Posted by sdb on July 15, 2007, at 0:05:43
In reply to Re: treatments hashimoto etc. }} Phillipa » sdb, posted by Phillipa on July 14, 2007, at 22:10:16
> Thanks sdb I copied and pasted it and filed it. Love Jan so much work for me.
No problem, here is more information from harrison's. If you're interested in treatment then look this chapture.
love sdb, busy...
AUTOIMMUNE HYPOTHYROIDISM
Classification
Autoimmune hypothyroidism may be associated with a goiter (Hashimoto's, or goitrous thyroiditis) or, at the later stages of the disease, minimal residual thyroid tissue (atrophic thyroiditis). Because the autoimmune process gradually reduces thyroid function, there is a phase of compensation when normal thyroid hormone levels are maintained by a rise in TSH. Though some patients may have minor symptoms, this state is called subclinical hypothyroidism or mild hypothyroidism. Later, free T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage (usually TSH > 10 mU/L), which is referred to as clinical hypothyroidism or overt hypothyroidism.
Prevalence
The mean annual incidence rate of autoimmune hypothyroidism is up to 4 per 1000 women and 1 per 1000 men. It is more common in certain populations, such as the Japanese, probably because of genetic factors and chronic exposure to a high-iodine diet. The mean age at diagnosis is 60 years, and the prevalence of overt hypothyroidism increases with age. Subclinical hypothyroidism is found in 6 to 8% of women (10% over the age of 60) and 3% of men. The annual risk of developing clinical hypothyroidism is about 4% when subclinical hypothyroidism is associated with positive TPO antibodies.
Pathogenesis
In Hashimoto's thyroiditis, there is a marked lymphocytic infiltration of the thyroid with germinal center formation, atrophy of the thyroid follicles accompanied by oxyphil metaplasia, absence of colloid, and mild to moderate fibrosis. In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte infiltration is less pronounced, and thyroid follicles are almost completely absent. Atrophic thyroiditis likely represents the end stage of Hashimoto's thyroiditis rather than a distinct disorder.
As with most autoimmune disorders, susceptibility to autoimmune hypothyroidism is determined by a combination of genetic and environmental factors, and the risk of either autoimmune hypothyroidism or Graves' disease is increased among siblings. HLA-DR polymorphisms are the best documented genetic risk factors for autoimmune hypothyroidism, especially HLA-DR3, -DR4, and -DR5 in Caucasians. A weak association also exists between polymorphisms in CTLA-4, a T cell–regulating gene, and autoimmune hypothyroidism. Both of these genetic associations are shared by other autoimmune diseases, which may explain the relationship between autoimmune hypothyroidism and other autoimmune diseases, especially type 1 diabetes mellitus, Addison disease, pernicious anemia, and vitiligo (Chap. 330). HLA-DR and CTLA-4 polymorphisms account for approximately half of the genetic susceptibility to autoimmune hypothyroidism. The other contributory loci remain to be identified. A gene on chromosome 21 may be responsible for the association between autoimmune hypothyroidism and Down syndrome. The female preponderance of thyroid autoimmunity is most likely due to the effects of sex steroids on the immune response, but an X chromosome–related genetic factor is also possible, which may account for the high frequency of autoimmune hypothyroidism in Turner syndrome. Environmental susceptibility factors are also poorly defined at present. A high iodine intake may increase the risk of autoimmune hypothyroidism by immunologic effects or direct thyroid toxicity. There is no convincing evidence for a role of infection, except for the congenital rubella syndrome, in which there is a high frequency of autoimmune hypothyroidism. Viral thyroiditis does not induce subsequent autoimmune thyroid disease.
The thyroid lymphocytic infiltrate in autoimmune hypothyroidism is composed of activated CD4+ and CD8+ T cells, as well as B cells. Thyroid cell destruction is believed to be primarily mediated by the CD8+ cytotoxic T cells, which destroy their targets by either perforin-induced cell necrosis or granzyme B–induced apoptosis. In addition, local T cell production of cytokines, such as tumor necrosis factor (TNF), IL-1, and interferon (IFN) γ, may render thyroid cells more susceptible to apoptosis mediated by death receptors, such as Fas, which are activated by their respective ligands on T cells. These cytokines also impair thyroid cell function directly, and induce the expression of other proinflammatory molecules by the thyroid cells themselves, such as cytokines, HLA class I and class II molecules, adhesion molecules, CD40, and nitric oxide. Administration of high concentrations of cytokines for therapeutic purposes (especially IFN-α) is associated with increased autoimmune thyroid disease, possibly through mechanisms similar to those in sporadic disease.
