Current views on hypothyroidism have benefited from several recent improvements and specific areas of interest have been delineated. Knowledge of the biology of thyroid hormone receptors is in rapid progress through the analysis of mutant receptors as well as the study of their regulation factors and also the analysis of the distribution of the various isoforms of the receptor in various tissues. Current research focuses also on the role of thyroid hormone in brain development at the earliest stages. The importance of this research is in line with the study of the neurological defects observed in areas of severe iodine deficiency as well as the recent observations of the potential role of maternal thyroid hormone in early fetal development. Finally, the increasing prevalence with age of subclinical hypothyroidism in the general population stresses the necessity of a better assessment of thyroid hormone effects at the level of the various functions and tissues.
Progession of the disease in usually slow. Due to the current availability of sensitive anti-TPO and TSH assays many patients are identified as antibody-positive or subclinically hypothyroid and have to be followed up. Progression to thyroid failure, however, occurs only in a minority of subjects so identified.
Finally, autoimmune thyroiditis accounts probably for spontaneous end-stage hypothyroidism sometimes observed in patients previously treated with antithyroid drugs for hyperthyroid Graves' disease. Another link between autoimmune thyroiditis and Graves' disease is the occurrence of Graves' ophthalmopathy in Hashimoto's thyroiditis, or of autoimmune thyroiditis in euthyroid Graves' ophthalmopathy.
The etiopathogenesis of autoimmune thyroiditis is unknown. The existence of a genetic predisposition is a common observation although non-characteristic except for a weak HLA type DR 3 and DR 5 contribution. Environmental factors (infections, iodine excess, toxic substances) are mainly hypothetical.
Occurrence of hypothyroidism by antithyroid drug or lithium treatment is not unexpected and should be prevented through regular monitoring.
Treatment with IL-2, and more commonly with IFN-a may induce in 10-20% of the cases a transient or permanent hypothyroidism of the autoimmune type. The presence of anti-thyroid antibodies before treatment increases the risk of thyroid dysfunction. Hypothyroidism may occur with or without a preceding phase of hyperthyroidism, a sequence reminiscent of that observed in post-partum thyroiditis or painless thyroiditis.
a) iodide transport defect: this very rare disease (35 patients reported) is characterized by an absent radioiodide uptake by the thyroid and most probably other tissues with iodide accumulation capacity. This disease is apparently autosomal recessive. The cause of the deffect is not characterized although the recent cloning of the thyroidal membrane Na+/I- symporter should help elucidate its mechanism.
b) defects in thyroglobulin synthesis or coupling: thyroglobulin defects are inherited as autosomal recessive traits. Two mutations have been described, one leading to a deletion of exon 4 which encodes for a thyroxinogenic site, the other to premature termination of the molecule. Other defects are probably to be described, responsible for abnormalities in thyroglobulin structure which could prevent normal coupling of iodotyrosines to form T4 and T3. In one patient, the thyroglobulin synthetic defect resulted from the low expression of the thyroid specific transcription factor TTF1.
c) iodide organification and Pendred's syndrome: this defect may result from abnormalities of either thyroperoxidase or the H2O2 generating system. They are transmitted as autosomal recessive traits. Eight different mutations have been identified in the peroxidase gene leading to a loss of activity of the enzyme. The lack of iodide peroxidation prevents the iodination of the tyrosine residues of thyroglobulin. Very recently a genome-wide linkage search mapped the disease locus on chromosome 7, excluding any abnormality in the thyroglobulin or TPD gene. Most probably a defect in H2O production is the cause of the organification impairment. However, no molecular abnormality of the H2O2 generating system has been characterized, yet. Pendred's syndrome combines a goiter, overt or subclinical hypothyroidism and sensori-neural deafness of variable intensity. The thyroid hormone synthesis defect is usually modest and detected-as the goiter- only in adolescence. This familial autosomal recessive trait affects 1/25000 newborns. The mechanism of hypothyroidism is not completely understood; it is probably not uniform although in many cases evidence of a defect in iodide organification may be demonstrated by a positive perchlorate discharge test.
