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As detailed in table 2, many mechanisms and causes, whether permanent or
transient, may induce peripheral thyroid failure.
Autoimmune thyroiditis Chronic autoimmune thyroiditis is the main cause of primary hypothyroidism. There are several forms of the disease according to the morphology of the thyroid gland and the conditions of occurrence but all may lead to functional failure. The main types are, a) the goitrous form (Hashimoto's thyroiditis), b) the atrophic form (primary myxedema), c) the juvenile form (goiter of the adolescents), d) post-partum thyroiditis, e) silent thyroiditis and f) focal thyroiditis. Among them, only Hashimoto's thyroiditis and primary myxedema are a usual cause of spontaneous permanent hypothyroidism. Progressive cytolytic and degenerative processes result from a widespread infiltration of the thyroid tissue by lymphocytes, plasma and inflammatory cells. Fibrosis and destruction of follicular epithelial cells are of variable intensity and evolution. Only some, not all, Hashimoto's goiters become atrophic over the years and in most cases of primary myxedema there is no pre-existing goiter. Injury to thyroid tissue results from both humoral and cell-mediated immune mechanisms involving anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase (anti-TPO) - rarely anti-TSH-receptor-antibodies - and auto-reactive activated T cells. Destructive processes involve complement - fixing anti-TPO antibodies, complement independent antibody-dependent cell cytotoxicity mediated by natural killer (NK) cells, the direct effect of auto-reactive cytolytic T cells and the release by T cells and activated macrophages of various cytokines and substances such as interferon (IFN)-a, interleukin (IL)-6, and prostaglandins, or IL-1, tumor necrosis factor (TNF), and oxygen radicals, respectively. However, by themselves TPO-antibodies do not appear to be pathogenic since in pregnancy, maternal transplacentally transfered antibodies do not affect the fetal thyroid. In contrast, blocking anti-TSH receptor antibodies occasionally encountered in autoimmune thyroiditis are pathogenic since they may induce fetal and neo-natal hypothyroidism. Overexpression by the follicular thyroid cells of HLA class I and II molecules and of adhesion molecules may potentiate the destructive processes. The specificity of the modalities leading to autoimmune goiter or atrophy are not understood yet. Table 1: General classification of hypothyroidism Acquired hypothyroidism primary (peripheral)
iatrogenic Congenial hypothyroidism
Table 2: Mechanism of acquired primary hypothyroidism Acquired primary hypothyroidism spontaneous
transient
transient 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. Infiltrative diseases of the thyroid In rare instances, systemic disorders may involve the thyroid gland leading to progressive loss of function. Riedel's thyroiditis, sarcoidosis, amyloidosis, hemochromatosis and scleroderma may, in some cases, be responsible for thyroid insufficiency. Cystinosis is often associated with hypothyroidism in the affected children. Riedels's thyroiditis is a rare disease, although not all cases are reported. Goiter is constant, resulting from a dense fibrosis of very hard consistency of the type encountered in anaplastic carcinoma. Elements of thyroid autoimmunity may be present. It is a systemic disease frequently with other localisations such as retroperinoteal fibrosis and, less frequently, mediastinal fibrosis, primary biliary cirrhosis, involvement of the lungs or retro-orbital tissue. Thyroid amyloidosis, either diffuse or nodular, may result form primary or secondary amyloidosis, goiter being not a constant feature. Despite diffuse infilitration of the gland, hypothyroidism is rare and cases of hyperthyroidism have even been observed. Severe iodine deficiency In areas of severe iodine deficiency (< 25 µg of iodine/day), the high prevalence of goiter is associated with elevated TSH, decreased T4 and normal or supranormal T3 serum levels, reminiscent of the subclinical hypothyroidism status. However, unless significantly elevated, circulating T3 levels may not be sufficient to maintain euthyroidism in brain. Subacute thyroiditis Also referred to as De Quervain's thyroiditis, granulomatous subacute thyroiditis is a self-limited inflammatory disease of the thyroid of probable viral origin. Pain and the remarkable tenderness in the region of the thyroid gland, together with fever and general clinical and laboratory signs of inflammation, often occurring after an episode of upper respiratory tract infection, are typical. Hypothyroidism occurs usually after the initial phase of destructive hyperthyroidism and may last 1 to 3 months with a progressive decrease to normal of serum TSH. Persistence of definitive hypothyroidism is exceptional. Post-partum thyroiditis This manifestation of autoimmune thyroiditis occurs in 2-7 % of pregnancies, 2 to 12 months after delivery. It is a form of lymphocytic thyroiditis, with some genetic predisposition (DR 3, 4, 5), presence of anti-TPO antibodies before or at the beginning of pregnancy in 50 % of the cases and recurrence of similar episodes at subsequent pregnancies. Activation of the auto-immune process is thought to result from the immunological rebound activity, which takes place at delivery after the relative and partial immunosuppressive state which prevails throughout pregnancy. The hypothyroid phase occurs between 5-7 months post-partum, is rarely clinically typical, sometimes responsible for a depressive mood but more often mild or even asymptomatic, characterized by an increased TSH and marginally decreased T4. It is usually self-limited. Permanent hypothyroidism is observed in approximately 20 % of the cases. Typically, the hypothyroid phase follows an initial phase of destructive hyperthyroidism of the painless thyroiditis type which takes place between 2 and 4 months post-partum. Silent or painless thyroiditis This entity is considered to be identical to post-partum thyroiditis but occurs unrelated to pregnancy. Affected patients are mostly between 30 and 60 years. The female to male ratio is about 1.5 : 1. Iatrogenic permanent causes of hypothyroidism Radioiodine-induced and post-operative hypothyroidism are considered less as a complication of the radical treatment of Graves' hyperthyroidism than as an efficient prevention against relapse. Hypothyroidism is frequent after each treatment, although exact figures are difficult to give depending on the residual post-surgery thyroid volume or on the dose of 131 iodine administered. Prevalence of immediate hypothyroidism ranges from 10 to 60 % after subtotal thyroidectomy with a subsequent 1-3 % yearly rate of thyroid failure. Frequency of hypothyroidism is approximately the same after radioiodine treatment and the risk of thyroid failure increases steadily over the years. Early post-radiation hypothyroidism may be transient. Hypothyroidism may also follow external cervical radiation for malignant diseases, like lymphoma, Hodgkin's disease or carcinoma of the larynx. It occurs usually several years later which warrants a regular follow up of these patients. Iatrogenic transient causes of hypothyroidism Iodine-induced hypothyroidism is observed in the case of prolonged administation of large amounts of iodine or iodine-containing preparations such as amiodarone. The typical clinical presentation is that of the iodine-induced hypothyroid goiter with marked elevation of TSH secretion. The mechanism involved is the inhibition of hormone synthesis through thyroperoxidase blockade as initially described by Wolff and Chaikoff. Patients with subclinical autoimmune thyroid disease or previously treated for Graves' disease are more prone to iodine-induced hypothyroidism. Thyroid blockade is reversible as excess intrathyroidal iodide is cleared. Due to its long half-life and accumulation in tissues, amiodarone is currently the main cause of iodine-induced hypothyroidism, the prevalence of which ranges from 5-12 %, is greater in areas with high iodine intake. Amiodarone-induced hypothyroidism may be long-lasting so that thyroid hormone substitution is necessary. It should be noted that amiodarone may also cause iodine-induced thyrotoxicosis, but discussion of this phenomenon is outside the scope if this monograph. 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. |