Antibodies to Tg and TPO are clinically useful markers of thyroid autoimmunity, but any pathogenic effect is restricted to a secondary role in amplifying an ongoing autoimmune response. TPO antibodies fix complement, and complement membrane attack complexes are present in the thyroid in autoimmune hypothyroidism. However, transplacental passage of Tg or TPO antibodies has no effect on the fetal thyroid, which suggests that T cell–mediated injury is required to initiate autoimmune damage to the thyroid. Up to 20% of patients with autoimmune hypothyroidism have antibodies against the TSH-R, which, in contrast to TSI, do not stimulate the receptor but prevent the binding of TSH. These TSH-R-blocking antibodies therefore cause hypothyroidism and, especially in Asian patients, thyroid atrophy. Their transplacental passage may induce transient neonatal hypothyroidism. Rarely, patients have a mixture of TSI- and TSH-R-blocking antibodies, and thyroid function can oscillate between hyperthyroidism and hypothyroidism as one or the other antibody becomes dominant. Predicting the course of disease in such individuals is difficult, and they require close monitoring of thyroid function. Bioassays can be used to document that TSH-R-blocking antibodies reduce the cyclic AMP–inducing effect of TSH on cultured TSH-R-expressing cells, but these assays are difficult to perform. Assays that measure the binding of antibodies to the receptor by competition with radiolabeled TSH [TSH-binding inhibiting immunoglobulins (TBII)] do not distinguish between TSI- and TSH-R-blocking antibodies, but a positive result in a patient with spontaneous hypothyroidism is strong evidence for the presence of blocking antibodies. The use of these assays does not generally alter clinical management, although they may be useful to confirm the cause of transient neonatal hypothyroidism.
Clinical Manifestations
The main clinical features of hypothyroidism are summarized in Table 320-5. The onset is usually insidious, and the patient may become aware of symptoms only when euthyroidism is restored. Patients with Hashimoto's thyroiditis may present because of goiter rather than symptoms of hypothyroidism. The goiter may not be large but is usually irregular and firm in consistency. It is often possible to palpate a pyramidal lobe, normally a vestigial remnant of the thyroglossal duct. Rarely, uncomplicated Hashimoto's thyroiditis is associated with pain.
Patients with atrophic thyroiditis, or the late stage of Hashimoto's thyroiditis, present with symptoms and signs of hypothyroidism. The skin is dry, and there is decreased sweating, thinning of the epidermis, and hyperkeratosis of the stratum corneum. Increased dermal glycosaminoglycan content traps water, giving rise to skin thickening without pitting (myxedema). Typical features include a puffy face with edematous eyelids and nonpitting pretibial edema (Fig. 320-4). There is pallor, often with a yellow tinge to the skin due to carotene accumulation. Nail growth is retarded, and hair is dry, brittle, difficult to manage, and falls out easily. In addition to diffuse alopecia, there is thinning of the outer third of the eyebrows, although this is not a specific sign of hypothyroidism.
Other common features include constipation and weight gain (despite a poor appetite). In contrast to popular perception, the weight gain is usually modest and due mainly to fluid retention in the myxedematous tissues. Libido is decreased in both sexes, and there may be oligomenorrhea or amenorrhea in long-standing disease, but menorrhagia is also common. Fertility is reduced and the incidence of miscarriage is increased. Prolactin levels are often modestly increased (Chap. 318) and may contribute to alterations in libido and fertility and cause galactorrhea.
Myocardial contractility and pulse rate are reduced, leading to a
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reduced stroke volume and bradycardia. Increased peripheral resistance may be accompanied by hypertension, particularly diastolic. Blood flow is diverted from the skin, producing the cool extremities. Pericardial effusions occur in up to 30% of patients but rarely compromise cardiac function. Though alterations in myosin heavy chain isoform expression have been documented, cardiomyopathy is unusual. Fluid may also accumulate in other serous cavities and in the middle ear, giving rise to conductive deafness. Pulmonary function is generally normal, but dyspnea may be caused by pleural effusion, impaired respiratory muscle function, diminished ventilatory drive, or sleep apnea.View Figure FIGURE 320-4 Facial appearance in hypothyroidism. Note puffy eyes and thickened, pale skin.