d) dehalogenase (deiodinase) defect: mono-iodo (MIT) and di-iodotyrosine (DIT) generated by the proteolysis of thyroglobulin during the process of T4 and T3 liberation are normally deiodinated. The iodine thus available is a major source of intrathyroidal iodine for new hormone synthesis. A hereditary disorder of the deiodinating system specific for iodotyrosines, the deshalogenase enzyme, lead to excessive renal loss of iodine as MIT and DIT, responsible for an iodine-deficient hypothyroid state with a goiter of variable size. Inheritance is autosomal recessive. The disease has not been characterized at the molecular level. Peripheral tyrosine desiodinases may or may not be affected.
Defects in the synthesis of TSH have been reported. Decreased bioactivity of TSH caused by mutations in the TSH b-subunit gene have been described. Also, mutations of the Pit-1 gene coding for the pituitary specific transcription factor, responsible for a selective loss of somatotroph, lactotroph and thyreotroph functions, have been described.
Endemic cretinism appears to correspond to two disctinct clinical presentations, neurologic cretinism on one hand and myxedematous cretinism on the other. Deaf-mutism, mental deficiency, spasticity of gait and motility without hypothyroidism are characteristic of the former, myxedema, growth retardation, bone dystrophy and slow psychomotor activity of the latter.
Endemic cretinism results from an insufficient exposure of the developping brain to thyroid hormones. Severe iodine deficiency is responsible for both maternal and fetal hypothyroxinemia. Maternal hypothyroxinemia could impair early brain development in the fetus. Indeed, it is now clear that a substantial amount of thyroxine is transferred from mother to fetus before the onset of significant thyroid function in the fetus (20 weeks). Prevalence of neurologic or myxedematous cretinism appears to be geographically determined. The myxedematous form is explained by co-existing selenium deficiency, that leads to decreased detoxification of H2O2, generated in the thyroid. Excess of H2O2 results in destruction of the thyroid gland.
Maternal blocking anti-TSH receptor antibodies transplacentally transferred to the fetus may induce fetal and neo-natal hypothyroidism. This condition should be suspected, and even systematically screened for, when the mother has a history of autoimmune thyroid disease, especially thyroxine-treated primary myxedema. Presence of high titers of blocking anti-TSH receptor antibodies in the mother during pregnancy and in the neonate is confirmatory. Neonatal hypothyroidism usually lasts for 1-4 months according to the initial level and the average 3 week half-life of the maternal antibodies in the infant's circulation. Maternal ingestion of any compound with antithyroid properties might induce iatrogenic congenital hypothyroidism. For this reason, high-dose iodine should be avoided during pregnancy especially near term. Since antithyroid drugs cross the placenta, one of the main concerns in the treatment of Graves' hyperthyroidism in pregnant patients is drug-induced fetal hypothyroidism and goiter. To this end, the rule is to maintain antithyroid drug at the lowest dosage possible and the free T4 in the mother's serum near the upper limit of normal. Administration of high-dose iodine to the newborn may also lead to transient hypothyroidism.
Transient hypothyroxinemia, without elevated TSH, is frequent in premature infants. It is thought to represent a stage of hypothalamic immaturity. An important question under current study is to know whether, in this condition, hypothyroxinemia might be deleterious for further brain development. In areas of low iodine intake, premature infants may switch from this central-type hypothyroidism to primary hypothyroidism with low T4 and elevated TSH after one to two weeks of extra-uterine life, because neonatal needs of iodine are not met. Transient neonatal hyperthyrotropinemia is unusual; it has been described mainly in Japan. Assay interferences and the existence of abnormal TSH molecules have been excluded. TSH values normalize in a few months. No satisfactory explanation has been proposed for this abnormality.
