Hypothyroidism is a persistent insufficiency in thyroid hormone production leading to a generalized decrease in metabolic functions (Thyroid Hormone: A Review of Its Synthesis and Release). It is the most prevalent of the pathologic hormone deficiencies, and can reduce physical and mental functional ability, quality of life, and long-term health. Hypothyroidism is classified on the basis of onset (congenital or acquired), endocrine dysfunction level (primary, secondary, or tertiary), and severity, which is classified as overt (clinical) or mild (subclinical) hypothyroidism. The total frequency of hypothyroidism, including subclinical cases, among adult females from all age groups, ranges from 3.0% to 7.5%, with significantly higher rates in women over 60 years old. Hypothyroidism occurs at a rate approximately 10 times higher in women than men.
Thyroid Hormone: A Review of Its Synthesis and Release
Iodide, which is primary nutritionally derived, is concentrated by the thyroid gland, converted to organic iodine by thyroid peroxidase (TPO), and then incorporated into tyrosine in thyroglobulin in the thyroid. Tyrosines are iodinated at one (monoiodotyrosine) or two (di-iodotyrosine) sites and then joined to form the hormones thyroxine, (T4) and tri-iodothyronine (T3). Another source of tri-iodothyronine within the thyroid gland is the result of the outer ring deiodination of thyroxine by a selenium-based enzyme. Tri-iodothyronine and thyroxine are cleaved from thyroglobulin by proteolytic lysosomes, resulting in release of free tri-iodothyronine and T4. The iodotyrosines (monoiodotyrosine and diiodotyrosine) are also released from thyroglobulin, but little reaches the bloodstream.
The thyroxine and tri-iodothyronine released from the thyroid reach the bloodstream where they are bound to thyroid hormone-binding serum proteins (primarily TBG and transthyretin) for transport. About 0.03% of the total serum thyroxine and 0.3% of the total serum tri-iodothyronine are free and in equilibrium with the bound hormones, and only free thyroxine and tri-iodothyronine are available to the peripheral tissues for thyroid hormone action. Tri-iodothyronine is the metabolically active hormone.
Thyroid-stimulating hormone (TSH), or thyrotropin, controls all reactions necessary for the formation of tri-iodothyronine and thyroxine and is itself controlled by the pituitary gland through a negative feedback mechanism regulated by the circulating level of free thyroxine and free tri-iodothyronine and by conversion of thyroxine to tri-iodothyronine in the pituitary. Increased levels of free thyroid hormones inhibit thyroid-stimulating hormone secretion from the pituitary decreased, whereas levels of thyroxine and tri-iodothyronine result in an increased thyroid-stimulating hormone release from the pituitary. thyroid-stimulating hormone secretion is also influenced by thyrotropin-releasing hormone (TRH) synthesized in the hypothalamus.
The thyroid produces about 20% of the circulating T3. The remaining 80% is produced by peripheral conversion of thyroxine primarily in the liver. A variation of this process also may produce reverse tri-iodothyronine (rT3), which has minimal metabolic activity. rT3 levels increase in chronic liver and renal disease, acute and chronic illness, starvation, carbohydrate-deficient diets, and possibly during extreme or prolonged stress. These states result in decreased production of the active hormone, T3, and in increased serum rT3 levels because of decreased reverse tri-iodothyronine clearance. The decreased production of tri-iodothyronine might be an adaptive response to illness, and can be seen in hypothyroidism.
