Herbs for Potential Adjunct Treatment of THYROID DISEASE

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A Review of Botanical Preparations for Hypo- and Hyperthyroidism, Thyroid Nodules, and Thyroid Cancer Summary

Diseases of the thyroid are varied and can take many forms, which may or may not produce clinical symptoms that alert patients to their existence. The most common thyroid disorders are the under- or over-functioning of the gland--hypothyroidism and hyperthyroidism, respectively. Both of these most often result from autoimmune disorders. Physical irregularities, often termed nodules, occurring on the thyroid are a distinct condition of the gland and may arise simultaneously with these diseases, or emerge idiopathically with no symptoms. An important minority of thyroid nodules are malignant. Botanical medicines to treat thyroid disease are limited and have not been widely studied in humans. Traditional Western herbal medicine lacks a body of herbs earmarked for thyroid health, but modern research on a few of these herbs reveals potential clinical applications toward hyperthyroidism in humans. There are no herbs indicated in the Western tradition for resolving thyroid nodules per se, and herbs to treat thyroid cancer are not distinct from other herbs used in this tradition for cancer. Chinese medicine, on the other hand, has several herbs and herbal formulas earmarked for the resolution of thyroid disease and thyroid nodules, which may be interpreted (depending on symptoms) in the context of traditional Chinese medicine (TCM) as a disturbance of qi, a condition of excess or insufficient yin, or an accumulation of stagnant "phlegm" or "blood." These herbs have also largely been studied individually only in vitro and in animals, but some clinical trial data are available on TCM herbal formulas for treating hyperthyroidism. Much of this data has been the subject of a recent systematic review. Both the TCM and Western modalities may employ the use of seaweed and sea products in thyroid formulas; these must be used with extreme caution due to the varying and often unpredictable effects of iodine supplementation on thyroid function.

Search Strategy
Secondary and tertiary sources of herbal medicine information in the American Botanical Council library and literature database were searched for basic information on herbs for thyroid disorders in the Western and Asian herbal medicine traditions. A list of plants with suspected thyroid activity was gathered, and their Latin binomials entered into the search engine of PubMed, a service of the US National Library of Medicine that includes over 16 million citations from MEDLINE and other life science journals for biomedical articles dating from the 1950s. Relevant articles were accessed and searched for information pertaining to thyroid. Latin binomials of plants with suspected thyroid activity were also entered into the search engine of NAPRALERT, a natural products database at the University of Illinois at Chicago encompassing over 200,000 scientific papers and reviews regarding organisms from all over the world, dating from 1975 through 2003. In addition, NAPRALERT was searched for plants with pharmacological activity using the search terms "antihypothyroid effect;" "antithyroid activity;" "thyroid agonist activity;" "thyroid hormone receptor antagonist;" "thyroid peroxidase inhibition;" and "thyroid type 1 deiodinase inhibition." Articles describing studies in humans were accessed and searched for information pertaining to thyroid.

Physiological Function of the Thyroid Gland
The thyroid is a two-lobed gland in the anterior neck composed of microscopic follicles that sits below the thyroid cartilage ("Adam's apple").( n1) The surface-layer cells (epithelium) of the thyroid's follicles perform the processes of synthesis and release of thyroid hormones. The two main thyroid hormones are thyroxine (T4) and triiodothyronine (T3). Once released into the blood plasma, T4 and T3 bind reversibly to plasma proteins. Most circulating thyroid hormones are protein bound, yet only the free (unbound) fraction is available to tissues, whose cells actively take up the hormone molecules. ( n2)

Thyroid hormones bind to a specific receptor located in the nucleus of most cells. Activation of this receptor affects many cellular functions, primarily cell growth and metabolism by direct influence on gene transcription and subsequent protein synthesis, or by direct effects on the cell or on mitochondria through stimulation of cell growth and respiration. Thyroid hormone is regulated by the hypothalamic-pituitary-thyroid axis via a negative feedback mechanism. Thyrotropin-releasing hormone (TRH), synthesized in the hypothalamus, stimulates the pituitary gland, which manufactures thyrotropin, also known as thyroid-stimulating hormone (TSH). TSH travels to the thyroid gland to stimulate synthesis and release of T4 and T3. A decrease in plasma T4 or T3 triggers an increase in plasma TSH, and vice-versa. ( n1)

