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HIPOTIROIDISMO.

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Presentación del tema: "HIPOTIROIDISMO."— Transcripción de la presentación:

1 HIPOTIROIDISMO

2 ANATOMIA Y FISIOLOGIA DE LA GLANDULA TIROIDES

3 GLÁNDULA TIROIDES Mide 1 cm de alto y 5 mm de grosor; sus extremidades laterales se continúan con los lóbulos. Su cara anterior se relaciona con los músculos infrahioideos, la aponeurosis y la piel.

4 GLÁNDULA TIROIDES Su cara posterior, cóncava, abraza el cricoides y los primeros anillos de la tráquea. Su borde inferior, cóncavo hacia abajo, corresponde al segundo anillo traqueal. Su borde superior, cóncavo hacia arriba, corresponde al primer anillo de la tráquea.

5 LÓBULOS LATERALES

6 Fisiología

7 Mecanismo de regulación
Figure 1. The Hypothalamic–Pituitary–Thyroid Axis and Extrathyroidal Pathways of Thyroid Hormone Metabolism. Triiodothyronine (T3) and thyroxine (T4) inhibit the secretion of thyrotropin (TSH) both directly and indirectly, by inhibiting the secretion of thyrotropin-releasing hormone (TRH). TSH stimulates the synthesis and secretion of T4 and T3 by the thyroid gland. T4 is converted to T3 in the liver (and many other tissues) by the action of T4 monodeiodinases. Some of the T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine; the T4 and T3 formed there may be reabsorbed. Drug interactions can occur at any of these sites. NEJM 1995; 333: 1688

8 ACCIÓN CALORÍGENA Al estimular la función cardiaca, de los músculos, del hígado y de los riñones se produce un incremento del consumo de oxígeno, del cual 30 a 40% se relaciona con aumento de la actividad cardiaca, lo cual incrementa el gasto calórico.

9 EFECTOS CARDIOVASCULARES
Las hormonas tiroideas influyen sobre la actividad cardiaca por medio de efectos directos e indirectos. a) Acción directa regulan la expresión de genes que codifican para la miosina y la Ca-ATPasa de la miosina. b) Acción indirecta, se ha observado que la sensibilidad de los miocitos cardiacos a las catecolaminas aumenta en el hipertiroidismo y está deprimida en el hipotiroidismo.

10 Las hormonas tiroideas influyen sobre la actividad cardiaca por medio de efectos directos e indirectos. a) Acción directa regulan la expresión de genes que codifican para la miosina y la Ca-ATPasa de la miosina b) Acción indirecta, se ha observado que la sensibilidad de los miocitos cardiacos a las catecolaminas aumenta en el hipertiroidismo y está deprimida en el hipotiroidismo.

11 EFECTOS METABOLICOS Las hormonas tiroideas estimulan el metabolismo del colesterol hacia ácidos biliares, incrementan la unión específica de LDL a las células hepáticas mediante el aumento de los receptores. Esto genera disminución de la concentración plasmática de colesterol, de manera que la hipercolesterolemia es un dato característico del hipotiroidismo.

12 Mayor al límite de referencia hasta ≤ 10 mU/L
DEFINICIÓN hipo TSH T4 Síntomas Subclínico Normal Usualmente ausentes. Algunos requieren la ausencia de síntoma como criterio. Se usa el término de hipotiroidismo leve para HS más síntomas Grado1 Mayor al límite de referencia hasta ≤ 10 mU/L Grado 2 mU/L Grado 3 > 20 mU/L Clínico Usualmente presente. BMJ 1997;314:1175

13 CLASIFICACIÓN DE HIPOTIROIDISMO
Primario Congénito Atireosis Ectopia dishormonogenesis Adquirido déficit de yodo autoinmunidad 131I Postquirurgico anti-tiroideos exceso de iodo 2) Secundario Tumor hipofisario Granuloma hipofisiario. 3) Terciario Craneofaringioma Déficit-TRH

14 CAUSAS Déficit de secreción de hormonas tiroideas.
Tiroiditis autoinmune crónica (Hashimoto) Cirugía Ablación con 131I Radiación externa Linfoma Litio e interferón Endocr Pract 2002;8: 461

15 DIAGNOSTICO

16 SIGNOS Y SÍNTOMAS Retardo en la fase de relajación del los reflejos
Ataxia Estreñimiento Alteración mental y de la memoria Disminución de la concentración Depresión Irregularidades menstruales e infertilidad Mialgias Hiperlipidemias Fatiga Ganancia de peso (retención de líquidos) Piel seca e intolerancia al frío Piel amarillenta Aspereza y caída del cabello Ronquera Bocio Bradicardia e hipotermia Mixedema Endocr Pract 2002;8: 461

17 DETECCIÓN Población general Poblaciones especiales
Hipotiroidismo congénito Poblaciones especiales Después de cualquier modalidad de tratamiento para hipertiroidismo Litio Amiodarona Tiroiditis post parto Desordenes bipolares afectivos Cáncer de mama General population screening Screening for congenital hypothyroidism is definitely worth while as it is relatively common (1:4000 births), the test is sensitive and specific (thyroid stimulating hormone measurement in heel prick specimens), it has serious consequences if untreated (brain damage), and effective treatment is available (thyroxine). However, screening for hypothyroidism in hospital patients is not effective.4 5 Although undiagnosed hypothyroidism is more common in adults than neonates, the non-specific effects of acute illness on thyroid function tests often produce abnormal results which correct themselves after recovery. The best current recommendation is to maintain a low threshold for suspecting hypothyroidism, particularly in its more obscure presentations, and to reserve testing for these patients.5 In apparently healthy people routine screening is generally not recommended, even in those over 60 and with a family history of thyroid disease.2 4 Reasons for this include a relatively low point prevalence of overt disease and uncertainty over the benefits of detecting subclinical hypothyroidism (see below). However, a cost utility analysis using a computer decision model to assess the consequences and costs of thyroid stimulating hormone screening recently came to the conclusion that testing 35 year old men and women, with repeat estimates every five years for 50 years, would be beneficial.6 The cost of detecting subclinical hypothyroidism was $9223 (£6148) for women and $ (£15 063) for men per quality adjusted life year.6 Most of the quality adjusted life years (52%) were accounted for by preventing progression to overt hypothyroidism and 30% by improving associated mild symptoms; 2% were estimated to be due to prevention of cardiovascular disease through the effect of hypothyroidism on cholesterol concentrations. This last estimate may be too high as the 20 year Whickham survey found no evidence of increased mortality or ischaemic heart disease in women with thyroid antibodies or raised thyroid stimulating hormone concentrations.7 Another assumption in the model was that only those patients with subclinical hypothyroidism plus thyroid antibodies are at risk of progression to overt hypothyroidism. Since raised thyroid stimulating hormone alone is a predictor of overt hypothyroidism, more cases at risk will be ascertained (which in turn will alter costs). Nevertheless, the final conclusion was that screening for hypothyroidism is as favourable as screening for hypertension in the same age group, providing a similar increase in quality adjusted days. It is also important to note that screening based on thyroid stimulating hormone concentrations will of course also turn up subclinical and overt thyrotoxicosis,8 and arguably this is even more important to recognise and treat. Further analyses based on existing local screening schemes are therefore needed to determine the true place of thyroid stimulating hormone testing for the general population. At present the benefits remain debatable. One reasonable alternative is the case finding approach, focusing testing on patients visiting their doctors for an unrelated reason; this is particularly effective in women over 40 with non-specific symptoms.4 Screening in special groups Hypothyroidism occurs after all types of treatment for hyperthyroidism, and patients who are euthyroid should be offered annual screening by means of a computerised register (box).2 Patients taking lithium or amiodarone are at risk of hypothyroidism and thyrotoxicosis and need regular monitoring of thyroid function.2 There is no consensus on the place of screening for postpartum thyroiditis.9 However, women with insulin dependent diabetes mellitus are three times more likely to develop postpartum thyroid dysfunction than non-diabetic controls and may have unsuspected thyroid disease in pregnancy.10 Ideally, all diabetic women should have thyroid antibody measurements in the first trimester, with careful follow up of those with positive results. Also, any woman who develops postpartum thyroiditis should be offered annual follow up, as about a quarter of these women will develop overt hypothyroidism within the next five years.11 Some psychiatric disorders may be exceptions to the rule that acutely ill patients should only be tested for hypothyroidism if there is clinical suspicion, in particular bipolar affective disorder with rapid cycling12 and refractory depression.13 The effect of thyroid treatment in these conditions is still uncertain. Delaying testing until the third week after admission avoids the transient disturbances due to the effects of acute psychiatric illness.14 Although frequently sought in dementia, unsuspected hypothyroidism is rare.4 There is an unexplained association between breast cancer and autoimmune (Hashimoto's) thyroiditis, with a threefold increase in the prevalence of thyroid antibodies, and it may be worth screening such patients for thyroid dysfunction.15 BMJ 1997;314:1175