Hypothyroidism is classified as primary, secondary, or tertiary. Primary hypothyroidism is significantly more common than secondary, occurring at a rate of approximately 1000:1, and tertiary hypothyroidism, resulting from disease in the hypothalamus, is rare. Myxoedema refers to severe or complicated cases of overt hypothyroidism with cretinism syndrome, and is extremely rare. Those at increased risk of developing hypothyroidism include:
• Postpartum women
• Women with family history of autoimmune thyroid disorders (AITD)
• Those with previous head, neck, or thyroid surgery or irradiation
• Those with other autoimmune endocrine disorders (e.g., type 1 diabetes mellitus, adrenal insufficiency, or ovarian failure)
• Those with nonendocrine autoimmune disorders (e.g., vitiligo, multiple sclerosis)
• Patients with primary pulmonary hypertension
• Those with Down’s or Turner’s syndromes
The following biological activities are particularly impaired by hypothyroidism:
• Calorigenic modification
• Oxygen consumption throughout most tissues
• Protein, fat, and carbohydrate metabolism
• Augmentation of calcium ATPase activity in cardiac muscle
• Mitochondrial ATP production
• G-protein-coupled membrane receptor activity
• Organ-specific effects
The clinical manifestations of hypothyroidism (see Symptoms) are the result of effects occurring at the molecular level because of the impact of thyroid hormone insufficiency.
Primary hypothyroidism is the most common form of hypothyroid disorder. It may be either congenital or acquired. Globally, the most common cause of congenital hypothyroidism is endemic iodine deficiency; however, it may also result from thyroid gland agenesis, defective thyroid hormone biosynthesis, or rarely, hemangiomas, which also may occur in young children. (Congenital hypothyroidism is not discussed in the remainder of this section.)
The most common form of primary hypothyroidism in areas of normal iodine intake is acquired primary hypothyroidism. It is most frequently a result of autoimmunity and is referred to as autoimmune thyroid disease (AITD) or autoimmune thyroiditis (Hashimoto’s disease), Antibodies are formed that bind to the thyroid (specifically against the thyroid peroxidase [TPO] enzyme, thyroglobulin, and thyroid-stimulating hormone receptors) and prevent the manufacture of sufficient levels of thyroid hormone. In addition to binding to thyroid tissue, these antibodies also may bind to the adrenal glands, pancreas, and parietal cells of the stomach. Autoimmunity as an etiologic factor is supported by the presence of lymphatic infiltration of the thyroid gland and the presence of circulating thyroid auto-antibodies in nearly all affected patients. In fact, the most common risk factor for both hypothyroidism and hyperthyroidism is the presence of thyroid peroxidase autoantibodies. Genetic predisposition (autosomal dominant inheritance) is a major factor in the etiology of AITD, accounting for as much as 79% of susceptibility to autoimmunity. Hormonal and environmental factors appear to account for the remaining etiologies. Autoimmune thyroiditis is increased in areas of high iodine intake, for example, in Iceland, suggesting an antigenic response.
Other causes of hypothyroidism include iatrogenesis secondary to radiation or medications that interfere with thyroid function, genetic defects of the tri-iodothyronine hormone receptors and excessive consumption of goitro-gens (substances that interfere with thyroid hormone production and release). Postpartum hypothyroidism is a transient form of hypothyroidism that affects 5% to 10% of postpartum women in the United States. Transient hypothyroidism may occur secondary to subacute thyroiditis caused by infection. Primary hypothyroidism is often idiopathic, with no definable cause.
The long-term consequences of untreated overt hypothyroidism are significant, and include elevated cholesterol and atherosclerosis, cardiac, renal, and neurologic diseases, increased susceptibility to infectious diseases, possibly increased rates of reproductive cancers, and ultimately, multiple organ failure if the disease progresses. Hypothyroidism is readily detectable and treatable; therefore, these consequences should be almost entirely avoidable with screening and early treatment.
Subclinical Hypothyroidism. Subclinical hypothyroidism refers to patients with primary hypothyroidism with normal serum free thyroxine (free T4) and elevated thyroid-stimulating hormone (TSH). These individuals may or may not be symptomatic. Low Dog suggests that symptomatic euthyroid state is a more appropriate label for these patients.
The prevalence of subclinical hypothyroidism is highest in the United States among white women (5.8%), and is 5.3% and 1.2% among Hispanic-American and African-American women, respectively. Rates tend to increase significantly with age, reaching as high as 8% to 10% in women ages 45 to 74 years, and 17.4% in women over 75 years.