The thyroid also contains another type of cell: parafollicular cells, known as "C cells," which synthesize and release the hormone calcitonin. Calcitonin lowers plasma calcium levels.( n3)

Thyroid Diseases: Classification and Diagnosis
The typical thyroid diseases discussed in this article are hypothyroidism, hyperthyroidism, thyroid nodular disease, and thyroid cancer. Classification and diagnosis of thyroid disease involves several steps. These include evaluating a patient for the following( n3): ( 1) presence of clinical symptoms (e.g., weakness, cold intolerance, headache, slow speech); ( 2) physical findings (e.g., thinning of hair and nails, tachycardia, bradycardia, peripheral edema, weight loss or gain); ( 3) blood chemistry (levels of circulating thyroid hormone, TSH, thyroid antibodies); and ( 4) presence of visible or palpable irregularities upon the thyroid gland itself (which require evaluation with biopsy and/or ultrasound to rule out thyroid cancer).

Hypothyroidism
This is defined as a clinical syndrome resulting from a deficiency of thyroid hormone. Clinical symptoms generally include cold intolerance, lethargy, weight gain, and muscle aches. Physical findings may include bradycardia; thinning of hair, skin, and nails; thickening of tongue; puffiness of face, eyelids, or peripheral edema; pallor. Hashimoto's disease is the most common cause of spontaneous hypothyroidism.

Hasbimoto's Disease: In this disease, antibodies attack thyroid tissue and impair production/release of thyroid hormone, leading to a hypothyroid condition, or sometimes a diffuse swelling or enlargement of the gland (goiter) with or without hormone deficiency. Physical irregularities of the thyroid gland that arise with Hashimoto's disease are usually multiple, presenting as a so-called "multinodular goiter"; minimal increased risk of thyroid cancer is linked to this disease, though thyroid cancer (including thyroid lymphoma) must be ruled out.( n4)

Hyperthyroidism
This is defined as a clinical syndrome resulting from an excess of thyroid hormone. Clinical symptoms generally include heat intolerance, irritability, insomnia, and fatigue. Physical findings may include hair loss, palpitations, ophthalmopathy, tremor, and diarrhea.( n1) Graves' disease is the most common cause of hyperthyroidism.

Graves' Disease: In this disease, antibodies stimulate thyroid tissue and cause it to overproduce/release too much thyroid hormone. Multinodular goiter is less common with Graves' disease than with Hashimoto's disease; in Graves' disease, a diffuse, non-nodular swelling of the entire gland usually occurs instead. There is an increased risk of thyroid cancer with Graves' disease.( n4)

Subacute Thyroiditis: This refers to a diffuse swelling of the thyroid gland, which occurs as an acute inflammatory reaction typically following several types of viral infection. In most cases the thyroid is large and very tender. Some instances of subacute thyroiditis are marked by a transient hyperthyroidism. This disease is typically self-limited, and both thyroid inflammation and transient hyperthyroidism resolve within a few months without lasting clinical symptoms.( n3) A hypothyroid phase may also follow the hyperthyroidism.

Thyroid Nodules
Physical irregularities of the thyroid gland not associated with abnormal antibody production may emerge as diffuse, singular, or multiple entities, and be either functional or non-functional parts of the gland. These physical irregularities are sometimes referred to as "nodular" or "multinodular," and they do not necessarily emerge because of one particular insult to the gland or disease; rather, they may manifest due to a variety of thyroid disorders and may or may not cause other clinically detectable symptoms. In countries where iodine deficiency has been corrected, physical irregularities of the thyroid gland are clinically detectable in about 4 to 7% of the population.( n5)

Nontoxic Goiter: This refers to thyroid enlargement or physical irregularities of the thyroid that are not associated with hyperthyroidism. Antibody production, cancer, or hypothyroidism may or may not be present. The cause of nontoxic goiters is unknown but may reflect a condition where the thyroid tissue over responds to physiologic levels of TSH. Impaired utilization of iodine may also be a cause. In the absence of hypothyroidism, patients with nontoxic goiter are usually asymptomatic, save for the discomfort of having a mass in the neck that can interfere with normal breathing and swallowing.( n1)