18 INDICACIONES PARA INVESTIGAR HIPOTIROIDISMO
Establecidas Congénito Radiación en cuello Tratamiento de hipertiroidismo Tratamiento o cirugía de hipófisis Paciente tomando amiodarona o litio BMJ 1997;314:1175

19 INDICACIONES PARA INVESTIGAR HIPOTIROIDISMO
Probablemente necesarias DM tipo 1 anteparto Episodio previo de tiroiditis postparto Infertilidad inexplicada Mujer > 40 años con síntomas no explicados Depresión refractaria Síndrome de Down y Turner Enfermedad de Addison autoinmune BMJ 1997;314:1175

20 INDICACIONES PARA INVESTIGAR HIPOTIROIDISMO
Inciertas Cáncer de mama Demencia Historia familiar de enfermedad tiroidea autoinmune Búsqueda en el embarazo de tiroiditis postparto Obesidad Edema idiopático No indicadas Paciente con enfermedad aguda sin sospecha de enfermedad tiroidea BMJ 1997;314:1175

21 TIPOS DE TIROIDITIS Tipo Sinónimo N Engl J Med 2003; 348:2646-2655
Tiroiditis de Hashimoto Tiroiditis linfocitica crónica Tiroiditis autoinmune crónica Bocio linfadenoide Tiroiditis postparto indolora (silenciosa) Tiroiditis postparto Tiroiditis linfocitica subaguda Tiroiditis esporádica indolora (silenciosa) Tiroiditis esporadica silenciosa Tiroiditis subaguda dolorosa Tiroiditis subaguda Tiroiditis de Quervain Tiroiditis de células gigantes Tiroiditis granulomatosa subaguda Tiroiditis seudogranulomatosa Tiroiditis inducida por drogas (amiodarona, litio, interferon-, interleukina-2 Tiroiditis de Riedel Tiroiditis fibrosa N Engl J Med 2003; 348:

22 CARACTERISTICA DE LAS TIROIDITIS
Tiroiditis de Hashimoto Tiroiditis postparto indolora (silenciosa) Tiroiditis esporádica indolora (silenciosa) Tiroiditis subaguda dolorosa Tiroiditis supurativa Tiroiditis de Riedel Edad de inicio en años Todas, pico a Edad reproducticva Todas, pico 30-40 20-60 Niños, 20-40 30-60 Razón sexo F:M 8-9:1 - 2.1 5:1 1.1 3-4:1 Causas Autoinmune Desconocida Infecciosa Patología Infiltración linfocitiica, centros germinales, fibrosis Infiltración linfocítica Células gigantes, granulomas Formación de abscesos Fibrosis densa Función tiroidea Hipotiroidismo Tirotoxicosis, hipotroidismo, ambas Usualmente eutiroideo Usualmente eutoroidismo Ac-TPO Títulos ↑ y persistentes Titulos ↓ o ausentes, transitorios Ausente Usualmente presente s VSG Normal Captación 131I 24 h Variable < 5% Baja o normal N Engl J Med 2003; 348:

23 PREVALENCIA DE CONCENTRACIONES DE AC ANTITROIDEOS
10% de la población en EE UU 25% en mujeres mayores de 60 años. 14.3% blancos. 10.9% méxico-americanos 5.3% negros 10% de mujeres menopáusicas con títulos altos tienen hipotiroidismo subclínico y % padecen de hipotiroidismo. Once helper T cells are activated, they induce B cells to secrete thyroid antibodies. Increased serum concentrations of thyroid antibodies are present in up to 10 percent of the general population in the United States5 and in approximately 25 percent of U.S. women over 60 years of age.6 The prevalence of high serum concentrations of thyroid antibodies varies according to race and ethnic background. In the third U.S. National Health and Nutrition Examination Survey of persons 12 years of age or older, high serum concentrations of thyroid antibodies were present in 14.3 percent of whites, in 10.9 percent of Mexican Americans, and in only 5.3 percent of blacks.7 The majority of patients with measurable thyroid antibody concentrations have normal thyroid function. In studies in England, 10 percent of postmenopausal women with high serum thyroid antibody concentrations had subclinical hypothyroidism and 0.5 percent had overt hypothyroidism, although euthyroid patients with high serum thyroid antibody concentrations had progression to overt hypothyroidism at a rate of 2 to 4 percent a year.5,8 In a 10-year prospective study conducted in Switzerland, high serum thyroid peroxidase antibody concentrations predicted the progression of subclinical hypothyroidism to overt hypothyroidism.9 The thyroid antibodies most frequently measured are those directed against thyroid peroxidase and against thyroglobulin. The former are closely associated with overt thyroid dysfunction, and their presence tends to correlate with thyroidal damage and lymphocytic inflammation. Thyroid peroxidase antibodies are complement-fixing and thus directly cytotoxic to thyrocytes,10 but there is limited evidence that this toxic effect is a primary destructive mechanism in autoimmune thyroiditis. Antibodies that block thyrotropin receptors have been reported in up to 10 percent of patients with Hashimoto's thyroiditis.11 In some patients, these antibodies may have a role in the development and severity of hypothyroidism, although they are not directly involved in the destruction of thyrocytes. Thyroglobulin antibodies are present less frequently, and their role is unclear. Antibodies to colloid antigen, thyroid hormones, and the sodium iodide symporter have also been detected in patients with autoimmune thyroiditis. N Engl J Med 2003; 348:

24 HIPOTIROIDISMO SUBCLINICO

25 HIPOTIROIDISMO SUBCLÍNICO
Espontáneo Sustitución inadecuada Causa mas común tiroiditis autoinmune Después de cirugía o 131I. Cambios reversibles Función ventricular Hipoacusia  permeabilidad capilar a proteínas Subclinical hypothyroidism occurs not only as a result of inadequate thyroxine replacement therapy but also spontaneously. The most common cause is chronic autoimmune thyroiditis, which occurs in 3 percent of adults and 10 percent of postmenopausal women25. It is also common after treatment of hyperthyroidism by surgery or iodine-131 and may result from the use of drugs such as lithium carbonate. Subclinical hypothyroidism is usually detected during follow-up of patients with a history of thyroid disease or as a result of biochemical screening for nonspecific symptoms, such as tiredness or weight gain. Whether patients with subclinical hypothyroidism benefit from thyroxine replacement is uncertain. There is some evidence that subclinical hypothyroidism is accompanied by reversible changes in the function of target organs, which are similar to but less marked than those that occur in overt hypothyroidism. These changes include impaired left ventricular function,26 reduced hearing,27 and increased capillary permeability to protein28. N Engl J Med 1994; 331:

26 HIPOTIROIDISMO SUBCLINICO
25%-50% de los pacientes se sienten mejor al tomar tiroxina. La evolución a hipotiroidismo post cirugía o I131 es 5% anual. En mayores de 65 años con tiroiditis autoinmune crónica la tasa de evolución a hipotiroidismo es 20% anual. Clinicians favoring therapy for patients with subclinical hypothyroidism will be most influenced by the knowledge that between 25 and 50 percent of such patients feel better while taking thyroxine39,40 and by the fact that the annual rate of evolution from subclinical to overt hypothyroidism is approximately 5 percent among patients with hyperthyroidism treated with iodine-131 or surgery41,42 and among those with chronic autoimmune thyroiditis43. In patients over 65 years of age, the latter disorder is associated with a higher risk of overt hypothyroidism (20 percent per year)44. N Engl J Med 1994; 331:

27 HIPOTIROIDISMO SUBCLINICO
Terapia de reemplazo TSH > 10 UI/mL TSH UI/mL con bocio y anticuerpos antiroideos positivos. TSH < 10 mU/L, sin bocio, sin historia de enfermedad tiroidea y sin ac antimicrosomales positivos Repetir TSH 3-6 meses después para descartar enfermedad no tiroidea. In patients with confirmed subclinical hypothyroidism, it makes sense to prevent the progression to overt hypothyroidism by prescribing thyroxine. As in patients with overt hypothyroidism, the goal of treatment with thyroxine in patients with subclinical hypothyroidism is to restore the serum thyrotropin concentration to a normal level. If, however, the serum thyrotropin concentration is only slightly elevated (e.g., less than 10 mU per liter) and the patient has no goiter, history of thyroid disease, or antithyroid peroxidase (microsomal) antibodies, it is advisable to repeat the thyrotropin measurement three to six months after the start of therapy to determine whether long-term treatment is warranted, because the initial raised concentration may simply reflect a nonthyroidal illness45 or transient thyroid injury from which the patient has recovered N Engl J Med 1994; 331: Endocr Pract 2002;8 : 461