Fully developped hypothyroidism is easily recognized (fig 1). The combination of the various full-blown manifestations is typical and allows for an immediate diagnosis which is also suggested as soon as the patient speaks with a typically hoarse voice. It should be stressed, however, that because of the insidious progression of the disease, characteristics of overt hypothyroidism may be overlooked by the persons who live with the patients. Clinical features include lack of energy, cold intolerance, acroparesthesia, dryness of the skin and hair, weight gain, constipation, hoarsness of the voice, typical facial puffiness and pallor and slow reactivity. This major degree of hypothyroidism either follows years of progressive spontaneous thyroid failure or may occur rapidly after therapeutic thyroid ablation.
Mild hypothyroidism
Clinical recognition of these patients is difficult since symptoms are minor or non-specific. In the past, clinical scores were devised in order to obviate this lack of sensitivity and specificity. Current biological means, notably the assay of circulating TSH, are potent diagnostic tools in subjects identified as at risk of mild hypothyroidism either on clinical presentation or on the presence of familial or personal history of thyroid disease or organ-specific autoimmune disease.
Subclinical hypothyroidism
This condition is defined as an asymptomatic state in which the reduction in thyroid hormone secretion is compensated for by an increased TSH production to maintain a clinically euthyroid status. As alluded to in the introduction, this a condition of increasing importance. Due to the availability of more specific and more sensitive TSH and anti-thyroid antibody assays, its prevalence appears to be growing so that prospective studies aiming at defining the evolution profiles and the more appropriate strategy of management of this condition are warranted.
The skin tends to be dry, because of decreased sebum excretion rate, cool and yellowish pale because of a combination of some degree of anemia and hypercarotenemia due to impaired conversion of carotene to vitamine A. The subcutaneous swelling is most marked in the eyelids, around the eyes and on the back of the hands and feet. It is a rather firm edema without pitting. It results from an accumulation of glycosaminoglycans in the subcutaneous tissues that on its turn bind excess water. The hair is coarse and dry; alopecia may be present although most of the cases of this manifestation are unrelated to hypothyroidism. Thinning of the outer part of the eyebrows is unreliable both because it may be absent in confirmed cases and present in healthy women around menopause.
Cardiorespiratory system
Classical manifestations of the "myxedema heart” include an enlarged dilated heart on chest x-ray, bradycardia, low voltage and depression of the ECG and ST complexes with flattened or inverted T waves. An other classical manifestation is pericardial effusion, a significant contributor to the ECG abnormalities. Peripheral edema and distended neck veins may reflect heart failure which however occurs extremely rarely in the absence of other causes. Hypothyroidism reduces the cardiac output, decreases stroke volume and prolongs circulation time. Systolic time intervals measured by simultaneous recording of the ECG, phonocardiogram and carotid pulse tracing is prolonged. PEP (pre-ejection period) is also elevated. For years, the question of a link between hypothyroidism and an increased prevalence of ischemic heart disease has been debated. As described below, hypothyroidism favors hyperlipoproteinemia. As a result of poor cardiovascular adaptation to exercise and a reduction of vital lung capacity and maximum ventilatory capacity, shortness of breath is common. Also, there may be features of airway obstruction. Similarly, sleep apnoea is not uncommon. Aggravation of these symptoms is a major contributor to the severity of myxedema coma. When pericardial effusion is present, pleural effusion, either unilateral or bilateral, may be observed, sometimes in combination with ascites, despite the absence of evidence of heart failure.
Brain, neuromuscular and skeletal systems
In severe hypothyroidism intellectual functions are slow, with somnolence, diminished memory and speech difficulties. Speech is characteristically slow and dysarthric with apparent difficulties at mobilisation of lips and jaws associated with the already mentionned hoarseness due to mucinous deposits in the vocal cords. In fact however, apparent intellectual ability is often surprisingly conserved in the face of very highly elevated TSH and nearly undetectable concentrations of both T4 and T3. However, longer and more careful observation of the patients, or stressful conditions, will demonstrate the impaired intellectual adaptability of the patients.