Toxic Nodular Goiter: Also known as TNG or Plummer's disease, this is a more common cause of hyperthyroidism than Graves' disease in the elderly. Patients with nontoxic multinodular goiter may develop this disease over time when some of the physical irregularities within the thyroid gland develop into functionally autonomous, hormone-secreting nodules.( n5) However, in TNG there is an absence of the thyroid autoantibodies characteristic of Graves'.( n4) Patients with TNG usually have less severe hyperthyroid symptoms than those with Graves' (i.e., no ophthalmopathy) and serum T3 and T4 concentrations are not as elevated, though other subsequent secondary symptoms (tachycardia, palpitations) may be just as clinically significant.( n3)

Thyroid Cancer
A thyroid nodule may be benign or malignant. Definitive evaluation of such nodules is done via fine needle aspiration biopsy (FNAB). Nodules may be imaged via ultrasound or radionuclide scan using iodine 123. While a hyperfunctioning or "hot" nodule on such a scan almost always indicates a benign lesion, a hypofunctioning or "cold" nodule may be either benign or malignant. Iodine scanning is usually reserved for determining the functional status of nodules coexisting with hyperthyroidism.( n4, n6)

The prevalence of thyroid cancer among thyroid nodules is approximately 5%. More than 75% of malignant nodules are well-differentiated cancers of the follicular epithelium: mostly papillary carcinomas carrying a relative low risk of death, and a smaller number of follicular carcinomas carrying a slightly higher risk. Rare cancers with a much higher mortality rate include: medullary cancer (originating in the calcitonin-producing cells of the thyroid, a familial form of cancer comprising 5-10% of the remaining thyroid carcinomas); thyroid lymphomas; and anaplastic carcinoma.( n4, n6)

Conventional Medical Treatment of Thyroid Diseases
The course of treatment of thyroid disease depends both on the underlying cause and the severity of secondary symptoms.

Hypothyroidism
For autoimmune (Hashimoto's disease) and non-autoimmune hypothyroid syndromes, treatment of choice is supplementation with some form of pharmaceutical thyroid hormone, such as levothyroxine (aka T4 or L-thyroxine, known by the brand names Synthroid® [Abbott Laboratories, Abbott Park, IL] and Levoxyl® [King Pharmaceuticals, Bristol, TN]), among others. The body converts this pharmaceutical L-thyroxine to the active form liothyronine (T3) as needed. Exogenous T3 (liothyronine, brand name Cytomel® [Forest Pharmaceuticals, New York, NY]) may also be given instead of T4 for symptoms of hypothyroidism, especially if blood tests suggest a particular patient has difficulty converting T4 to T3. Combination T4/T3 products also exist, such as a pharmaceutical preparation made of natural porcine thyroid glands (Armour® Thyroid [Forest Pharmaceuticals, New York, NY]); risk of drug-induced hyperthyroidism can be increased through administration of exogenous T3 and combination products.( n4)

Hyperthyroidism
For autoimmune (Graves' disease) and non-autoimmune (TNG) hyperthyroid syndromes, conventional medical treatments include antithyroid drugs, radioactive iodine therapy, and surgery.

The two currently approved antihyperthyroid drugs in the United States are both classified as thioureylene compounds: methimazole (Tapazole®, King Pharmaceuticals, Bristol, TN) and propylthiouracil (PTU). Both of these drugs interfere with biosynthesis of thyroid hormone by interfering with the incorporation of iodine into thyroglobulin.( n2) Long-term treatment with these drugs sometimes leads to remission of the disease.

Radioactive iodine therapy with iodine 131 is the most common treatment used in the United States for hyperthyroidism.( n4) Radioactive iodine therapy usually renders the thyroid gland non-functional, requiring supplementation with exogenous thyroid hormone (levothyroxine, aka T4 or L-thyroxine) after treatment. Armour® thyroid, the commercial pharmaceutical product derived from porcine thyroid glands, may be given as thyroid replacement instead.

Thyroidectomy is reserved for those patients with contraindications to antithyroid drugs and radioactive iodine therapy, coexisting suspicion for cancer, or with large, swollen thyroids that cause physical discomfort. Supplementation with some form of pharmaceutical thyroid hormone is required after surgery.

