic action potentials, hyperirritability, repetitive discharge, and low-voltage, short-duration motor unit potentials have been described. In the hypothyroid rat the rate of isometric relaxation is slow, and tension is less than in euthyroid or hypothyroid rat muscle at the same frequency of stimulation.

Generalized muscular hypertrophy, accompanied by easy fatigue and slowness of movements, occurs in some cretins and myxedematous children or adults. It has been referred to as the Kocher-Debré-Sémélaigne syndrome in children ⁶ and as Hoffmann's syndrome in adults ⁷. These patients do not have the classic electromyographic findings of myotonia. The myopathy of hypothyroidism is in some patients associated with weakness even though the muscles are hypertrophied.

Chronic hypothyroid myopathy with increased muscular volume rarely cause entrapment syndromes ⁸. Reflex contraction and relaxation time is prolonged mainly because of the intrinsic alterations in muscle contractility. Nerve conduction time may also be prolonged. Delayed reflex relaxation is characteristic and has been developed into a diagnostic test of thyroid function ⁹. As with many other peripheral tissue function tests, there is considerable overlap between normal and mildly hypothyroid ranges. The rate-limiting step in muscle relaxation is the reuptake of calcium by the sarcoplasmic reticulum. In skeletal muscle, this process is dependent on the content of calcium ATPase. Recent studies have indicated that calcium ATPase activity of the fast twitch variety (SERCA-1) is markedly reduced in hypothyroidism ¹⁰, and there is an accompanying impairment of calcium reuptake as a consequence. This occurs at a transcriptional level, since thyroid hormone response elements have been identified in the 5' flanking region of the SERCA-1 calcium ATPase gene ¹¹. The reduction in calcium ATPase would appear to explain one of the most obvious clinical manifestations of hypothyroidism, namely, delayed relaxation of the deep tendon reflexes.

Joints. At the clinical level, patients with hypothyroidism may present with many manifestations, suggesting rheumatic disease such as arthralgias, joint stiffness, effusions, and carpal tunnel syndrome ^12,13. On the other hand, the symptoms may also suggest polymyalgia rheumatica, or primary myositis. The similarity of the symptoms of hypothyroidism to those of rheumatoid arthritis or osteoarthritis, especially when these are combined with the paresthesias of more severe hypothyroidism, should automatically lead to a consideration of hypothyroidism in any patient presenting with these symptoms. For example, in 5 to 10 percent of patients with carpal tunnel syndrome, primary hypothyroidism may be the cause, due to the accumulation of the hygroscopic glycosaminoglycan in the interstitial space with compression of the median nerve. Bones. While calcium, phosphate, and bone density are generally normal in hypothyroidism, there is evidence of reduced bone turnover and resistance to the action of parathyroid hormone (PTH) ^14-21. Thus, serum (PTH) levels are elevated ¹⁶. This is presumably the cause of the elevation in 1a, 25(OH)2-vitamin D3 ¹⁹. 25-OH-vitamin D3 levels are normal. The increase in PTH and vitamin D in turn increases calcium absorption. The reduction in glomerular filtration rate (GFR) and reduced bone turnover reduce urinary calcium and hydroxyproline levels and cause subnormal alkaline phosphatase, osteocalcin, and IGF-1 levels ¹⁵. The alkaline phosphatase reduction is particularly important in children, in whom this enzyme is normally elevated due to bone growth. In children delayed linear growth or short stature are well-recognized signs suggesting the possibility of hypothyroidism. In addition, it is well recognized that epiphyseal dysgenesis and the delayed appearance of calcification centers are characteristic of hypothyroidism in infants and children. This subject is discussed in greater detail in Chapter 15.

9.5.7 GASTROINTESTINAL SYSTEM

The symptoms from the digestive system are essentially the expression of the slow rate at which the living machinery is turning over. Anorexia, which is common, can reasonably be interpreted as the reflection of a lowered food requirement, and constipation, which is frequently present, is the result of a lowered food intake and decreased peristaltic activity. Although two-third of patients have reported weight gain, it is modest degree and due largely to the accumulation of fluid rather than fat. Contrary to popular belief, obesity is decidedly not a feature of hypothyroidism.