Psychiatric disturbances may be observed, such as depression or, more rarely, paranoid or agitated states, the so-called "myxedema madness”. Hearing loss is common, of the perceptive reversible type, different from the type observed in Pendred's syndrome. Vertigo is a common complaint, sometimes associated with cerebellar ataxia. Thyroid dysfunction is often demonstrated in depressed patients. Interestingly enough this combination is observed also with "subclinical” hypothyroidism. There are observations suggesting a link between the presence of antithyroid antibodies and depression which clearly deserve further followup studies.
Paraesthesias, numbness of the fingers and toes are frequent and may represent early manifestations of nerve entrapment syndromes more frequently observed in the median nerve at the wrist than for other nerves at other sites, for example the tarsal tunnel. These are due to mucinous deposits. True peripheral neuropathy is rare. Muscles and, to a lesser degree, joints are painful, which is aggravated in the cold. Nocturnal muscle cramps and stifness are one of the more common complaints. Muscular exercice and strength, on the contrary, appear normal. The prolonged relaxation phase of the tendon reflex is very common but the lack of specificity and sensitivity of this feature which was the basis of the measurement of the Achilles tendon reflex duration led to abandon this test. Muscle abnormalities in hypothyroidism are confirmed by electromyographic alterations. There is no correlation between blood concentration of CPK and oxalo-acetate transaminase and severity of muscle involvement. Bone metabolism is affected with a slowing of bone remodelling activity leading, possibly, to a thickening of bone trabeculae as demonstrated for instance by the observation of thicker than normal iliac cortices. Also, urinary hydroxyproline excretion and serum osteocalcin levels have been found to be low in untreated hypothyroid patients.
Gastro-intestinal tract
Constipation, leading rarely to paralytic ileus or pseudo-obstruction, is very common and usually unspecific. Anorexia is frequent, contrasting with a usual moderate weight gain which is mainly due to tissue infiltration. Achlorhydria and mucosal atrophy, associated with circulating anti-gastric parietal cell antibodies, should be suspected in the context of polyautoimmune disease. About 10% of patients with autoimmune hypothyroidism may have an autoimmune gastritis.
Renal function
Glomerular filtration rate and effective renal plasma flow are often reduced. Urinary output is decreased without evidence of renal insufficiency. Protein extravasation and accumulation of water and mucopolysaccharides in interstitial spaces account for the myxedematous appearance and the serous effusion. The mechanism of the dilutional hyponatremia observed in some patients with peripheral hypothyroidism is unclear but appears to result from the decreased renal blood flow and glomerular filtration rate and to involve some degree of inappropriate antidiuretic hormone effect or secretion. Hyponatremia is common in myxedema coma. In central hypothyroidism, hyponatremia is rather due to ACTH deficiency.
Hematological system
Anemia is very common in hypothyroidism, affecting more that 25% of the patients. It may be normocytic, macrocytic or microcytic, depending upon the more dominant effect of the three mechanisms potentially involved: the lack of stimulation of hematopoiesis by thyroid hormone, the deficiency in vitamine B12 due to an associated pernicious anemia or an iron deficiency resulting both from polymenorrhea and achlorhydria-related impaired iron absorption, respectively.
Metabolism and endocrine functions
The hallmark of hypothyroidism is the 35-40% decrease in the basal metabolic rate with reduction in oxygen consumption and decreased heat production. Lipid metabolism is affected: total cholesterol tends to be elevated with a predominant increased of LDL and, less frequently of VLDL, remnants or HDL with an augmented Apo A1 constituant. Hypertriglyceridemia results from increased hepatic output of VLDL. ApoB synthesis is also increased, as well as that of ApoE. Receptor-mediated catabolism of LDL is reduced because of a decreased expression of the LDL cell surface receptors, a modification which is dependent on a polymorphism of the LDL receptor gene. In contrast, hepatic cholesterol synthesis is decreased in hypothyroidism.