Drug treatment with antihyperthyroid drugs is not indicated for subacute thyroiditis with transient hyperthyroidism, since antihyperthyroid drugs will not affect the leaking of stored thyroid hormone. Other types of drugs may be offered to these patients to address the secondary symptoms of hyperthyroidism only (such as sedatives for insomnia and beta-blockers for palpitations or tachycardia).( n1)

Thyroid Nodules
Patients with nodular irregularities of the thyroid in whom malignancy has been excluded or deemed unlikely should proceed with periodic clinical observation. Benign nodules may shrink with administration of levothyroxine (so-called "thyroid hormone suppression therapy"), which may be tried if the patient's serum TSH is high or normal. Large multinodular goiters, though benign, may exert compressive symptoms and sometimes respond to thyroid hormone suppression therapy, or they may require surgical removal. Radioactive iodine 131 to reduce gland size is also an option, especially if surgery is contraindicated; however, radioiodine is more effective in, and usually reserved for, hyperthyroid conditions.( n4)

Thyroid Cancer
Full or partial thyroidectomy is the treatment of choice for differentiated thyroid cancers (papillary and follicular carcinomas). After such surgery, total body radioiodine scanning may be done to look for metastatic spread, and radioiodine treatment given to ablate remnant thyroid or metastatic tissue. Some form of pharmaceutical thyroid hormone product is given after surgery to replace thyroid hormone and suppress TSH, a thyroid tumor growth factor, to normal or low-normal levels. Follow up includes monitoring serum thyroglobulin levels, which should be low to undetectable after effective therapy.( n4)

Medullary thyroid cancer usually requires full thyroidectomy and cervical lymph node dissection. Serum calcitonin levels should be monitored.( n4)

Non-differentiated (anaplastic) thyroid cancers are rare but comprise aggressive forms of cancer with poor prognoses. Surgery, radiation and chemotherapy are palliative only.( n4)

Herbal Treatment of Thyroid Disorders Western Herbal Tradition
There are few herbs in the Western herbal tradition specifically indicated for thyroid disease. Of these, there are little to no data on their effectiveness in humans. There are no herbs specifically indicated for the treatment of physical irregularities of the thyroid or thyroid cancer per se; rather, herbs in Western alternative and complementary medicine believed to affect the thyroid specifically address symptoms of either hypothyroidism or hyperthyroidism only.

Hypothyroidism
Kelp (Laminaria spp., Laminariaceae) is recommended by many herbalists for the treatment of hypothyroidism or thyroid nodules.( n7) Kelp is a rich source of iodine, which is necessary for the formation of thyroid hormone. Historically, iodine deficiency was the largest cause of thyroid swelling (commonly known as "goiter"); however, while iodine deficiency may precipitate hypothyroidism, goiter, or physical irregularities of the gland,( n6) this deficiency is rare in developed countries. Autoimmune disease, rather than iodine deficiency, is the primary cause of hypothyroidism in the United States.( n4)

While iodine is one of the oldest known remedies for thyroid diseases,( n2) iodine supplements and seaweed products should be used with caution and under medical supervision in all patients with thyroid disorders, since the effects of iodine supplementation on thyroid function are unpredictable and vary over time. Excess iodine can trigger hyperthyroidism in some patients with seemingly normal thyroid function, yet the normal physiologic response to an acute increase in plasma iodine load is temporary hypothyroidism (an adaptive response to prevent dangerous fluctuations of thyroid levels, known as the "Wolff-Chaikoff effect").( n8) In hyperthyroid patients, supplemental iodine may temporarily suppress, but then later increase, synthesis of thyroid hormone.( n9) A recent study of 3018 subjects in China demonstrated that excessive iodine intake may lead to hypothyroidism and autoimmune thyroiditis.( n10) Improper use of a kelp-containing supplement has been linked to at least one case of iodine-induced hyperthyroidism.( n11)

Hyperthyroidism
Four herbs are commonly suggested by Western herbalists, other practitioners of complementary and alternative medicine, and naturopathic medical textbooks for treating hyperthyroidism.( n11, n12, n13) Three herbs appear to have effects on thyroid hormone--lemon balm (Melissa officinalis, Lamiaceae), bugleweed (Lycopus virginicus, Lamiaceae), and gromwell (Lithospermum officinale, Boraginaceae); and one appears to reduce secondary symptoms of hyperthyroidism (heart palpitations and tachycardia), motherwort (Leonurus cardiaca, Lamiaceae).