There is strong evidence from high-quality longitudinal studies that subclinical hypothyroidism places women at significant risk for the later development of overt hypothyroidism, yet it frequently goes undetected and untreated. Untreated subclinical hypothyroidism can lead to daily interference with optimal physical, neurologic, psychological, and emotional functioning, and can cause a diminished quality of life. Controversy exists regarding the routine screening and treatment of subclinical hypothyroidism for all women, a practice that has not been well studied or determined to be conclusively beneficial. Its proponents argue that preventa-tive treatment with thyroxine is relatively safe, effective, and inexpensive, and can prevent the development of overt hypothyroidism and its consequences. Further, women who have been treated for subclinical hypothyroidism have retrospectively reported improvements in their physical and mental wellness. Patients with subclinical hypothyroidism and abnormal lipid profiles may experience improvement within 1 month of thyroxine treatment. Subtle and reversible changes in myocar-dial performance also have been reported in women with mild hypothyroidism. Careful follow-up is essential, with periodic re-evaluation of relevant laboratory markers and symptoms. Because of the frequency of hypothyroidism in older women, routine screening and treatment may be justified in this population. Routine screening also may be prudent during pregnancy, because of the serious consequences of long-term cognitive dysfunction and decreased intelligence in the offspring of women with untreated prenatal hypothyroidi sm.
Secondary hypothyroidism can result from diseases that interfere with thyrotropin-releasing hormone (TRH) production by the hypothalamus, its delivery by the pituitary stalk, or with problems of pituitary thyrotropin production (e.g., pituitary adenomas, hypothalamic tumors, or their treatments such as surgery or radiation therapy). Head trauma, metastatic disease, and infection can also lead to secondary hypotyroidism. Iatrogenic hypothyroidism is the second most common cause and is the result of radioactive iodine therapy or ablation treatment for Graves’ disease and other forms of hyperthyroidism.
Signs and Symptoms
Any of the symptoms listed in Signs and Symptoms of Hypothyroidism may be present in degrees ranging from mild (requiring careful discernment of the clinical picture) to severe. Hypothyroidism may also be asymptomatic, detectable only by laboratory screening. Hypothyroidism is commonly overlooked clinically because of the presence of these symptoms in any number of other diseases.
Signs and Symptoms of Hypothyroidism
- Carpal tunnel syndrome
- Cold intolerance
- Decreased energy
- Decreased exercise tolerance
- Delayed reflexes
- Diastolic hypertension
- Dry or brittle hair
- Dry skin
- Loss of libido
- Low body temperature
- Low-pitched or hoarse voice
- Menstrual irregularities
- Muscle cramps
- Muscle weakness
- Periorbital edema
- Poor memory
- Psychomotor retardation
- Slow speech
- Water retention
- Weight gain
Hypothyroidism: Conventional Treatment
Treatment of hypothyroidism with thyroid extract has been practiced since 1891, when Murray first reported the use of sheep thyroid extract. Thyroid hormone was first crystallized in 1914, and initial testing with thyrox-ine began in 1927. Exogenous thyroid hormone replacement remains the standard treatment, with thyroxine (T4) considered the treatment of choice based on its general efficacy and relatively small risk of adverse effects when given at the proper dose. Conventional practice advocates the use of thyroxine alone over tri-iodothyronine and thyroxine combinations, the latter of which may provide tri-iodothyronine in excess of normal thyroid secretion. However, many physicians find that the addition of tri-iodothyronine can be beneficial for patients not responding optimally to thyroxine alone.
Dosing of thyroid replacement therapies should be carefully monitored because of the narrow toxic-to-therapeutic ratio of thyroid hormone, with the patient maintaining on the lowest possible effective dose, which will be individually determined. The typical required daily dose is 1.5 ng/lb body weight, with doses for older adults at approximately 70% of that required for younger women. It has been estimated by some researchers that as many as 20% of hypothyroid patients are receiving excessive doses. Adverse reactions to thyroxine are usually related to excessive dosing or increased thyroid hormone activity. Tri-iodothyronine supplementation may be implemented for patients unresponsive to thyroxine treatment alone.