28 HIPOTIROIDISMO POR FARMACOS : AMIODARONA

29 CAMBIOS EN FUNCIÓN TIROIDEA POR AMIODARONA
Hipertiroidismo TSH ↓ ↑ posterior de T4, T4L, e indice de T4L ↑ T3, T3L e indice de T3L Hipotiroidismo TSH ↑ (valor no útil en los primeros 3 meses de Tx) ↓ T4, T4L e índice de T4L ↓ T3, T3L e índice de T3L Test de descarga de perclorato positiva Table 1. Changes in Thyroid Function Test Results with Development of Hyperthyroidism and Hypothyroidism in Patients Treated with Amiodarone Ann Intern Med 1997; 126:

30 EFECTOS DE AMIODARONA SOBRE PFT EN EUTIROIDEOS
Duración del tratamiento Test Subaguda (hasta 3 meses) Crónica: > 3 meses T3 Incremento modesto Permanece ↑ hasta 40% sobre el valor basal. Puede estart en el rango de referencia alto o ligeramente ↓. T4 ↓ usualmente debajo del rango de referencia Permanece en el rango de referencia inferior o ligeramente ↓ TSH ↑ transitorio hasta 20 UI/mL Normal, pero puede tener períodos de aumento y descenso. rT3 Incrementada Heart 1998;79;

31 EFECTOS DE AMIODARONA SOBRE LA TIROIDES
Rasgo Tirotoxicosis tipo I Tirotoxicosis tipo II Hipotiroidismo mecansismo Exceso de I (común en áreas deficientes de I) Tiroiditis destructiva-inflamatoria Exceso de I (común en áreas suficientes de I) Ac antitiroideos Presente común Usualmente ausente Función tioidea Tirotoxicosis Captación de 123 I a las 24 horas Baja en regiones suficientes de I pero puede estar a aumentada en áreas deficientes de I < 5% Usualmente baja en regiones suficientes de I Hallazgos a la ultrasonido doppler Hipervascularidad Reducción del flujo sanguineo Variable Terapia Dosis grandes de antiroideos , posiblemente perclorato de K o acido yopanoico antes de la tiroidectomía Dosis grandes de corticoides, acido yopanoico Levotiroxina sódica The various effects of amiodarone on the thyroid (Table 3) and the peripheral metabolism of the thyroid hormones have recently been reviewed.57 Amiodarone-induced hypothyroidism, which is due to excess iodine, occurs in up to 20 percent of patients in iodine-sufficient regions. Patients with preexisting thyroid autoimmunity are at increased risk for the development of hypothyroidism while receiving amiodarone. Treatment with levothyroxine sodium is indicated in hypothyroid patients, and amiodarone may be continued. The dose of levothyroxine sodium needed to normalize the serum concentration of thyrotropin is often higher than the usual dose, because amiodarone decreases 5'-deiodinase activity in peripheral tissues, thus also decreasing production of T3. Amiodarone-induced thyrotoxicosis occurs in up to 23 percent of patients receiving amiodarone and is far more prevalent in iodine-deficient regions.58 Type I amiodarone-induced thyrotoxicosis is defined as synthesis and release of excessive thyroid hormone; it is iodine-induced, and it is more likely to occur in patients with preexisting subclinical thyroid disorders, especially nodular goiter. Type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis that causes the release of preformed thyroid hormone from the damaged thyroid gland. Distinguishing between the two forms of amiodarone-induced thyrotoxicosis is difficult, especially since some patients have both types. In patients in the United States, 123I uptake values are typically low in type I and type II amiodarone-induced thyrotoxicosis. Color-flow Doppler ultrasonography may show hypervascularity in type I disease but reduced blood flow in type II.59 Although the serum interleukin-6 concentration was initially reported to be more elevated in type II amiodarone-induced thyrotoxicosis than in type I,60 subsequent studies have not replicated this finding. Type I amiodarone-induced thyrotoxicosis is best treated with high doses of antithyroid drugs (methimazole or propylthiouracil), sometimes with the addition of potassium perchlorate to prevent further uptake of iodine by the thyroid. Lithium has also been suggested as therapy for type I disease.61 Type II amiodarone-induced thyrotoxicosis responds to high-dose corticosteroids. Iopanoic acid has recently been reported to be effective in patients with type II amiodarone-induced thyrotoxicosis,62 although less so than corticosteroids,63 and in those with type I disease who require thyroidectomy.64 Careful examination of the thyroid, base-line thyroid-function tests, and measurements of serum concentrations of thyroid peroxidase and thyroglobulin antibodies should be performed before amiodarone therapy is instituted, and thyroid function should be monitored every six months as long as patients are receiving the drug (Figure 3). N Engl J Med 2003; 348:

32 AMIODARONA E HIPOTIROIDISMO
Incidencia 13% en áreas con ingestión alta de I. 6.4% en áreas con ingestión baja de I. Patogénesis Fracaso de la tiroides para escapar del efecto inhibitorio de Wolff-Chaikoff, siendo afectada por anormalidades subyacentes de la glándula tiroides (autoinmunidad), las mujeres con anticuerpos antiperoxidasa positivos tienen un riesgo aumentado en 7 veces. Amiodarone is a potent broad spectrum antiarrhythmic comprising 37% iodide. It has a strong affinity for intralysosomal phospholipids, inhibiting their degradation by phospholipases and leading to phospholipidosis and disturbances of lysosomal function. These inclusion bodies have been found in the lungs, liver, heart, skin, corneal epithelium, and peripheral nerves, which explains the toxic effects in many organs and the proportional relation between toxicity and duration of use and cumulative dosage.21 Sequential effects on thyroid homeostasis The sequential effects of amiodarone on thyroid homeostasis are: (a) amiodarone releases pharmacological quantities of iodide the standard maintenance dose of  mg/day releases  mg organic iodide (normal daily requirement  mg); (b) thyroid iodide uptake increases, peaking at 6 weeks. The chronic iodide excess transiently decreases thyroxine production (Wolff-Chaikoff effect), with a consequent increase in thyroid stimulating hormone concentrations; and (c) within 3 months the thyroid gland is free of this inhibitory effect, with normalisation of thyroxine production. In up to 50% of euthyroid patients on long term amiodarone, thyroid function tests may show minimal increases in thyroxine concentration, suppression of triiodothyronine, and sometimes suppression of thyroid stimulating hormone. These changes do not require further management apart from monitoring with thyroid function tests. Box 4 gives a brief review of thyroid dysfunction caused by amiodarone, with emphasis on the practical aspects and recent concepts.22 23 BMJ 1999;319:

33 AMIODARONA E HIPOTIROIDISMO
Diagnostico  TSH con T4  y T3   TSH no es diagnóstica de hipotiroidismo inducido por amiodarona en los primeros 3 meses de tratamiento (puede ser transitorio). Tratamiento Continuar amiodarona pero agregar L-tiroxina. Amiodarone is a potent broad spectrum antiarrhythmic comprising 37% iodide. It has a strong affinity for intralysosomal phospholipids, inhibiting their degradation by phospholipases and leading to phospholipidosis and disturbances of lysosomal function. These inclusion bodies have been found in the lungs, liver, heart, skin, corneal epithelium, and peripheral nerves, which explains the toxic effects in many organs and the proportional relation between toxicity and duration of use and cumulative dosage.21 Sequential effects on thyroid homeostasis The sequential effects of amiodarone on thyroid homeostasis are: (a) amiodarone releases pharmacological quantities of iodide the standard maintenance dose of  mg/day releases  mg organic iodide (normal daily requirement  mg); (b) thyroid iodide uptake increases, peaking at 6 weeks. The chronic iodide excess transiently decreases thyroxine production (Wolff-Chaikoff effect), with a consequent increase in thyroid stimulating hormone concentrations; and (c) within 3 months the thyroid gland is free of this inhibitory effect, with normalisation of thyroxine production. In up to 50% of euthyroid patients on long term amiodarone, thyroid function tests may show minimal increases in thyroxine concentration, suppression of triiodothyronine, and sometimes suppression of thyroid stimulating hormone. These changes do not require further management apart from monitoring with thyroid function tests. Box 4 gives a brief review of thyroid dysfunction caused by amiodarone, with emphasis on the practical aspects and recent concepts.22 23 BMJ 1999;319:

34 HIPOTIROIDISMO TRANSITORIO
Tiroiditis subaguda silenciosa (tiroiditis postparto) Tiroiditis autoinmune crónica Antisépticos conteniendo yodo. Hijos de madre con tiroiditis autoinmune crónica Tiroidectomía subtotal I131 Most patients with primary hypothyroidism require lifelong thyroxine therapy. There are, however, well-recognized situations in which hypothyroidism is transient. For example, during the recovery phase of subacute or painless thyroiditis (including postpartum thyroiditis),51 patients may have asymptomatic or mild hypothyroidism for a few weeks. Hypothyroidism caused by chronic autoimmune thyroiditis may remit spontaneously,52 particularly if excessive iodine intake has been implicated53. The use of iodine-containing antiseptics applied vaginally during labor54 or topically to the skin of newborn infants55 may result in transient hypothyroidism, and the condition may also occur in infants born to mothers with chronic autoimmune thyroiditis because of the transplacental passage of thyrotropin-receptor-blocking antibodies56. Patients with untreated or inadequately treated Addison's disease may have somewhat elevated serum thyrotropin concentrations that usually decline to the normal range during glucocorticoid-replacement therapy57. Hypothyroidism may also be transient after a subtotal thyroidectomy; the common failure to appreciate this possibility has led to unnecessary treatment and a falsely high estimate of the frequency of postoperative thyroid failure. A low serum thyroxine concentration and a high serum thyrotropin concentration, with or without associated features of mild hypothyroidism, occur in about 30 percent of patients three months after surgery, but by the sixth month the serum thyroxine concentration and usually the serum thyrotropin concentration have returned to normal levels in the majority of such patients58. A similar pattern of thyroid function may occur after treatment of hyperthyroidism with iodine Permanent hypothyroidism should therefore not be diagnosed before six months have elapsed since surgery or iodine-131 treatment of hyperthyroidism. If, for clinical reasons, thyroxine has to be prescribed earlier, it should be given in a suboptimal dose of 50 to 75 µg daily. Measurement of the serum thyroxine and thyrotropin concentrations at six months will indicate whether continued treatment with a higher dose is necessary (in the case of a raised serum thyrotropin concentration) or whether the thyroxine should be discontinued (in the case of a normal or low thyrotropin concentration); the patient should be reevaluated in four to six weeks. N Engl J Med 1994; 331:

35 HIPOTIROIDISMO EN EL ANCIANO

36 INTRODUCCIÓN Los trastornos tiroideos son frecuentes en las personas mayores de 60 años. La prevalencia del hipotiroidismo clínico es de 2-5% en mayores de 65 años, cifras que alcanzan 5-10% si se considera aquellas que presentan hipotiroidismo subclínico. Esta prevalencia aumenta con la edad y es más elevada en las mujeres.

37 INTRODUCCIÓN La disfunción tiroidea pasa desapercibida debido a sus escasas manifestaciones. Las pruebas bioquímicas empleadas se afectan por el uso de diversos medicamentos. Tanto la hipofunción como la hiperfunción tiroidea pueden ser muy graves en los adultos mayores o agravar problemas geriátricos.

38 ETIOLOGÍA Las causas del hipotiroidismo clínico y subclínico son similares en los ancianos y en personas jóvenes. La enfermedad de hashimoto La irradiación o extirpación de la tiroides El hipotiroidismo idiopático Puede aparecer hipotiroidismo transitorio tras la cirugía tiroidea o después del tratamiento con yoduro sódico radiactivo (131I) cuando la tiroides ha vaciado sus depósitos de hormona.

39 FISIOPATOLOGÍA La captación de yodo y la síntesis y secreción de hormonas tiroideas se reducen con la edad. La degradación periférica de T4 también disminuye. La capacidad fijadora de las proteínas transportadoras de T4 también experimenta reducción. La concentración de la fracción libre de la T4 no experimenta cambios significativos. La concentración de T3 demuestra una disminución gradual con el envejecimiento.

40 FISIOPATOLOGÍA Mayor discrepancia existe en la valoración de las concentraciones de TSH en la ancianidad. Los ancianos normales presentan una respuesta de TSH posterior al estímulo con TRH de al menos 3 μU/ml o la elevación al doble de las concentraciones basales. La glándula tiroides de los ancianos es más susceptible que la de las personas jóvenes a los efectos autoinmunes de la enfermedad de Hashimoto.

41 DIAGNÓSTICO CLÍNICO Y DE LABORATORIO
En los ancianos el hipotiroidismo es un gran simulador. Los síntomas suelen confundirse con los propios del envejecimiento. Los pacientes ancianos tienden a presentar muchos menos síntomas específicos. Muchos ancianos con hipotiroidismo presentan síndromes geriátricos inespecíficos: confusión anorexia pérdida de peso caídas incontinencia disminución de la movilidad

42 DIAGNÓSTICO CLÍNICO Y DE LABORATORIO
En ocasiones, aparecen derrames no inflamatorios en las articulaciones y en las cavidades pleural, pericárdica y peritoneal. El diagnóstico de hipotiroidismo constituye muchas veces un reto.

43

44 DIAGNÓSTICO CLÍNICO Y DE LABORATORIO
Cuadro clínico Se ha encontrado que menos de la tercera parte de ancianos con hipotiroidismo manifiestan signos y síntomas. Pueden predominar síntomas relacionados con: El aparato cardiovascular El aparato digestivo El sistema nervioso

45 DIAGNÓSTICO CLÍNICO Y DE LABORATORIO
El hipotiroidismo puede presentarse con manifestaciones clínicas inespecíficas o atribuibles al proceso de envejecimiento. Confusión mental Anorexia Acinesia Intolerancia al frío Somnolencia Estreñimiento Apatía Sequedad de la piel Ataxia o hiporreflexia

46 TRATAMIENTO

47 TERAPIA CON LEVOTIROXINA
Se recomienda el uso de preparaciones de levotiroxina de alta calidad. La bioequivalencia de las preparaciones de levotiroxina están basadas en las mediciones de T4 no en las concentraciones de TSH. Bioequivalencia no es igual a equivalencia terapéutica. Endocr Pract 2002;8: 461

48 TERAPIA CON LEVOTIROXINA
Muchas marcas de levotiroxina no son comparadas contra una formulación estándar. Preferiblemente el paciente debe recibir las misma marca durante todo su tratamiento. No usar Hormona tiroidea disecada Combinaciones de hormonas tiroideas Triyodotironina Endocr Pract 2002;8: 461

49 TERAPIA CON LEVOTIROXINA
Hipotiroidismo primario Carcinoma tiroideo Hipotiroidismo subclínico Thyroxine therapy is given to replace thyroid hormone secretion when it is deficient (hypothyroidism) and also in certain circumstances when suppression of thyrotropin secretion is considered to be of value, such as in patients with thyroid carcinoma. It is perhaps surprising that any problems are perceived, other than compliance, with a treatment that has been available in one form or another for over a century. However, the availability of increasingly sensitive assays for thyrotropin1 has led to controversy about the dose of thyroxine needed for replacement therapy and about the safety of long-term suppressive treatment. Other issues include whether patients with subclinical hypothyroidism (defined as an elevated serum thyrotropin concentration but a normal serum thyroxine concentration in an asymptomatic patient) should be treated or simply followed, the need for variations in the dose of thyroxine in patients with hypothyroidism, and the recognition of transient thyroid failure N Engl J Med 1994; 331:

50 FORMAS DE SUSTITUCIÓN Levotiroxina sódica
Combinación de tiroxina y triyodotironina Thyroxine, in the form of levothyroxine sodium, is the most widely prescribed treatment for hypothyroidism. Combinations of thyroxine and triiodothyronine are available as either synthetic preparations, such as liotrix, or preparations derived from animal thyroid glands, such as thyroid extract or thyroglobulin. Patients receiving combination therapy have a supraphysiologic rise in the serum triiodothyronine concentration several hours after taking the combined drugs, which may be associated with troublesome palpitations, and it is not sufficiently recognized that the serum thyroxine concentration should be in the lower part of the normal range, often leading to an inappropriate increase in dose. For these reasons, combination therapy cannot be recommended. The main advantage of treatment with thyroxine is that the serum concentration of triiodothyronine -- formed in extrathyroidal tissue from the ingested thyroxine -- is controlled physiologically, which may be of benefit during illness or fasting, when extrathyroidal production of triiodothyronine is usually decreased and the serum concentration is low N Engl J Med 1994; 331:

51 DOSIFICACIÓN Hace muchos años se inicio con 200-400 µg.
Se buscaba mantener la concentración de T4 arriba del rango normal para compensar la falta de T3. Las dosis disminuyeron al aparecer pruebas para TSH y cuando se entendió que la mayor parte de la T3 se derivaba de la deiodinación extratiroidea de T4. Before assays for thyrotropin were available, the recommended daily dose of thyroxine for patients with primary hypothyroidism was 200 to 400 microg. The appropriate dose for an individual patient was largely a matter of clinical judgment, although it was customary to maintain the serum total thyroxine concentration above the normal range as a compensation for the lack of triiodothyronine secretion by the thyroid. The recommended dose was reduced when serum thyrotropin assays became available and when it was realized that most triiodothyronine is produced by extrathyroidal deiodination of thyroxine. N Engl J Med 1994; 331:

52 DOSIFICACIÓN La dosis media de reemplazo es de 1.6 g/k/d.
Una dosis inicial de 50 µg al día se considera apropiada. La dosis se puede incrementar en intervalos de 3-4 semanas a µg. En menores de años y cuando el hipotiroidismo se ha desarrollado rápidamente y detectado temprano la dósis inicial puede ser de 100 µg. N Engl J Med 1994; 331:

53 DOSIFICACIÓN Tres o cuatro meses después se puede medir T4L, T4 total y TSH para ajustar la dosis. La dosis puede ser suspendida en casos necesarios por 7 días pero no mas de 2 semanas. The total daily secretion of thyroxine is related to body mass, but it is not customary to prescribe thyroxine in microgs per kilogram of body weight. In patients with uncomplicated primary hypothyroidism, an initial oral dose of 50 µg daily is appropriate, with the dose increased at intervals of three to four weeks to 100 and 150 µg daily as a single dose. In patients under 30 to 40 years of age and in those in whom hypothyroidism has developed rapidly and was detected early (e.g., patients who have undergone a thyroidectomy), the initial dose of thyroxine can be 100 µg daily. Three to four months after the start of treatment, measurement of the serum concentrations of free or total thyroxine and thyrotropin will dictate any need for a minor adjustment in the dose. Patients with hypothyroidism of long duration notice an improvement in well-being two to three weeks after starting treatment. Reductions in weight and puffiness and increases in the pulse rate and pulse pressure occur early in the treatment, but hoarseness, anemia, and changes in skin and hair may take many months to resolve. N Engl J Med 1994; 331:

54 SUSTITUCIÓN EXCESIVA Dosis que suprimen TSH  FC nocturna
Acorta el intervalo sistólico  excreción de Na urinario  actividad serica de enzimas musculares y hepáticas  concentraciones séricas de colesterol Substantial overtreatment with thyroxine results in clinical manifestations of hyperthyroidism. Does it matter whether the serum thyrotropin concentration is suppressed to a level of 0.1 mU per liter or lower with thyroxine therapy in otherwise healthy hypothyroid patients in whom there are no clinical features of hyperthyroidism? The secretion of thyrotropin is sensitive to very small changes in serum thyroxine and triiodothyronine concentrations, even within their respective normal ranges,5 but is the pituitary unique in this respect among target organs? In rats 50 percent of the triiodothyronine occupying nuclear receptors in the anterior pituitary is derived from intrapituitary monodeiodination of thyroxine, whereas in other organs, such as the liver and kidneys, only 20 percent of nuclear triiodothyronine is derived from intracellular thyroxine, with most coming from thyroxine in the circulation6. If these findings applied to humans, suppression of thyrotropin secretion would not necessarily be accompanied by changes indicative of excessive thyroxine and triiodothyronine in other target organs. As a result of treatment with thyroxine, the combination of a low serum thyrotropin concentration, a normal or raised thyroxine concentration, and a normal triiodothyronine concentration, known as subclinical hyperthyroidism, would therefore be of no clinical importance. Doses of thyroxine that suppress thyrotropin secretion, however, have more widespread effects, such as increasing the nocturnal heart rate, shortening the systolic time interval, increasing urinary sodium excretion and serum enzyme activities in the liver and muscles, and decreasing the serum cholesterol concentration7,8. These effects are similar to, but less marked than, those in overt hyperthyroidism. N Engl J Med 1994; 331:

55 SUSTITUCIÓN EXCESIVA  resorción ósea  concentración de calcio sérico
 concentración de PTH  la excreción de enlaces cruzados de piridinio  concentración sérica de osteocalcina In patients with hyperthyroidism and also, to a lesser extent, in those taking sufficient thyroxine to suppress thyrotropin secretion, bone resorption is increased, as indicated by increased serum calcium concentrations, decreased serum parathyroid hormone concentrations,10 and increased urinary excretion of pyridinium cross-links, which are specific markers of bone resorption11. Serum osteocalcin, a marker of bone formation, is increased in patients receiving suppressive doses of thyroxine, presumably as a result of the increase in bone resorption12. Therefore, a primary concern about overreplacement with thyroxine is its possibly deleterious effect on bone. Significant decreases in bone mineral density at various sites have been found in some but by no means all studies of pre- and postmenopausal women receiving long-term thyroxine therapy in doses sufficient to lower thyrotropin secretion to a level below the normal range,12,13,14,15,16,17,18,19,20,21,22 but there is no evidence of an increased rate of fracture4,23. N Engl J Med 1994; 331:

56 SUSTITUCIÓN INADECUADA
T4 , TSH  Rasgos clínicos de hipotiroidismo Incremento en la morbilidad Hipotiroidismo subclínico (TSH ) Si no hay datos de adherencia pobre se puede aumentar la dosis a g/día y reevaluar en 3 meses. N Engl J Med 1994; 331:

57 CAUSAS DE TSH AUMENTADA CON REEMPLAZO ADECUADO
Pobre cumplimiento Malabsorción Agentes farmacológicos  absorción Sucralfato Colestiramina Sulfato ferroso Hidroxido de aluminioo  Conversión de T4 a T3 Amiodarona Management of thyroid disorders usually requires prolonged, and often lifelong, courses of treatment. Hence adequate compliance is needed to achieve and maintain euthyroidism. The sensitive assay for thyroid stimulating hormone has advantages over assays for thyroxine, triiodothyronine, and free thyroxine, and both the free thyroxine index and older versions of the thyroid stimulating hormone radioimmunoassay. The sensitive assay helps to differentiate normal concentrations of thyroid stimulating hormone in euthyroid subjects from low concentrations (for example, hypothyroidism secondary to pituitary insufficiency, subclinical hyperthyroidism). The assay is also independent of changes in concentrations of thyroxine binding globulin, which occur, for example, during pregnancy and hormone replacement therapy.1 Poor compliance (box 1) is the most common cause of persistently increased thyroid stimulating hormone concentrations in patients who take excessive doses of thyroxine for their size or who have wide variations in thyroid function test results on the same dose of thyroxine (box 1). In the absence of clear evidence of malabsorption for example, with bowel bypass surgery or sprue there is no evidence that malabsorption of thyroxine exists as an isolated entity.2 Occasionally patients take multiple daily doses of thyroxine just before their follow up visit. This results in increased free thryoxine concentrations and an increased free thryoxine index but an inappropriately raised thyroid stimulating hormone concentration. As well as increased thyroid stimulating hormone concentrations, poor compliance with thyroxine can result in several challenging presentations.3 Several methods may improve compliance with treatment: (a) thyroid patient groups, by increasing the understanding of thyroid disease4; (b) education (particularly of the primary care team) so that the education of patients is improved5; and (c) thyroid registers for example, WAFUR and SAFUR, the Welsh and Scottish automated follow up registers respectively (patients are registered on a computer once they are both clinically and biochemically euthyroid then recalled annually for review and a thyroid function test, the results of which are reviewed centrally thereby limiting follow up only to those with abnormal test results). Funding registers, despite their proved cost effectiveness,6 remain a problem. In one study, 48% of patients taking thyroxine had abnormal thyroid stimulating hormone concentrations 27% high and 21% low concentrations. The relation between the prescribed thyroxine dose and the thyroid stimulating hormone concentration suggested that undertreatment and overtreatment were common and that these largely reflected inappropriate dosage rather than poor compliance (high concentrations were found in 47% of patients taking less than 100 µg thyroxine, whereas low concentrations were found in 24% of patients taking more than 100 µg thyroxine).7 Thyroid registers recall patients with abnormal thyroid function test results who become lost to follow up, thus reducing poor compliance or inappropriate dosage.8 The most important way of improving patient compliance is to simplify the treatment regimen for example, by widening the strength range of thyroxine tablets in hypothyroid patients so that the drug can be taken less frequently.9 More hyperthyroid patients (83%) were compliant when taking methimazole once daily than when taking propylthiouracil every 8 hours (53%).10 It should be noted that patients receiving thyroxine may have total or free thyroxine concentrations above the normal reference range of the laboratory. This should not be taken as indicating a reduction in thyroxine dose, especially if the patient is clinically euthyroid and has normal thyroid stimulating hormone concentrations. BMJ 1999;319:

58 HIPOTIROIDISMO MATERNO
Frecuencia Clínico 0.3%-0.5%, Subclínico 2%-3% 2.5% (TSH > 6 mUI/L) SG Clin Endocrinol (Oxf). 35:41–46 0.3% (TSH ↑ y T4 ↓) Clin Endocrinol (Oxf). 35:41–46 2.2% (TSH ↑), 19 % antiTPO (+) Endocr Rev. 18:404–433 0.14% mujeres japonesas N Engl J Med. 341:2016 Hypothyroidism in Pregnancy: Consequences to Neonatal Health The Journal of Clinical Endocrinology & Metabolism 2001 Vol. 86, No Maternal hypothyroidism The frequency of mild and overt hypothyroidism among pregnant women was described by Klein et al. (10), who found a serum TSH level greater than 6 mIU/L in 2.5% (49 of 2,000) of women at 15–18 weeks gestation. Overt hypothyroidism (i.e. an elevated serum TSH plus a T4 2.5 SD below the mean or lower) was present in 0.3% of women. Glinoer (2) found an elevated serum TSH concentration in 2.2% of 1,900 pregnant women. Sixteen of those 41 (19%) women had anti-TPO antibodies. In contrast, Fukushi et al. (22) detected a high serum TSH concentration in only 0.14% (102 of 70, 632) of Japanese women. In North America, maternal hypothyroidism is mainly due to autoimmune thyroid disease. Untreated hypothyroidism is associated with several complications, most notably preeclampsia and low birth weight, but also abruptio placentae and increased risk of spontaneous miscarriage and perinatal mortality. Treatment with L-thyroxine reduces the complications substantially (23). Although effects of maternal hypothyroidism on fetal brain development are not well defined, several recent reports indicate that IQ is modestly affected (24, 25, 26). These studies have increased the concern that even mild hypothyroidism can interfere with normal brain development. Indeed, several authors have proposed screening programs for thyroid dysfunction during or even before pregnancy. The economic impact is not inconsequential, and so it is important to understand not only the underlying potential problems but also the goals of intervention. Man et al. (24), in the 1970s, studied the effects of hypothyroidism and thyroid hormone replacement on IQ. Using the butanol extractable iodine (BEI) test as a measure of serum T4, they found that 3% of 1349 pregnant Rhode Island women were "hypothyroxinemic" (low BEI). Mean IQ of their offspring at 4 and 7 yr was lower by 6 and 5 points, respectively, than children of euthyroid women. At age 7, the IQs of children whose mothers had a low BEI were less than 80 in 24% vs. only 10% of control children. Furthermore, thyroid hormone therapy apparently prevented these effects on IQ. The iodine status and prevalence of thyroid autoimmunity in these mothers were not studied. In 1999, Pop et al. (25) tested mental and psychomotor development in month-old infants living in The Netherlands, an iodine-sufficient country. They found that if the mother’s free T4 was in the lowest 10th percentile at 12 weeks gestation, the infants had increased risk of delayed psychomotor development (relative risk, 5.8). These mothers were three times as likely to be TPO antibody positive (25% vs. 8%). However, there were other potential factors beyond hypothyroxinemia that may have contributed to the neurocognitive abnormalities described. Major depression, a known risk factor for impaired childhood development, was present in some mothers. In a previous study, those authors reported that impaired development based on the Gestalt Cognitive Scale at 5 yr of age was observed in children whose mothers were anti-TPO antibody positive but with entirely normal thyroid function (27). The same year, Haddow et al. (26) did neuropsychological testing in 62 offspring (of 25,216 women screened) whose mothers were retrospectively found to have a serum TSH greater than the 99.7th percentile (n = 47) or a TSH at the 98–99.6th percentiles with T4 less than 7.75 µg/dL (n = 15). Mean total and free T4 levels were also 30% lower in the hypothyroid mothers. Forty-eight of the 62 women received no L-thyroxine during pregnancy. The IQs of children born to affected mothers were 7 points lower than those of controls. Furthermore, the full scale IQ was less than 85 in 19% of affected offspring vs. 5% born to euthyroid mothers. Fourteen mothers had been treated with an inadequate dose of thyroid hormone during pregnancy with resulting serum TSH and free T4 levels that were similar to the 48 untreated women. Nevertheless, the mean IQ of children born to treated mothers was normal, and no child had an IQ less than 85. TPO antibody was present in 77% of the 62 hypothyroid women and in 14% of 125 control women. A recent report by Smit et al. (28) described the status of infants whose mothers had subclinical hypothyroidism. They found a decrease in the mental development index at 6 and 12 months, but not 24 months. Psychomotor development and neurophysiologic and neurologic assessments were unaffected. There is one study showing no effect of severe first trimester hypothyroidism (low T4: TSH, 25–190 mU/L) when mothers had normal thyroid function later in pregnancy and children had IQ tests at age 4–10 yr (29). The importance of monitoring pregnant women with known thyroid dysfunction, including those being treated with L-thyroxine, has been recognized for more than 10 yr. A recent review of 17 articles found that 10.0% (range, 2.8–19.6) of 12,592 women were positive for microsomal or TPO antibody during or shortly after pregnancy (30). Many of these women may have decreased thyroid reserve that would lead to maternal and fetal hypothyroidism in the setting of an increase in T4 catabolism during pregnancy. Furthermore, many women with known hypothyroidism that is being treated will have a substantially increased T4 dose requirement (31). In our review of four series (total of 108 women), serum TSH increased in 58%. The mean L-thyroxine dose increased from 117 µg to 150 µg (Table 2 ). J. Clin. Endocrinol. Metab., June 1, 2001; 86(6):

59 HIPOTIROIDISMO Y EMBARAZO
Causas Fetal Congénita Fármacos antitiroideos Prematuridad Materna y Fetal Deficiencia de yodo (leve/moderado, severa) Materna (clínico, subclínico) Autoinmunidad (principal), hipofisitis linfocítica, tratamiento para hipertiroidismo Postiroidectomía Factores de riesgo DM Deficiencia de yodo Ablación o cirugía tiroidea Historia de enfermedad tiroidea Bocio Historia de abortos espontáneos Síntomas Hypothyroidism in Pregnancy: Consequences to Neonatal Health The Journal of Clinical Endocrinology & Metabolism 2001 Vol. 86, No Abnormal thyroid gland function may be restricted to the fetus, the expectant mother, or both (Table 1 ). Fetal hypothyroidism can be permanent or transient. When transient, it results from transplacental passage of autoantibodies or drugs, or to immaturity of the HPT axis in premature infants. Combined maternal and fetal hypothyroidism is almost always due to iodine deficiency (2, 3, 6), but thyroid-binding inhibitory immunoglobulin (TBII) has been implicated on occasion (9). Severe maternal hypothyroidism is not common, but mild thyroid failure in which the serum TSH is elevated with a normal free T4 level has been reported in 2.5% of pregnancies (10). The impact of severe iodine deficiency or congenital hypothyroidism on the fetus and newborn is profound, as are the effects of overt maternal hypothyroidism on pregnancy. The severity, timing of onset and duration, as well as postnatal management, all influence fetal and neonatal brain development. It is now believed than even mild maternal hypothyroidism (from mild iodine deficiency, thyroid autoimmunity, or thyroid under-replacement) may affect fetal brain development. The implications of this finding are yet to be clearly defined, but have raised many questions that need resolution. J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): J. Clin. Endocrinol. Metab., Jan 2007; 92:

60 REPERCUSIONES DEL HIPOTIROIDISMO EN EMBARAZO
MATERNAS Disminución de la fertilidad. Riesgo aumentado de abortos Anemia Hipertensión gestacional Abruptio placentae Hemorragia postparto FETALES Parto prematuro Peso bajo al nacer Distress respiratorio Muerte fetal y perinatal Repercussions of hypothyroidism on pregnancy: maternal aspects. There is a known association between hypothyroidism and decreased fertility, although hypothyroidism does not preclude the possibility to conceive. In a study by Abalovich et al. (2 ), 34% of hypothyroid women became pregnant without treatment: 11% of them had OH and 89% SCH. When hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for early and late obstetrical complications, such as increased prevalence of abortion, anemia, gestational hypertension, placental abruption, and postpartum hemorrhages. These complications are more frequent with OH than with SCH and, most importantly, adequate thyroxine treatment greatly decreases the risk of a poorer obstetrical outcome ( ). Repercussions of hypothyroidism on pregnancy: fetal aspects. Untreated maternal OH is associated with adverse neonatal outcomes including premature birth, low birth weight, and neonatal respiratory distress. Increased prevalence of fetal and perinatal death has also been described, although it has not been confirmed in all studies. Obstetrical adverse effects such as gestational hypertension may also contribute to the overall increase in neonatal risks ( ). Though less frequent than with OH, complications have also been described in newborns from mothers with SCH. Casey et al. (2 ) screened pregnant women before 20 wk gestation and reported a doubling of the rate of preterm delivery in those with SCH. Stagnaro-Green et al. (2 ) compared the thyroid status of women with preterm delivery to matched controls who delivered at term and showed that women with very preterm deliveries (before 32 wk) had a 3-fold increase in SCH. In a recent prospective randomized intervention trial by Negro et al. (2 ), the authors reported a significant decrease in the rate of preterm delivery among thyroid-antibody-positive women who had been treated with thyroxine, compared with thyroid-antibody-positive women who did not receive thyroxine administration and in whom thyroid function showed a gradual evolution toward SCH during gestation J. Clin. Endocrinol. Metab., Aug 2007; 92: s1 - s Endocrine Reviews 1997,18 (3):