Lemon balm is approved by the German Commission E for use internally for nervous sleeping disorders and gastrointestinal complaints.( n14) A systematic review of published articles conducted by the Natural Standard Research Collaboration in 2005 revealed that although no serious adverse effects have been reported with use of the herb, there is insufficient evidence for the use of lemon balm in treating Graves' disease or cancer.( n15) However, freeze-dried extracts of lemon balm have been shown to have antithyroid activity in vitro by binding to TSH and preventing binding to its receptor, which prevents subsequent thyroid hormone manufacture and release. Likewise, lemon balm has been shown in vitro to interact with and prevent the binding of autoantibodies to the TSH receptor, suggesting the plant may have some use in Graves' disease.( n16) The mechanism of action may be inhibition of TSH-stimulated cyclic adenosine monophosphate (cAMP, an enzyme activator) production.( n17) Another in vitro study revealed that aqueous extract of lemon balm inhibited the peripheral conversion of T4 to T3.( n18) No human trials have yet evaluated the efficacy of lemon balm for hyperthyroidism.

Bugleweed has also been shown in vitro to bind with TSH and TSH-like immunoglobulins, preventing binding to the receptor.( n16, n19) Likewise, an aqueous extract of bugleweed appeared in vitro to inhibit the enzymatic reaction that converts peripheral T4 to T3.( n18, n19) In rats, aqueous extracts of bugleweed appear to inhibit thyroid hormone production, possibly by inhibiting TSH.( n20, n21) Although no human trials have demonstrated the efficacy of bugleweed for hyperthyroidism, the German Commission E approves internal use of the fresh or dried above-ground parts for mild thyroid hyperfunction, noting that in rare cases, with extended therapy and high doses, sudden enlargement of the thyroid can occur. The Commission E also warns against abrupt discontinuation of bugleweed.( n22)

Freeze-dried and aqueous extracts of gromwell, like those of lemon balm and bugleweed, have demonstrated TSH-binding and hormone conversion-preventing effects in vitro, respectively.( n16, n17, n18) Another study revealed that injections of gromwell lowered TSH, T4 and T3 levels in animals.( n23) In rats, aqueous gromwell extract has been shown to inhibit TSH( n20, n21) and decrease conversion of T4 to T3.( n24) Again, no human trials have examined gromwell's efficacy for treating hyperthyroidism.

Motherwort is traditionally known as a heart tonic and uterine stimulant.( n25) In vitro the plant has demonstrated negative chronotropic effects.( n26, n27) There are no complete studies in humans for motherwort. It is approved by the German Commission E for nervous cardiac disorders and as an adjuvant for thyroid hyperfunction.( n14)

Some common plant foods contain substances that can prevent the utilization of iodine, and, subsequently, impact thyroid hormone function. They include, most prominently, members of the family Brassicaceae: cabbage (Brassica oleracea), turnips (B. rapa), and rutabagas (B. napobrassica); soybeans, peanuts, pine nuts, and millet have also been reported to interfere with thyroid iodine uptake.( n28) While these foods must be consumed raw and in large quantities to have an antithyroid effect, this may be of clinical significance in some rare cases.( n12)

Herbal Treatment of Thyroid Disorders: Eastern Herbal Traditions
Ayurvedic Medicine
One herb in traditional Ayurvedic medicine has been studied in animals for its effects on the thyroid--the fruit of amla (Emblica officinalis, Phyllanthaceae, syn. Pbyllanthus emblica). Administration of amla extract to hyperthyroid mice reduced T3 and T4 concentrations to a greater extent than the prescription antithyroid drug propylthiouracil (PTU).( n29) There are no studies of the fruit's effect in humans.