No studies of controlled treatment of subclinical hypothyroidism have been conducted.
Commonly used thyroid medications include:
• Synthroid and other synthetic preparations containing only T4
• Liotrix and Thyrolar: synthetic mixtures of tri-iodothyronine and thyroxine in similar ratios
• Cytomel: a synthetic tri-iodothyronine preparation
• Desiccated “natural” thyroid preparations (e.g., Armour thyroid): provide thyroxine and T3, plus amino acids and micronutrients. A popular criticism of natural thyroid preparations is that they lack consistency and reliability, and as stated, may provide tri-iodothyronine in excess.
Hypothyroidism: Nutritional Considerations
A variety of food antigens may induce antibodies that cross-react with the thyroid gland. A food elimination diet free of gluten containing grains and casein-containing dairy products may be helpful in the treatment of autoimmune hypothyroidism. The inges-tion of goitrogens — foods that block iodine utilization — are best limited in those patents with goiter. These include such foods as turnips, cabbage, mustard, cassava root, soybean, peanuts, pine nuts, and millet. Cooking usually inactivates goitrogens. Rich sources of iodine include ocean fish, sea vegetables (kelp, dulse, arame, hijiki, nori, wakame, kombu), and iodized salt, and should be included when there is iodine deficiency, but reduced when there is iodine excess.
Thyroid function may be supported nutritionally, even with the use of thyroid replacement therapy. Nutrients that may be beneficial supplements include selenium, zinc, tyrosine, and vitamins A, D, E, and C. Good sources of zinc include seafood (especially oysters), beef, oatmeal, chicken, liver, spinach, nuts, and seeds. The richest food source of selenium is Brazil nuts, especially those that are unshelled.
Selenium is a cofactor in normal thyroid hormone production. Selenium deficiency decreases conversion of thyroxine to T3. People with selenium deficiency have elevated thyroxine and TSH. Patients with normal circulating hormone levels who display clinical hypothyroid symptoms may be selenium deficient; thus, selenium levels should be evaluated and supplementation provided if deficiency is present. In a double-blind, placebo-controlled trial of selenium supplementation of 100 μg/day for 3 months among older subjects showed an improvement in selenium indices, a decrease in T4, and a trend toward normalization of T3:T4 ratio.
Zinc is involved with synthesis of hypothalamic thyrotropin-releasing hormone (TRH); a zinc deficiency may lower 5′-deiodinase function, thereby contributing to a lower conversion of thyroxine to T3. Supplementation with zinc acts to normalize the TRH-induced thyroid-stimulating hormone reaction and increase conversion of thyroxine to T3. The recommended dose is zinc picolinate, 30 mg/day.
Tyrosine is an amino acid used as a precursor for making thyroid hormone. Tyrosine deficiency can contribute to low thyroid function. Low protein diets may provide insufficient tyrosine for normal thyroid hormone production. Supplementation of tyrosine at a dose of 500 to 1500 mg daily has therapeutic benefits in hypothyroidism.
• Improve overall metabolism with diet, exercise, and herbs. Green tea is an excellent herb for gently boosting metabolism, and the adaptogens are a good long-term treatment.
• Remove stressors and improve adrenal and thyroid functioning with the use of adaptogens.
• Use botanicals to directly augment thyroid function.*
• Monitor progress with regular thyroid testing.
• Avoid foods that stimulate antigen cross-reactivity with the thyroid, such as gluten and casein.
• Avoid excessive intake of foods that act as goitrogens.
• Evaluate and ensure adequacy of dietary iodine intake: ocean-caught fish, iodized sea salt, and sea vegetables (kelp, wakame, nori) are good sources.
• Supplement with zinc, selenium, and vitamins A, C, D, and E.
• Initiate an exercise program to improve metabolism and prevent weight gain; dieting is discouraged as it can reduce metabolic function.
*Do not combine thyroid-stimulating herbal therapies with pharmaceutical thyroid medication. Consult with the patient’s physician if the patient wants to make a switch between conventional and botanical therapies. In many cases, conventional treatment is the optimal choice.