Carpal tunnel and other entrapment syndromes are common, as is impairment of muscle function with stiffness, cramps, and pain. On examination, there may be slow relaxation of tendon reflexes and pseudomyotonia. Memory and concentration are impaired. Rare neurologic problems include reversible cerebellar ataxia, dementia, psychosis, and myxedema coma. Hashimoto's encephalopathy is a rare and distinctive syndrome associated with myoclonus and slow-wave activity on electroencephalography, which can progress to confusion, coma, and death. It is steroid-responsive and may occur in the presence of autoimmune thyroiditis, without hypothyroidism. The hoarse voice and occasionally clumsy speech of hypothyroidism reflect fluid accumulation in the vocal cords and tongue.
The features described above are the consequence of thyroid hormone deficiency. However, autoimmune hypothyroidism may be associated with signs or symptoms of other autoimmune diseases, particularly vitiligo, pernicious anemia, Addison disease, alopecia areata, and type 1 diabetes mellitus. Less common associations include celiac disease, dermatitis herpetiformis, chronic active hepatitis, rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjögren's syndrome. Thyroid-associated ophthalmopathy, which usually occurs in Graves' disease (see below), occurs in about 5% of patients with autoimmune hypothyroidism.
Autoimmune hypothyroidism is uncommon in children and usually presents with slow growth and delayed facial maturation. The appearance of permanent teeth is also delayed. Myopathy, with muscle swelling, is more common in children than in adults. In most cases, puberty is delayed, but precocious puberty sometimes occurs. There may be intellectual impairment if the onset is before 3 years and the hormone deficiency is severe.
Laboratory Evaluation
A summary of the investigations used to determine the existence and cause of hypothyroidism is provided in Fig. 320-5. A normal TSH level excludes primary (but not secondary) hypothyroidism. If the TSH is elevated, an unbound T4 level is needed to confirm the presence of clinical hypothyroidism, but T4 is inferior to TSH when used as a screening test, as it will not detect subclinical or mild hypothyroidism. Circulating unbound T3 levels are normal in about 25% of patients, reflecting adaptive responses to hypothyroidism. T3 measurements are therefore not indicated.View Figure FIGURE 320-5 Evaluation of hypothyroidism. TPOAb+, thyroid peroxidase antibodies present; TPOAb-, thyroid peroxidase antibodies not present. TSH, thyroid-stimulating hormone.
Once clinical or subclinical hypothyroidism is confirmed, the etiology is usually easily established by demonstrating the presence of TPO antibodies, which are present in 90 to 95% of patients with autoimmune hypothyroidism. TBII can be found in 10 to 20% of patients, but these determinations are not needed routinely. If there is any doubt about the cause of a goiter associated with hypothyroidism, FNA biopsy can be used to confirm the presence of autoimmune thyroiditis. Other abnormal laboratory findings in hypothyroidism may include increased creatine phosphokinase, elevated cholesterol and triglycerides, and anemia (usually normocytic or macrocytic). Except when accompanied by iron deficiency, the anemia and other abnormalities gradually resolve with thyroxine replacement.
Differential Diagnosis
An asymmetric goiter in Hashimoto's thyroiditis may be confused with a multinodular goiter or thyroid carcinoma, in which thyroid antibodies may also be present. Ultrasound can be used to show the presence of a solitary lesion or a multinodular goiter, rather than the heterogeneous thyroid enlargement typical of Hashimoto's thyroiditis. FNA biopsy is useful in the investigation of focal nodules. Other causes of hypothyroidism are discussed below but rarely cause diagnostic confusion (Table 320-4).
OTHER CAUSES OF HYPOTHYROIDISM
Iatrogenic hypothyroidism is a common cause of hypothyroidism and can often be detected by screening before symptoms develop. In the first 3 to 4 months after radioiodine treatment, transient hypothyroidism may occur due to reversible radiation damage rather than to cellular destruction. Low-dose thyroxine treatment can be withdrawn if recovery occurs. Because TSH levels are suppressed by hyperthyroidism, unbound T4 levels are a better measure of thyroid function than TSH in the months following radioiodine
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treatment. Mild hypothyroidism after subtotal thyroidectomy may also resolve after several months, as the gland remnant is stimulated by increased TSH levels.