Complete achlorhydria occurs in more than half of myxedematous patients ¹. As many as 25 percent of patients with myxedema, like those with Hashimoto's thyroiditis, have circulating antibodies directed against the gastric parietal cells. This finding explains, at least in part, the frequency of achlorhydria and impaired absorption of vitamin B12 described later. It is reported that up to 14 percent of patients with idiopathic myxedema have coincident pernicious anemia ².

Gastric emptying and intestinal transit time are prolonged ³. Gaseous distention may be a persistent and troublesome symptom. It responds slowly to thyroid therapy. Fecal impaction may occur. The syndrome of ileus may be seen occasionally ⁴ and a megacolon may be evident on radiography ^5,6. Intestinal absorption is slowed. Galactose and glucose tolerance curves show a delayed rise to a lower peak than normal and a delayed return to baseline. Xylose absorption is impaired ⁷. Myxedematous ascites is rare ⁸.

Overt hypothyroidism is associated with bacterial overgrowth development. Excess bacteria could influence clinical gastrointestinal manifestations. Bacterial overgrowth decontamination is associated with improved gastrointestinal symptoms. However, fermenting carbohydrate luminal bacteria do not interfere with thyroid hormone levels. Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A. Association between hypothyroidism and small intestinal bacterial overgrowth. J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4.

Symptoms or signs of disturbed liver or exocrine pancreatic function are usually not encountered, but chemical examination may suggest disease. Serum glutamine-oxaloacetic transaminase (GOT), lactate dehydrogenase (LDH), and CPK levels are elevated in patients with hypothyroidism ^9,12. The enzymes return to normal over 2 to 4 weeks during treatment. Urinary amylase levels may be increased. CEA levels are also increased and drop with therapy ^8,10 Gallbladder motility is decreased, and the gallbladder may appear distended on x-ray examination ¹¹.

Table 9-8. Gastrointestinal manifestations of hypothyroidism.

9.5.8 RENAL FUNCTION, WATER AND ELECTROLYTES

Hypothyroid patients tend to drink small amounts of water and to have diminished urinary output. Clinical evidence of renal failure is not often found, but laboratory examination may disclose certain departures from normal renal function; serum creatinine is raised by 10-20% ¹. Because of decreased cardiac output and blood volume, renal blood flow is decreased, but it remains the same percentage of cardiac output. The glomerular filtration rate and effective renal plasma flow are decreased, but the filtration fraction is normal or variably altered ^2,3,4.

The response to water loading is variable. Moses et al. ⁵ reported that deficient diuresis after water loading is a sign of pituitary myxedema, but others, notably Crispell and co-workers ⁶ have found that severe primary myxedema may be associated with a delay excretion that is not corrected by cortisone but rather by replacement with thyroid hormone. Perhaps the difference in opinion arises from interpretation of the normal response to water loading. This possibility is suggested by the data of Bleifer et al. ⁷, who found a decrease in maximal diuresis in some patients with primary myxedema to below the normal lower limit of urine flow (3 ml/min), but not down to the 1 to 3 ml/min seen in panhypopituitarisn. The role of antidiuretic hormone and of solute excretion in producing the decreased response to water loading is unknown. The defect is usually attributed to a decreased glomerular filtration rate, but in some patients inappropriately high levels of serum vasopressin have been demonstrated ^8-12. Since urinary hydroxycorticoid excretion is decreased, the adrenals might be incriminated as responsible for delayed water excretion. Other evidence, however, suggests (see below) that the tissue supply of adrenal cortical hormones is usually normal in myxedema. The diminished free water clearance in hypothyroidism occurs irrespective of the presence of hyponatremia. The inappropriate antiduresis in hypothyroidism is thus not fully understood; a pure renal mechanism might be involved, independent of vasopressin¹⁸.

Occasionally, minimal proteinuria is seen. This condition could be due to congestive heart failure or to the increased capillary transudation of protein typical of hypothyroidism.