Chinese Medicine
Thyroid disease is often treated by herbal medicine in China. As with Western herbal medicine, in traditional Chinese medicine (TCM) the greatest use for herbs lies in treatments for hyperthyroidism, the symptoms of which are characterized in this modality as a "yin deficiency" or syndrome of "excess fire." Hypothyroidism, in contrast, is characterized as "yang deficiency." TCM also employs herbs for treating thyroid masses and nodules, which are interpreted as "entangled qi," "accumulated phlegm," and "static blood."( n30, n31, n32)

Chinese herbal remedies are traditionally given as combinations rather than single herbs. Some traditional combinations are known for use in thyroid conditions and may be sold in supplements in this form: for example, Jia Kang Wan and Pingyin Fufang.( n30) Both of these formulas contain herbs meant to target the thyroid, such as kelp, brown seaweed (Sargassum spp., Sargassaceae), Chinese yam (Dioscorea oppositifolia, Dioscoreaceae), fritillary (Fritillaria spp., Liliaceae), Prunella (Prunella vulgaris, Lamiaceae), scrophularia (Scrophularia ningpoensis, Scrophulariaceae), and rehmannia (Rehmannia glutinosa, Scrophulariaceae), in addition to other herbs. Both of the formulas also contain oyster shell, a common ingredient in TCM thyroid formulas, as sea materials with a high mineral content are considered in this modality to soften and remove masses.( n32)

The Cochrane Collaboration recently published a systematic review, "Chinese Herbal Medicines for Hyperthyroidism.''( n33) Cochrane reviews (published quarterly and available by subscription) regularly collect and review all available evidence for and against the effectiveness of various treatments (medications, surgery, etc) for specific conditions, taking care to include evidence that is unpublished, published in languages other than English, or unlikely to appear in major databases. In order to assess the effects of Chinese herbal medicines for treating hyperthyroidism, the authors of the review searched several databases (both in English and Chinese) for randomized controlled clinical trials of therapy for hyperthyroidism with Chinese herbs alone, or herbs in combination with antihyperthyroid drugs or radioactive iodine. Studies that met review inclusion criteria were obtained and the original authors contacted and interviewed to determine whether trial participants were correctly randomized. Only 13 trials met the Cochrane reviewers' criteria at the time of completion of the review, while the authors of 52 additional trials could not be contacted; those are still waiting assessment.

Reviewers assessed the quality of evidence and detailed the specific outcomes in each of the 13 trials. Trials could not be directly compared, since the herbal preparations used in the studies were all different from each other. The reviewers found that none of the trials used double blinding. Exact causes of hyperthyroidism were detailed in only 4 of the studies. Primary outcomes in the trials varied and included relapse rates, adverse effects, clinical symptoms, physical symptoms, and thyroid function tests (serum T3, T4, and TSH). Each of the 13 studies evaluated a specific formula containing at least 5 or more combined Chinese herbs (2 of these studies did not mention the specific contents of formulas). Formula types tested by the studies included capsules of dried herbs, tablets of dried herbs, ampoules of decocted herbs, and injections of decocted herbs. A total of 65 different Chinese herbs were identified throughout the 13 formulas.

While the Cochrane review authors conclude in their systematic review that Chinese herbal medicines, combined with conventional antihyperthyroid drugs, may be of some benefit to patients in relieving hyperthyroid symptoms, they also conclude that the current available studies of Chinese herbal medicine used to treat hyperthyroidism were too poorly controlled and subject to potential conflicts of interest to provide a reliable indication for any type of Chinese herbal formula for treating hyperthyroidism. Therefore, according to the criteria employed by this systematic review, there is currently no strong clinical trial-based evidence for the use of any Chinese herb or herbal formula for the treatment of hyperthyroidism. Randomized, double-blind, placebo-controlled trials of Chinese herbs and herbal formulas are still needed to provide evidence for the efficacy of Chinese herbs in treating one or more specific causes or symptoms of hyperthyroidism.

Data from some of the clinical studies in humans for TCM formulas containing the following herbs are summarized in English in the Cochrane review, and also in other secondary sources.( n30, n31, n32) In vitro and animal data on these herbs published in English are also referenced below.