In the female, menorrhagia is frequent and may lead to unnecessary hysterectomy if the diagnosis of hypothyroidism is not considered. Amenorrhea and anovulation are frequent, as well as infertility. Pregnancy may occur but is usually complicated if appropriate thyroxine treatment is not rapidly institued. Galactorrhea and hyperprolactinemia may be observed, which are corrected by thyroxine treatment. Also, in cases with pituitary enlargement due to thyrotroph hyperplasia, differential diagnosis with prolactinoma rests on the moderate elevation of prolactin levels (<100ng/ml) and the co-existence of severe long-standing hypothyroidism. Indeed, the pituitary gland may be enlarged in long-lasting primary hypothyroidism which is reverted after several months of substitutive treatment. Thyroid hormone regulates positively both GH secretion and IGF-I action. This accounts, at least in part, for the retardation of growth observed in hypothyroid children.
Peripheral metabolism of adrenal steroids is affected by hypothyroidism with a usual reduction of urinary steroid excretion and of cortisol disposal rate. However, plasma cortisol, as well as aldosterone levels, are normal, although the stimulation of the corticotroph by hypoglycemia or metyrapone, as well as that of the adrenal by ACTH, might be occasionnaly reduced. It is important to note that thyroid hormone administration might decompensate associated corticotroph insufficiency in the case of central hypothyroidism, or adrenal function in the case of associated autoimmune thyroid and adrenal deficiency known as Schmidt's syndrome. Indeed, chronic autoimmune thyroiditis may be associated with other autoimmune disorders in the context of type II polyglandular autoimmune syndrome. It is twice as frequent in females than in males. In this syndrome prevalences of adrenal or thyroid insufficiency and diabetes mellitus are around 60, 70 and 50%, respectively; vitiligo, hypogonadism and permicious anemia are less frequent. In contrast, hypothyroidism is much less frequent (10%) in Type I polyglandular autoimmune syndrome, an early onset disease characterized by the presence of mucocutaneous candidiasis, alopecia, malabsorption, hypoparathyroidism, adrenal insufficiency, hypogonadism and chronic active hepatitis.
The prevalence of overt hypothyroidism, as well as that of subclinical hypothyroidism, and the frequency of detection of antithyroid antibodies, tend to increase with age to reach 0.7-1.3% and 1.8-5.3% for overt hypothyroidism in men and women, more than 60 year of age, respectively. Subclinical hypothyroidism may affect up to 14% of a senior population while anti-TPO antibodies are detected in approximately 2% of men and 10% of women. In some series, 6-7% of perimenopausal women may present with a hypothyroid state. In contrast, clinical manifestations of hypothyroidism are especially misleading in elderly patients because of a greater lack of sensitivity and specificity. Biological tests may also be difficult to interpret (see "Diagnosis”). However, firm diagnosis and prognosis are mandatory since the benefit of treating aging hypothyroid patients is unquestionable.
Obesity
Despite the evidence accumulated for decades that common obesity does not result from hypothyroidism, numerous obese patients are still referred for a thyroid work-up. Except for the periods of caloric restriction which may be responsible for a fall of T3 and an increase of rT3, thyroid status is normal in obesity and administration of thyroid hormone or thyroid preparations is, on the whole, harmful. Hypothyroidism usually favors a 2-3kg weight gain which will be corrected by the treatment.
Myxedematous coma
This complication of profound and long-standing hypothyroidism is exceptional. It is a life-threatening condition, occurring mostly in elderly subjects, characterized by mental confusion, severe hypothermia, shock and coma. In most of the cases, myxedematous or hypothyroid coma is triggered by exposure to cold or any intercurrent medical event, including anesthesia, administration of central nervous system depressants, infections, cardio-vascular or respiratory disease. The main symptom is hypothermia around 32-36°C with progressive lethargy. Cerebral hypoxia results from central respiratory depression and decreased cardiac output with marked bradycardia. Hypoventilation with hypercapnia and respiratory acidosis needs special assistance. Hyponatremia, hypoglycemia and hypotension are usual. Signs of profound hypothyroidism are present. Seizures may occur. Prompt and aggressive emergency treatment is mandatory.