The total body sodium content is increased. The excessive sodium is presumably bound to extracellular mucopolysaccharides. In spite of reduced renal blood flow and blood volume, the sodium retention is probably not a reflection of altered renal function. In fact, salt loads are usually excreted readily and serum sodium concentrations tend to be low ¹³, in contrast to other clinical situations associated with sodium retention, such as congestive heart failure ⁸. The dilutional syndrome may be a result of inappropriate secretion of ADH ^9-12, but not in all patients. Thus, the dilutional syndrome in severe myxedema may be due to a resetting of the osmolar receptor, which causes water to be retained at a lower level of plasma osmotic pressure. The various changes in renal function may not return to normal at the same rate after treatment. The serum uric acid level is elevated in hypothyroid men and postmenopausal women, apparently as a consequence of a decrease in renal blood flow characteristic of the disease ¹⁴. No consistent changes in plasma potassium levels have been reported. Total magnesium levels may be elevated and the bound fraction and urinary excretion are reduced ¹⁵. A modest hypocalcemia has been observed in some patients. The significance of low ANF concentrations in hypothyroidism is presently unclear ¹⁶.

Plasma homocysteine concentrations are increased in hypothyroidism, related to lower folate levels and a lower creatinine clearance in thyroid hormone deficiency; restoration of the euthyroid state decreases plasma homocysteine levels into the normal range^1,17.

9.5.9 REPRODUCTIVE FUNCTION

In both sexes libido is usually, but not invariably decreased. The man may be impotent. The testicles are histologically immature if hypothyroidism preceded puberty and show tubular involution if onset was after puberty ¹. In adult hypothyroid men, semen analysis is usually normal. Although infertility may be a problem in either sex, the literature contains many reports of pregnancy in untreated myxedematous women ^2,3. When treatment has been started during pregnancy, more often than not a normal child is produced, but abortion is frequent in the myxedematous woman. Pregnancy-induced hypertension is 2 to 3 times more common in hypothyroid women ⁴; low birth weight is secondary to premature delivery for gestational hypertension. The incidence of various congenital abnormalities may be increased, but recent studies do not report an increased risk of fetal death or congenital anomalies with proper treatment ^2-7. The prevalence of an elevated serum TSH among pregnant women is in the order of 2%²¹. Mothers not receiving adequate L-thyroxine treatment have a higher abortion rate²², and the IQs of their children are 7 points lower than the IQs of control children²³. In adult premenopausal hypothyroid women, 77% have regular cycles and 23% irregular periods; corresponding figures in controls are 92% and 8% respectively⁸. Oligomenoerhoea and menorrahgia are the most common menstrual disturbances, which tend to be more frequent in severe hypothyroid patients. Menorrhagia is sufficiently impressive in ordinary myxedema⁹ so that in several cases that have come to our attention, patients have actually had dilatation and curettage or hysterectomy for it, the diagnosis of myxedema having been missed. The endometrium in premenopausal patients is typically proliferative or, less commonly, atrophic. The proliferative endometrium and low urinary pregnanetriol levels suggest failure of luteinizing hormone (LH) production and of ovulation ¹⁰. Indeed the pulsatile gonadotropin release in the follicular phase is normal ¹¹, but the ovulatory surge may not happen. In some patients, amenorrhea rather than menorrhagia occurs, with a reinstitution of a normal menstrual pattern after therapy. Although less frequent, amenorrhea and galactorrhea are occasionally found in adult hypothyroidism due to hyperprolactinemia and are reversible with treatment ¹². In children, hypothyroidism sometimes induces precocious puberty with menstruation and breast development ¹³. On rare occasions, precocious testicular enlargement with early seminiferous tubular maturation has also been reported ¹⁴. These abnormalities promptly subside with the correction of the hypothyroid state, and are explained by spillover of the action of TRH on gonadotropes and of TSH on FSH receptors ^15,16.

Alterations in both androgens and estrogens associated with hypothyroidism are rather complex and are due to the consequences of thyroid hormone deprivation on the production, metabolic pathways, and serum transport of these steroids. The concentrations of both testosterone and estradiol in serum are decreased, predominantly due to a diminution in the concentration of the carrier sex hormone-binding globulin (SHBG) ¹⁷, but because of the concomitant increase in the unbound fraction of the steroids, their absolute free concentration remains normal.