Iodine deficiency is responsible for endemic goiter and cretinism but is an uncommon cause of adult hypothyroidism unless the iodine intake is very low or there are complicating factors, such as the consumption of thiocyanates in cassava or selenium deficiency. Though hypothyroidism due to iodine deficiency can be treated with thyroxine, public health measures to improve iodine intake should be advocated to eliminate this problem. Iodized salt or bread or a single bolus of oral or intramuscular iodized oil have all been used successfully.
Paradoxically, chronic iodine excess can also induce goiter and hypothyroidism. The intracellular events that account for this effect are unclear, but individuals with autoimmune thyroiditis are especially susceptible. Iodine excess is responsible for the hypothyroidism that occurs in up to 13% of patients treated with amiodarone (see below). Other drugs, particularly lithium, may also cause hypothyroidism. Transient hypothyroidism caused by thyroiditis is discussed below.
Secondary hypothyroidism is usually diagnosed in the context of other anterior pituitary hormone deficiencies; isolated TSH deficiency is very rare (Chap. 318). TSH levels may be low, normal, or even slightly increased in secondary hypothyroidism; the latter is due to secretion of immunoactive but bioinactive forms of TSH. The diagnosis is confirmed by detecting a low unbound T4 level. The goal of treatment is to maintain unbound T4 levels in the upper half of the reference range, as TSH levels cannot be used to monitor therapy.
TREATMENT
Clinical Hypothyroidism
If there is no residual thyroid function, the daily replacement dose of levothyroxine is usually 1.6 µg/kg body weight (typically 100 to 150 µg). In many patients, however, lower doses suffice until residual thyroid tissue is destroyed. In patients who develop hypothyroidism after the treatment of Graves' disease, there is often underlying autonomous function, necessitating lower replacement doses (typically 75 to 125 µg/d).
Adult patients under 60 without evidence of heart disease may be started on 50 to 100 µg levothyroxine (T4) daily. The dose is adjusted on the basis of TSH levels, with the goal of treatment being a normal TSH, ideally in the lower half of the reference range. TSH responses are gradual and should be measured about 2 months after instituting treatment or after any subsequent change in levothyroxine dosage. The clinical effects of levothyroxine replacement are often slow to appear. Patients may not experience full relief from symptoms until 3 to 6 months after normal TSH levels are restored. Adjustment of levothyroxine dosage is made in 12.5- or 25-µg increments if the TSH is high; decrements of the same magnitude should be made if the TSH is suppressed. Patients with a suppressed TSH of any cause, including T4 overtreatment, have an increased risk of atrial fibrillation and reduced bone density.
Although dessicated animal thyroid preparations (thyroid extract USP) are available, they are not recommended as potency and composition vary between batches. Interest in using levothyroxine combined with liothyronine (triiodothyronine, T3) has been revived, based on studies suggesting that patients feel better when taking the T4/T3 combination compared to T4 alone. However, a long-term benefit from this combination is not established. There is no place for liothyronine alone as long-term replacement, because the short half-life necessitates three or four daily doses and is associated with fluctuating T3 levels.
Once full replacement is achieved and TSH levels are stable, follow-up measurement of TSH is recommended at annual intervals and may be extended to every 2 to 3 years, if a normal TSH is maintained over several years. It is important to ensure ongoing compliance, however, as patients do not feel any difference after missing a few doses of levothyroxine, this sometimes leads to self-discontinuation.
In patients of normal body weight who are taking ≥200 µg of levothyroxine per day, an elevated TSH level is often a sign of poor compliance. This is also the likely explanation for fluctuating TSH levels, despite a constant levothyroxine dosage. Such patients often have normal or high unbound T4 levels, despite an elevated TSH, because they remember to take medication for a few days before testing; this is sufficient to normalize T4, but not TSH, levels. It is important to consider variable compliance, as this pattern of thyroid function tests is otherwise suggestive of disorders associated with inappropriate TSH secretion (Table 320-3). Because T4 has a long half-life (7 days), patients who miss doses can be advised to take up to three doses of the skipped tablets at once. Other causes of increased levothyroxine requirements must be excluded, particularly malabsorption (e.g., celiac disease, small-bowel surgery), estrogen therapy, and drugs that interfere with T4 absorption or clearance such as cholestyramine, ferrous sulfate, calcium supplements, lovastatin, aluminum hydroxide, rifampicin, amiodarone, carbamazepine, and phenytoin.