At birth, clinical recognition of hypothyroidism is difficult and most infants appear normal. The full-blown picture develops progressively over weeks and months. Initially, hypothyroid newborns may be post-mature (gestational age > 42 weeks), may weigh more than 4 kg, present with hypothermia and a cool skin, peripheral edema, abdominal distension and a posterior fontanel more than 5 mm in diameter; they feed poorly and have prolonged jaundice (> 3 days). During the first 4 weeks , signs and symtoms include macroglossia, failure to thrive, peripheral cyanosis and respiratory difficulties, lethargy, decreased activity and constipation. Later, during the third month of age, the picture appears more classical with myxedema, umbilical hernia, hypotonia, dry, yellowish pale skin, hoarsness of the voice, loud breathing and constipation (fig 2).
In childhood and adolescence, growth retardation is the major feature with persistence of juvenile proportions of the body and delayed bone age with dystrophic ossification centers (epiphyseal dysgenesis). Because of the lack of maturation of the facial bones, the childish naso-orbital configuration persists. Permanent dentition is delayed. Sexual maturation is usually retarded with delayed puberty. However, sexual precocity has been observed in either sex. Intellectual development is impaired, which results from the lack of thyroid hormone effect on the many targets in the central nervous system.
Neonatal screening is the typical example of a systematic dignostic strategy efficient both at the detection and therapeutic levels. The same screening-type approach prevails in situations in which presence or occurrence of hypothyroidism is not unlikely, for instance hypothalamic or pituitary disorders, or a diffuse goiter even more typical of autoimmune thyroiditis if firm, associated with vitiligo or other personal or family history of autoimmune diseases. Iatrogenic hypothyroidism should be looked for systematically, even using recall programms for those patients who had a radical treatment for Graves' hyperthyroidism. Systematic laboratory thyroid testing in selected adult populations - for instance elderly subjects or psychiatric patients - has been studied with various cost-effectiveness results.
Serum T4 concentration may be measured by several types of competitive protein binding assays using thyroxine binding protein (TBG) or anti-T4 antibodies. These procedures measure total serum T4 concentration. Because 99.97% of the circulating T4 is bound to TBG, transthyretin and albumin, total T4 concentration is affected by alterations in binding proteins. Therefore various methods have been devised to estimate indirectly or directly the unbound (free) fraction of T4. Free T4 index corrects total T4 with an estimate of the residual TBG capacity. T4/TBG ratio has the same significance. Both methods require two different assays to be performed. Current free T4 radioimmunoassays are both simpler and faster and most are of good sensitivity for the detection of hypothyroidism.
Determination of serum T3 concentration, either total or free, is useless for the diagnosis of hypothyroidism because T3 tends to fall later than T4 in patients developing thyroid failure, and may be even elevated in early hypothyroidism.
The assay of Serum TSH provides an exquisitely sensitive marker of primary hypothyroidism. Moreover, the combination of elevated TSH and decreased free T4 is diagnostic of primary hypothyroidism. However, this combination may be observed in patients with non-thyroidal illnesses (NTI). The frequency of decreased free T4 in NTI depends partly on the assay method used which is variably affected by the alterations in serum binding protein concentrations or the inhibition of hormone binding to transport proteins in sick patients. Informations on this point are to be provided by the manufacturers of the assay kits. About 5 % of the patients admitted to the hospital for NTI have elevated TSH. In few instances, values may be > 20 µU/ml. The relationship between serum TSH and free T4 is often altered in NTI or psychiatric disorders. The observation of a slightly elevated TSH and a normal free T4 is typical of NTI. Thyroid test abnormalities due to NTI are reversible with recovery from the causal illness. Therefore, the rule is to retest TSH and free T4 after the acute phase of the disease before considering the diagnosis of thyroid insufficiency. Some treatments, such as dopamine infusion or high dose glucocorticoid therapy may blunt serum TSH so that primary hypothyroidism might present transiently with normal TSH and with low free T4.