61 HIPOTIROIDISMO SUBCLÍNICO EN EL EMBARAZO
Mujeres hipotiroideas son relativamente menos fértiles 34% de hipotiroideas se embarazan: 11% HC, 89% HSC Hipotiroidismo en embarazo 0.3%-0.7%. Mas frecuente en embarazadas con DMT1 Ac antitiroideos (+) Ac antitiroideos son 5 veces más frecuentes en hipotiroidismo subclínico. III. Pathological Alterations of Thyroidal Regulation Associated with Pregnancy B. Hypothyroidism and pregnancy 3. Subclinical hypothyroidism in pregnancy. As already alluded to above, maternal hypothyroidism is considered uncommon or even rare in pregnancy because hypothyroid women are relatively less fertile (216, 217, 218). The frequency of established hypothyroidism in pregnancy is not clearly known, but conservative estimates suggest a prevalence of 0.3–0.7%, compared with 0.6–1.4% in the general population (219). In such women, if hypothyroidism has been diagnosed before gestation starts, appropriate measures to maintain euthyroidism can be implemented. Perhaps as important (but more subtle) is undisclosed subclinical hypothyroidism in pregnant women. Three sets of studies have addressed this question and are of great value to evaluate its clinical relevance. Subclinical hypothyroidism has been shown to occur more frequently in pregnant women with type I diabetes, who had normal serum TSH levels before conception (a significant proportion of them display thyroid antibody positivity) (220, 221). Also, Klein et al. (222) carried out a retrospective study on a serum data bank from 2,000 consecutive pregnant women in Maine at 15–18 weeks of gestation. The authors showed that 2.5% of all pregnant women had supranormal TSH concentrations (above 6 mU/liter), with one tenth of them exhibiting overt hypothyroidism. They also found that the prevalence of positive thyroid antibodies in women with subclinical hypothyroidism was 5-fold more frequent than in control pregnant women. We have investigated prospectively the occurrence of previously undiagnosed subclinical hypothyroidism (150). Among 1,900 consecutive pregnant women who attended the prenatal clinic for the first visit between June 1990 and December 1992 and who were systematically screened by determining serum TSH concentrations and thyroid antibody positivity, 41 women had an elevation of serum TSH, thus yielding an overall prevalence of 2.2% (comparable to the 2.5% prevalence reported by Klein et al.). Serum TSH ranged between 4 and 20 mU/liter; in most instances, the TSH elevation was initially mild, below 10 mU/liter. Free T4 concentrations were not systematically subnormal but tended to cluster near the lower limits of normal. We considered these women as having "asymptomatic" subclinical hypothyroidism. In all women for whom a TRH test was carried out, the TSH response was markedly exaggerated (average increment in TSH: 31 ± 5 mU/liter). These women were systematically given L-T4(50–125 µg/day) throughout gestation, a treatment that resulted in a clear-cut improvement in thyroid function parameters. In four patients, a spontaneous miscarriage occurred before the therapeutic intervention could be implemented (as will be discussed later, spontaneous miscarriage occurs with a greater frequency in such women). In 16 of the 41 women (40%), the cause of hypothyroidism clearly was related to thyroid autoimmunity, with thyroperoxidase antibody (TPO-Ab) titers between 400 and 5,000 U/ml. In the remainder, the etiology of hypothyroidism could not be determined in the absence of detectable antibody titers or a family history of goiter or hypothyroidism. Thyroid ultrasonography, however, when performed in these women, showed that one quarter of them had a reduced volume, below 7 ml, strongly suggesting thyroid hypotrophy. Women with thyroid hypotrophy before pregnancy presumably have a sufficient functional reserve for the thyroid gland to function adequately before gestation (hence allowing them to become pregnant), but not after establishment of the pregnant state. An argument in favor of this hypothesis is our observation that, when monitored during the postpartum period, thyroid function reverted to normal despite withdrawal of L-T4 (personal unpublished information). Thus, at least two population-based surveys, carried out in areas with different iodine intake, suggest a 2.5% overall prevalence of compensated or uncompensated hypothyroidism during pregnancy. Additional studies are warranted because many important questions remain unanswered. For instance, it is not known whether a mild decrease of maternal thyroid function predisposes to an increased risk of obstetrical complications or impaired fetal brain development. Furthermore, there have been no follow-up studies of thyroid function in affected women after parturition or during subsequent pregnancies. Endocrine Reviews 1997,18 (3):

62 CARACTERISTICAS MATERNAS DE HIPOTIROIDISMO SUBCLÍNICO
Características maternas Hipotiroidismo subclínico (N= 404) TSH normal (N=15,689) P Edad (años) 26.9  5.9 25.5  5.6 < .001  35 a 4 (11) 1,161 (7) .009 Raza o etnicidad Hispana 341 (84) 13,472 (86) Afroamericana 27 (7) 1,588 (10) Blanca 16 (4) 321 (2) Otra 20 (5) 308 (2) Nuliparidad 145 (36) 5,672 (36) .915 Semana de reclutamiento 12.2  4.0 11.9  3.8 .211 IMC (k/m2) 32.1  6.3 31.7  5.5 .163 Subclinical Hypothyroidism and Pregnancy Outcomes BACKGROUND: Clinical thyroid dysfunction has been associated with pregnancy complications such as hypertension, preterm birth, low birth weight, placental abruption, and fetal death. The relationship between subclinical hypothyroidism and pregnancy outcomes has not been well studied. We undertook this prospective thyroid screening study to evaluate pregnancy outcomes in women with elevated thyrotropin (thyroid-stimulating hormone, TSH) and normal free thyroxine levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than ng/dL were retrospectively identified with subclinical hypothyroidism. Pregnancy outcomes were compared with those in pregnant women with normal TSH values between the 5th and 95th percentiles. RESULTS: A total of 25,756 women underwent thyroid screening and were delivered of a singleton infant. There were 17,298 (67%) women enrolled for prenatal care at 20 weeks of gestation or less, and 404 (2.3%) of these were considered to have subclinical hypothyroidism. Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1–8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1–2.9). CONCLUSION: We speculate that the previously reported reduction in intelligence quotient of offspring of women with subclinical hypothyroidism may be related to the effects of prematurity Subclinical hypothyroidism has a prevalence of 2% to 5% in pregnant women.8,9,10 Concerns that mild maternal thyroid hormone deficiency might be harmful to embryofetal brain development were addressed in several recent landmark studies in Pop and colleagues11 found that during pregnancy maternal free thyroxine levels less than the 10th percentile at 12 weeks of gestation, but not at 32 weeks, were associated with a significant 5.8-fold risk for impaired psychomotor development in infants evaluated at 10 months of age. These findings were later confirmed through developmental testing of a cohort of these children at ages 1 and 2 years.12 Haddow and colleagues13 reported that children of women whose TSH levels were elevated during the midtrimester of pregnancy had a slight but significant reduction in intelligence quotient scores between 7 and 9 years of age when compared with infants of euthyroid women. Women with TSH values more than 10 mU/L also had significantly more stillborn infants.14 Somewhat related are previous reports that subclinical maternal hypothyroidism might be associated with poor pregnancy outcomes such as placental abruption, preterm birth, and low birth weight infants.4,5 To further elucidate these observations, we designed this prospective screening study of a large obstetric population to evaluate pregnancy outcomes in women with subclinical hypothyroidism Women with subclinical hypothyroidism are compared with 15,689 pregnant controls identified with TSH values between the 5th and the 95th percentiles in Table 1. The incidence of subclinical hypothyroidism was higher in white women and those classified as "Other" ethnicity. Also, women with subclinical hypothyroidism were significantly older than control women. For example, 11% of women with an elevated TSH value were aged 35 years or greater compared with only 7% of healthy controls. (P = .009). There was no difference between the groups in relation to parity or body mass index. The gestational age at screening was similar between the 2 groups There are several important findings from this prospective analysis of more than 17,000 women who underwent screening for abnormal thyroid function during the first half of pregnancy. First, subclinical hypothyroidism was identified in 2.3% of the population tested, and this corresponds with virtually all previous reports.8,9,14 Second, women with subclinical hypothyroidism had a significant, almost 2-fold higher incidence of preterm delivery at or before 34 weeks of gestation. A third finding was a significant 3-fold increase in the incidence of placental abruption in women in the subclinical hypothyroid group compared with healthy controls. Related to the second 2 findings, the proportion of infants of hypothyroid mothers admitted to the neonatal intensive care unit, as well as those who developed respiratory distress syndrome, was significantly doubled when compared with infants of euthyroid women Table 1. Maternal Characteristics of Women Who Underwent Thyroid-Stimulating Hormone Screening at or Before 20 Weeks of Gestation Los valores están en DE  o %. Se comparan mujeres con TSH en o arriba del percentil 95 y T4L normal (hipotiroidismo subclínico) con mujeres cuyos valores de TSH están entre el 5 y 95 percentil (normal) Obstet. Gynecol., February 1, 2005; 105(2):