The metabolic clearance rate of testosterone increases in hypothyroidism ^18,19. The conversion ratio of testosterone to androstenedione increases and that to androsterone decreases ^18,20.

9.5.10 ENDOCRINE SYSTEM

Pituitary. Thyrotroph hyperplasia caused by primary hypothyroidism may result in sellar enlargement, particularly when the condition has remained untreated for a long period of time ^1,2. Rarely, such hyperplasia may give rise to a pituitary macroadenoma that shrinks after thyroxine replacement ^3,4. The serum prolactin concentration is elevated in approximately one-third of patients with primary hypothyroidism ⁵. The hyperprolactinemia is modest in degree and is rarely associated with galactorrhea ^6,37. When present, it subsides with thyroid hormone replacement in conjunction with the reduction in the serum prolactin level. Since thyroid hormone decreases the mRNA for pre-pro TRH in the paraventricular nuclei, it is conceivable that hypothyroidism leads to increased TRH secretion, unopposed by thyroid hormones, with consequent hyperprolactinemia. In contrast, the growth hormone response to insulin-induced hypoglycemia is blunted in hypothyroidism ⁷. Growth hormone secretion is decreased in hypothyroidism related to an increase in hypothalamic somatostatinergic tone ⁸, resulting in low serum IGF-1 concentrations ⁹. It may cause growth retardation in hypothyroid children. Serum IGF-2, IGFBP-1 and IGFBP-3 also fall, whereas IGFBP-2 rises; these changes are reversible upon treatment ¹⁰. A recent study reports slightly different results: IGF-1 and IGFBP-3 in hypothyroid patients indeed were lower than in healthy volunteers but did not change upon replacement therapy with levothyroxine, whereas the raised levels of IGFBP-1 in hypothyroidism decreased significantly after therapy³⁶.

Adrenal cortex. Adrenal steroid hormone production and metabolism are considerably affected. Serum cortisol levels are normal, but the turnover time is slowed. This slowing is principally due to a decrease in the rate of cortisol oxidation as a result of reduced 11- -hydroxysteroid dehydrogenase activity ¹¹. Conjugation with glucuronic acid in the liver is normal ¹². Reflecting these alterations, urinary 17-hydroxycorticoid (as well as 17-ketosteroid) excretion is reduced ^11,13. The turnover rate of aldosterone is also decreased in hypothyroidism ¹¹. This reduction is probably due to an alteration in steroid reductases that tends to diminish the proportion of androsterone formed and reciprocally increases the level of the etiocholanolone metabolite ¹⁴. The serum concentration of aldosterone is low or normal ¹⁵. Renin activity is also often reduced, as is the sensitivity to angiotensin II ¹⁶.

Adrenal responsiveness to adrenocorticotrophic hormone (ACTH) may be reduced, or the response may be delayed until the second and third days of the standard ACTH test, with an actual augmentation of the total response ¹⁷. The adrenal glands often atrophy. Pituitary responsiveness to the metyrapone test has been variable. Normal but delayed peak response ¹⁸, impaired response ¹⁹, or even lack of response ¹⁹ has been reported. Grossly impaired responses to the stimulation with lysine-8-vasopressin and a delayed increase in serum cortisol levels after insulin-induced hypoglycemia have also been observed ^20,21,22.

A general picture of adrenal function in the hypothyroid patient who is not under stress seems clear. Adrenal steroid metabolism and production decrease. The decreased production is accomplished automatically by the pituitary through decreased ACTH secretion. The result is a normal concentration of free cortisol in the serum. Presumably, sufficient hormone is produced for the reduced needs of the hypothyroid subject. Whether steroid production can be augmented sufficiently in times of stress is not clear, but the provocative test results suggest that these patients usually have a mildly impaired hypothalamic-pituitary adrenal axis ^23,24.