Mild Hypothyroidism
By definition, subclinical or mild hypothyroidism refers to biochemical evidence of thyroid hormone deficiency in patients who have few or no apparent clinical features of hypothyroidism. There are no universally accepted guidelines for the treatment of mild hypothyroidism. As long as excessive treatment is avoided, there is little risk in correcting a slightly increased TSH, and some patients likely derive modest clinical benefit from treatment. Moreover, there is some risk that patients will progress to overt hypothyroidism, particularly when the TSH level is >6 mU/L and TPO antibodies are present. Treatment is administered by starting with a low dose of levothyroxine (25 to 50 µg/d) with the goal of normalizing TSH. If thyroxine is not given, thyroid function should be evaluated annually.
Special Treatment Considerations
Rarely, levothyroxine replacement is associated with pseudotumor cerebri in children. Presentation appears to be idiosyncratic and occurs months after treatment has begun. Women with a history or high risk of hypothyroidism should ensure that they are euthyroid prior to conception and during early pregnancy as maternal hypothyroidism may adversely affect fetal neural development. Thyroid function should be evaluated once pregnancy is confirmed and at the beginning of the second and third trimesters. The dose of levothyroxine may need to be increased by ≥50% during pregnancy and returned to previous levels after delivery. Elderly patients may require up to 20% less thyroxine than younger patients. In the elderly, especially patients with known coronary artery disease, the starting dose of levothyroxine is 12.5 to 25 µg/d with similar increments every 2 to 3 months until TSH is normalized. In some patients it may be impossible to achieve full replacement, despite optimal antianginal treatment. Emergency surgery is generally safe in patients with untreated hypothyroidism, although routine surgery in a hypothyroid patient should be deferred until euthyroidism is achieved.
Myxedema coma still has a high mortality rate, despite intensive treatment. Clinical manifestations include reduced level of consciousness, sometimes associated with seizures, as well as the other features of hypothyroidism (Table 320-5). Hypothermia can reach 23°C (74°F). There may be a history of treated hypothyroidism with poor compliance, or the patient may be previously undiagnosed. Myxedema coma almost always occurs in the elderly and is usually precipitated by factors that impair respiration, such as drugs (especially sedatives, anesthetics, antidepressants), pneumonia, congestive heart failure, myocardial infarction, gastrointestinal bleeding, or cerebrovascular accidents. Sepsis should also be suspected. Exposure to cold may also be a risk factor. Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to the development of myxedema coma.
Levothyroxine can initially be administered as a single intravenous bolus of 500 µg, which serves as a loading dose. Although further levothyroxine is not strictly necessary for several days, it is usually continued at a dose of 50 to 100 µg/d. If suitable intravenous preparation is not available, the same initial dose of levothyroxine can be given by nasogastric tube (though absorption may be impaired in myxedema). An alternative is to give liothyronine (T3) intravenously or
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via nasogastric tube, in doses ranging from 10 to 25 µg every 8 to 12 h. This treatment has been advocated because T4 → T3 conversion is impaired in myxedema coma. However, excess liothyroxine has the potential to provoke arrhythmias. Another option is to combine levothyroxine (200 µg) and liothyronine (25 µg) as a single, initial intravenous bolus followed by daily treatment with levothyroxine (50 to 100 µg/d) and liothyronine (10 µg every 8 h).
Supportive therapy should be provided to correct any associated metabolic disturbances. External warming is indicated only if the temperature is <30°C, as it can result in cardiovascular collapse (Chap. 16). Space blankets should be used to prevent further heat loss. Parenteral hydrocortisone (50 mg every 6 h) should be administered, as there is impaired adrenal reserve in profound hypothyroidism. Any precipitating factors should be treated, including the early use of broad-spectrum antibiotics, pending the exclusion of infection. Ventilatory support with regular blood gas analysis is usually needed during the first 48 h. Hypertonic saline or intravenous glucose may be needed if there is hyponatremia or hypoglycemia; hypotonic intravenous fluids should be avoided because they may exacerbate water retention secondary to reduced renal perfusion and inappropriate vasopressin secretion. The metabolism of most medications is impaired, and sedatives should be avoided if possible or used in reduced doses. Medication blood levels should be monitored, when available, to guide dosage.
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