The combination of a moderately elevated TSH (< 25 µU/ml) with a normal free T4 defines subclinical hypothyroidism, a common condition which eventually may evolve towards overt hypothyroidism especially in persons with anti-thyroid antibodies. The differential diagnosis of elevated serum TSH includes assay interferences with heterophilic anti-TSH antibodies or the exceptional anti-TSH autoantibodies, an effect of therapy with metoclopramide or domperidone and TSH- secreting pituitary adenoma and the thyroid hormone resistance syndrome.
Central hypothyroidism is characterized by the combination of decreased free T4 and decreased TSH. However, TSH may be normal or, rarely, moderately elevated, due to decreased biological activity of the TSH molecule.
The TRH test is no longer useful for the diagnosis of primary hypothyroidism. As far as central hypothyroidism is concerned, the TRH test does not distinguish reliably between hypothalamic and pituitary hypothyroidism. The test may contribute to assess the bioactivity of endogenous TSH. The lack of a 30-100% increase in serum T3, 120-180 min after an i.v. injection of 200 mg of TRH is indicative of central hypothyroidism (provided primary hypothyroidism has been excluded), and of the secretion of bio-inactive TSH if concomitant immunoreactive TSH is normal or elevated.
Highly specific and sensitive asays are available for anti-TPO and anti-TG antibodies. More than 90 % of patients with autoimmune thyroiditis have anti-thyroid antibodies, especially anti-TPO. Anti-TPO antibodies are detectable in apparently normal people; their prevalence is 0-5 % in subjects less than 60 and increases to 15-20 % in women over 60 years of age; titers are usually in the low or medium range. Elevated titers (> 1000 u/ml) are indicative of a risk of thyroid dysfunction. Anti-TPO antibodies have a strong predictive value for hypothyroidism (odds ratio 1 : 38) in subjects with subclinical hypothyroidism. The presence of anti-TPO-antibodies before or at the beginning of pregnancy is a significant risk factor for postpartum thyroiditis.
The assay of anti-TSH receptor antibodies is useful in pregnant women with atrophic primary hypothyroidism. Strong positivity is indicative for a risk of fetal and neo-natal transient hypothyroidism due to blocking anti-TSH receptor antibodies. Antibodies should also be assayed in the hypothyroid neonate whenever the thyroid is normally located.
Newborn screening for congenital hypothyroidism is based on T4 and/or TSH measurement on a dried blood spot sample collected 3-5 days after birth. In the T4 measurement-based programs, TSH is assayed in samples with T4 values in the lowest 5-10 %. The TSH cut-off value is 20-40 mU/l. Prompt clinical and biological evaluation of the infants positively screened is mandatory. The diagnosis of congenital hypothyroidism is confirmed by measurements of T4 and TSH serum concentrations. In order to delineate the cause of the disease, complementary thyroid work-up includes thyroid scintiscan, measurement of thyroid uptake of technetium or 123I, thyroid ultrasound and serum thyroglobulin determination; bone age should also be measured.
Suspicion of inherited disorders of thyroid function requires a series of specialized biological tests to be programmed in a logical order. In some cases, study of thyroid tissue fragments is appropriate. In vivo measurements include thyroid uptake of iodine, perchlorate discharge test and determination of iodotyrosine dehalogenase activity. Concentration and structure evaluation of circulating and intrathyroidal thyroglobulin is useful. Iodinating and H2O2 production capacities of fresh thyroid tissue can be measured in vitro. The gene or the cDNA coding for the TSH-b subunit, TSH receptor, Gsa, thyroglobulin, thyroperoxidase, the Na+/I- symporter, the thyroid hormone receptor(s) and, possibly, pituitary or thyroid transcription factors, might be tested for abnormalities, as suggested by clinical and biological data.