9.5.11 HEMATOPOIETIC SYSTEM

Erythrocytes. In hypothyroidism, plasma volume and RBC mass are both diminished, and blood volume is decreased. Anemia of mild degree is commonly present, and the hemoglobin level may be as low as 8 to 9 g/dl. In two reports on a large series of patients with hypothyroidism from various causes, the incidence of anemia ranged from 32 percent 1 to as high as 84 percent 2. The anemia may be a result of a specific depression of marrow that lacks thyroid hormone 3 or may be due to blood loss from menorrhagia, to decreased absorption because of gastric achlorhydria, to conincident true Addisonian pernicious anemia, or to a decreased absorption of vitamin B12 which has been found to occur in certain patients with myxedema as a result of diminished intrinsic factor or diminished production of erythropoietin by the kidney. The erythropoietic effect of thyroid hormone is mediated through erythropoietin 4. This substance increases RBC production by stimulating the erythroid differentiation of the bone marrow, and its secretion by the kidney appears to be related to the oxygen tension of the tissue. Anemia caused by hypothyroidism per se may be normocytic or macrocytic and respond to thyroid therapy. If iron deficiency develops from menorrhagia, a hypochromic and microcytic anemia may occur. This condition usually responds to iron alone, but may respond optimally only to combined iron and thyroid hormone 5. Hypothyroidism per se causes diminished blood cell formation probably as a response to decreased oxygen demand 6. Plasma and RBC iron turnover are decreased, and the bone marrow is frequently hypoplastic. The relationship between hypothyroidism and pernicious anemia has been well established. Patients have been reported who developed pernicious anemia while hypothyroid, and who lost their need for parenteral vitamin B12 when hypothyroidism was treated. It is also known that some hypothyroid patients absorb oral vitamin B12 poorly, and the defect is sometimes corrected by intrinsic factor 7,8. After thyroid therapy, the absorption defect may disappear or may persist 8. The incidence of pernicious anemia is higher than normal in myxedematous persons 5,8. In Tudhope and Wilson's series of 73 patients with spontaneous primary hypothyroidism, 12.3 percent had true Addison's anemia that responded to vitamin B12 8. They believe that macrocytic anemia in hypothyroidism should not be accepted as a manifestation of thyroid hormone lack per se, but that it is due instead to the increased coincidence of Addison's anemia. Half of the patients with Addisonian anemia have serum antibodies against the thyroid gland and half of the patients with Hashimoto's thyroiditis have antibodies against gastric cell cytoplasm, parietal cells or intrinsic factor.

Megaloblastic anemia due to folic acid deficiency has also been demonstrated in hypothyroidism. Reduced intestinal absorption secondary to hypothyroidism may be responsible for this deficiency, as suggested by the changes observed in a patient given tritiated pteroylglutamate before and after treatment with thyroid hormone 9. Also, a peculiar RBC abnormality has been described in patients with untreated hypothyroidism 10: a small number of irregularly contracted RBCs resembling burr cells are present. The significance of this condition, which may be reversed by the administration of thyroid hormone, is unknown.

Leucocytes and thrombocytes. Granulocyte, lymphocyte and platelet counts are usually normal in hypothyroidism. Leukopenia might indicate associated vitamin B12 or folic acid deficiency. Mean platelet volume can be decreased. The erythrocyte sedimentation rate may be elevated in uncomplicated hypothyroidism 11.

Hemostasis. Hypothyroid patients may have bleeding symptoms such as easy bruising, menorrhagia, or prolonged bleeding after tooth extraction. The most frequent defects in hemostasis are prolonged bleeding time, decreased platelet adhesiveness, and low plasma concentrations of factor VIII and Von Willebrand factor 12,13. Desmopressin rapidly reduces these abnormalities 14, and may be of value for the acute treatment of bleeding or as cover for surgery. Usually the clinical relevance of these abnormalities is limited, as illustrated by no excess blood loss or bleeding complications during and after surgery in a large series of hypothyroid patients 15.

In patients with moderate hypothyroidism a hypofibrinolytic state has been found, which carries a risk of developing thrombosis 16. In contrast, patients with severe hypothyroidism have low levels of von Willebrand factor and activation of the fibrinolytic system; its clinical relevance is debatable 16.