63 RELACIÓN ENTRE LA CONCENTRACIÓN DE HORMONAS MATERNAS Y EL DESARROLLO CEREBRAL
Aumento del riesgo de deterioro del índice de desarrollo neurosicologico Disminución de IQ al menos 7 puntos menos comparados con hijos de mujeres sanas o adecuadamente tratadas con LT4. La deficiencia de yodo puede provocar una reducción de 13.5 puntos del IQ en las funciones neuromotoras y cognitivas. Maternal thyroid hormones and fetal brain development. A large body of evidence strongly suggests that thyroid hormone is an important factor contributing to normal fetal brain development (2 2 2 ). At early gestational stages, the presence of thyroid hormones in fetal structures can only be explained by transfer of maternal thyroid hormones to the fetal compartment, because fetal production of thyroid hormones does not become efficient until mid-gestation. Thyroid hormone and specific nuclear receptors are found in fetal brain at 8 wk after conception (2 ). Physiological amounts of free T4 are found in the coelomic and amniotic fluids bathing the developing embryo in the first trimester (2 ). Studies of different cerebral areas in human fetuses indicated the presence of increasing concentrations of T4 and T3 by 11–18 wk after conception (2 ). The ontogenic patterns of thyroid hormone concentrations and the activity of iodothyronine deiodinases show a complex interplay between the changing activities of the specific D2 and D3 iodothyronine deiodinases during gestation. This dual enzymatic system is interpreted to represent a regulatory pathway that fine-tunes the availability of T3 required for normal brain development and avoids, at the same time, the presence of excessive amounts of T3 (2 2 2 ). Clinical studies on the role of maternal hypothyroidism for the psychoneurological outcome in the progeny. Because of the heterogeneity of what is commonly referred to as gestational "hypothyroidism," different clinical conditions must be considered. Thyroid insufficiency varies widely with regard to time of onset (first trimester vs. later), degree of severity (SCH vs. OH), progressive aggravation with gestation time (depending on the cause), and adequacy of treatment. To reconcile these variable clinical conditions into a global view of the repercussions of maternal hypothyroidism on the progeny is difficult. However, a common pattern clearly emerges. Overall, the results showed that there was a significantly increased risk of impairment in neuropsychological developmental indices, IQ scores, and school learning abilities in the offspring of hypothyroid mothers. Three decades ago Evelyn Man and colleagues (2 2 2 ) published a series of articles suggesting that children born to mothers with inadequately treated hypothyroidism had significantly reduced IQs. However, the first large-scale prospective study on the outcome of children born to mothers with hypothyroidism during pregnancy was reported by Haddow et al. in 1999 (2 ). In this study, the severity of hypothyroidism varied from OH to probable SCH among the women whose children were investigated at school age. The main finding on extensive neuropsychological testing was that children born to untreated hypothyroid women had, on the average, an IQ score that was fully 7 points below the mean IQ of children born to healthy women and thyroxine-treated women. Furthermore, there were three times as many children with IQs that were 2 SD scores below the mean IQ of controls in the children born to untreated hypothyroid women. The study indicated that undisclosed and untreated hypothyroidism (and probable SCH) during pregnancy was associated with a risk of a poorer outcome in the progeny and a 3-fold increased predisposition for having learning disabilities. Although still unpublished, a large set of data were reported at the 2004 annual meeting of the American Thyroid Association by Rovet et al. (2 ). The interest of this remarkable work is double. First, the authors investigated children born to women who had been treated for hypothyroidism during pregnancy, but in whom thyroxine administration was suboptimal (mean TSH between 5 and 7 mIU/liter). Second, the children were followed up and tested with extremely refined techniques up to 5 yr of age. Results were that some components of intelligence were affected, whereas others were not. At preschool age, the study-case children had a mild reduction in global intelligence that was inversely correlated with third trimester’s maternal TSH. On the other hand, there was no negative impact on language, visual-spatial ability, fine motor performance, or preschool ability. The conclusion was that the offspring of women with suboptimally treated maternal hypothyroidism may be at risk for subtle and selective clinically relevant cognitive deficits, which depend specifically on severity and timing of inadequate maternal thyroid hormone availability. A Dutch study investigated the developmental outcome in children born to women with early (first trimester) isolated low T4 levels (i.e. a serum free T4 < 10.4 pmol/liter, in the lowest 10th decile of "normal" pregnant T4 values, with normal TSH) (2 ). Results suggested that early maternal low free T4 was associated with a lower developmental index in the children at approximately 10 months of age. The same authors later published a second study based on similar selection criteria, but with a larger cohort and more refined motor and mental evaluations in infants aged 1 and 2 yr (2 ). Results were that children born to mothers with prolonged low T4 (until wk 24 or later) showed an 8- to 10-point deficit for motor and mental development. Of interest, infants of women with early low T4, whose free T4 level recovered spontaneously to normal later in gestation, had a normal development, suggesting that prolonged low T4 was needed to impair fetal neuro-development. Neural development in ID. The consequences of maternal hypothyroidism on the progeny must be considered separately because ID exposes both mother and fetus to thyroid underfunction (2 ). In a meta-analysis of 19 studies of infants’ outcome in relation to ID, a significant downward shift of the frequency distribution of IQs was evidenced, with a mean 13.5 IQ points reduction in neuro-motor and cognitive functions (2 ). Because that meta-analysis encompassed conditions with more or less severe ID, the results cannot be fully extrapolated to mild-moderate ID. For this reason, the main results of seven studies (reported between 1989 and 1996) that have investigated the late outcome in children born to mothers with mild-moderate ID are summarized in Table 1 ( ). Finally, a recent publication on the outcome of children born to mothers with ID during pregnancy, carried out in Sicily in an area with mild-moderate ID, indicated that the children had a greater than 10-point average deficit in global IQ. Furthermore, the study also pointed to attention deficit and hyperactivity disorder, which was found in 69% of the children born to mothers who had gestational hypothyroxinemia (2 ). J. Clin. Endocrinol. Metab., Aug 2007; 92: s1 - s47

64 HIPOTIROIDISMO Y EMBARAZO The Endocrine Society
HIPOTIROIDISMO Y EMBARAZO The Endocrine Society. The Latin American Thyroid Society, Asia and Oceania Thyroid Society, American Thyroid Association, t European Thyroid Association, and the American Association of Clinical Endocrinologists Mayor aporte de I (250 /d) a embarazadas y lactantes. Hipotiroidismo clínico y subclínico efectos adversos en el embarazo y feto Corregir el hipotiroidismo antes del embarazo. Tratar hipotiroidismo subclínico. A. The USPSTF strongly recommends that clinicians provide (the service) to eligible patients. The USPSTF found good evidence that (the service) improves important health outcomes and concludes that benefits substantially outweigh harms. B. The USPSTF recommends that clinicians provide (the service) to eligible patients. The USPSTF found at least fair evidence that (the service) improves important health outcomes and concludes that benefits outweigh harms. C. The USPSTF makes no recommendation for or against routine provision of (the service). The USPSTF found at least fair evidence that (the service) can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. D. The USPSTF recommends against routinely providing (the service) to asymptomatic patients. The USPSTF found good evidence that (the service) is ineffective or that harms outweigh benefits. I. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing (the service). Evidence that (the service) is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined. The USPSTF grades the quality of the overall evidence for a service on a three-point scale (good, fair, or poor), defined as follows: Good: Evidence includes consistent results from well designed, well conducted studies in representative populations that directly assess effects on health outcomes. Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes. In addition to the USPSTF grading of recommendations, we have also included the appropriate recommendation level as indicated by the GRADE system. The value of an evidence-based recommendation, using the GRADE system, is scored from strong to moderate (1–2) and accompanied by symbols indicating the value of the evidence: high (1, or ), moderate (2, ), low ( ), and very low ( ). (There are no equivalents in the GRADE system for the recommendation levels C, D, and I used in the USPSTF system.) J. Clin. Endocrinol. Metab., Aug 2007; 92: s1 - s47

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