Finally, various tests are available as markers of thyroid hormone action on tissues and functions. Except for TSH, none is sensitive and specific enough to stand as a "thyroid test”. They have to be interpreted against the thyroid hormone and TSH levels as well as the clinical picture of the patient. A non-exhaustive list includes for the a) heart: the resting pulse, cardiac time intervals (PEP/LVET) and the QKd interval (msec); b) bone: bone age, bone mineral density, osteocalcin, pyridinolin and deoxipyridinolin; c) liver: sex hormone binding globulin, blood lipids, ferritin; d) muscles: ankle reflex time, creatine kinase, myoglobin; e) basal metabolic rate.
Initiation of therapy should be adapted to the age and condition of the patient, and duration and severity of hypothyroidism. In young healthy adults, L-T4 is generally instituted at a dose of 50-75 µg per day and thyroid function tests is assessed after 6-8 weeks of therapy. The daily dose can be increased by 50 µg every 4-6 weeks until clinical and biochemical euthyroidism is achieved. Alternatively, the initial dose may be maintained for 3-4 months, then increased by 25 µg every 4-6 month. The goal of the treatment is to normalize serum TSH, which may require up to 6 months. A thyrotoxic range for serum TSH should be avoided. In this condition, free T4 is usually normal, but often in the high normal range, while free T3 is normal. Once a constant dose of T4 has been reached, thyroid function should be evaluated every 9-12 months unless interference with drugs (anti-epileptic drugs, rifampin, amiodarone) or an event such as pregnancy occurs. The main difficulty with T4 treatment may be the compliance of the patient. Treatment is usually a definitive one. Despite a few examples, mainly from Japan, of reversal of hypothyroidism either with the prevention of excess iodine intake or because of the disappearance of blocking anti-TSH receptor antibodies, systematic regular testing of restoration of thyroid function is not cost-effective and should not be recommended.
In hypothyroidism of rapid onset, such as in iatrogenic hypothyroidism, substitution treatment should be rapidly instituted with full initial dosage.
In patients with ischemic heart disease, initiation of treatment requires special attention. It may be necessary to start with a very small dose, such as 25 µg on alternate days, and a slow increasing program. It may not be possibile to achieve full replacement therapy in some patients with coronary artery disease so that concomitant coronary revascularization may be necessary.
In the elderly patient, the replacement dose of L-T4 is somewhat lower - by 10 % approximately - than in younger adults because daily production rates of T4 and T3 are reduced with advanced age. Also, the cardiac risk of initiation of treatment should be considered. During pregnancy, thyroid economy is modifided in that L-T4 needs are increased by 50-100 µg per day or approximately doubled. In view of the likely importance for early brain development of maternal-to-fetus T4 transfer during the first weeks of pregnancy, the dose of L-T4 should be adjusted without delay aiming at an upper normal free T4 level. TSH should be maintained well within the normal range. The same rule should apply throughout pregnancy since significant transfer of maternal T4 to fetus has also be demonstrated in late pregnancy. It should be mentioned that if, because of the presence of a goiter at ultrasonography, fetal hypothyroidism is considered, biological thyroid workup may be performed on blood sampled through cordocentesis with a 1 % morbidity. Once confirmed, fetal hypothyroidism may be treated with intra-amniotic L-T4 injections, 250-500 µg per week for 2 to 4 weeks.
In neonatal hypothyroidism, L-T4 replacement therapy should be prompt and adequate so that serum T4 is normalized with a delay less than 3 weeks. The rule is to maintain serum T4 in the upper half of the normal range. Initial L-T4 dosage is 10-15 µg/kg/day for 6 months, then adjusted at 4-6 week intervals for 6 months and every 2-3 months thereafter. Serum TSH concentrations may remain elevated although values less than 20 mU/l are usual when T4 levels are high normal. However, iatrogenic thyrotoxicosis should be avoided. Treatment promptness and adequacy insure normal intellectual developement.
Correspondence Address:
Prof. Jacques Orgiazzi, M.D.
Centre Hospitalier Lyon Sud
69495 PIERRE BENITE
Unité INSERM U 449
Faculté Laennec
rue Guillaume Paradin
69372 LYON Cedex 08
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