Kelp and Brown Seaweed: Kelp seaweed (Kun Bu in Mandarin) and brown seaweed (Hai Zao and Lou Shu in Mandarin and Hoi Chou in Cantonese) are common ingredients in TCM remedies for thyroid. Seaweeds are known traditionally as dissolvents that can soften chronic swellings, decongest lymphatic tissue, and reduce tumors.( n34)

Modern research confirms seaweed as a rich source of trace minerals, including iodine; however, the iodine content varies with species and preparation of the plant.( n35) Bioavailability of iodine contained in seaweed is generally high (80-96%).( n36) As a result, clinicians must carefully dose and observe patients treated with seaweed-containing products due to these variabilities and also the unpredictable effects that iodine can have on thyroid tissue, as enumerated previously. Another issue regarding use of seaweed in treatments is the potential for contamination by pollutants. Research shows that Sargassum biosorbs cationic metals, especially lead, in both low- and high-salt containing wastewater.( n37)

Clinical studies in English evaluating the effects of Laminaria spp. or Sargassum spp. on thyroid disorders in humans are lacking.

Chinese Yam: Traditional use of Chinese yam (Huang Yao Zi in Mandarin and Wong San Ji in Cantonese) root include to strengthen yin,( n38) resolve thyroid tumors, and hypo- and hyperthyroidism (decoction or tincture).( n34) Modern in vitro research reveals antibacterial( n39) and antitumor( n40) properties, but no studies or abstracts in English were found documenting the root's effect on thyroid disease in humans. Dioscorea rhizome or shanyao was identified as a component of a TCM herbal formula in one of the 13 trials evaluated by the Cochrane review.( n33) This unblinded trial of 147 patients with Graves' disease evaluated 20 mL 3 times daily of the decocted herbal formula Jiakangxin plus radioiodine, versus the antithyroid pharmaceutical drug methimazole alone, versus radioiodine alone.( n41) Outcomes evaluated included subjective symptoms, body weight, and thyroid hormone levels after 6 months of treatment. Statistical significance was found in improved hormone levels only in the radioiodine and radioiodine plus Jiakangxin groups, compared to the methimazole alone group, but the Cochrane review concluded the presence of potential conflicts of interest in the study.

Fritillary: The bulb of two species of fritillary (Fritillaria cirrhosa and F. thunbergii, Bei Mu in Chinese) is employed in TCM for "heat clearing" properties valuable in resolving cough, nodules, swellings, and thyroid cancer, among other things.( n34, n38) Modern research reveals the genus to be rich in a wide range of steroidal alkaloids.( n42) Some may have acetylcholinesterase-inhibiting properties,( n43) which raises the potential for toxicity similar to organophosphate insecticides (with hypersecretion, excitation, diarrhea, bronchospasm, slowed or rapid pulse, and even seizu res). No studies or abstracts in English were found documenting the bulb's effect on thyroid disease in humans. Thunberg fritillary bulb or zhebeimu was identified as a component in formulas studied in two of the 13 trials evaluated by the Cochrane review.

The first, in 2003, was a parallel group, unblinded trial of 368 cases of hyperthyroidism defined by specific threshold levels of plasma thyroid function tests.( n44) One ampoule per day of the herbal formula Erdong Tang with Xiaoluwan Jiawei was decocted with water and orally taken in the morning and evening and compared to the control group taking either propylthiouracil (PTU) or methimazole. Outcomes included symptom relief, plasma thyroid hormone levels for 1 year after discontinuing the herbal formula or drugs, and relapse rates. While the study found symptom relief improvement, plasma hormone improvement, and relapse rates to be better in the herbal treatment versus the control group, the Cochrane reviewers note potential conflicts of interest in the study.

The second trial including fritillary, published in 2005, was also of parallel design and unblinded.( n45) It evaluated 62 cases of hyperthyroidism with symptoms of sweating, dysphoria, palpitations and emaciation. Interventions compared were the herbal formula Jiakangxiao (which included fritillary bulb) plus treatment with either methimazole or PTU, versus methimazole or PTU alone. Outcomes included symptom relief, measurement of plasma thyroid hormones after 50 days of treatment, and relapse rates after 1 year. The study found statistically significant improvement in the treatment versus control group in all outcomes, though the Cochrane reviewers note potential conflicts of interest in the study.

Prunella: The flower spike of selfheal (aka Prunella, Xia Ku Cao in Mandarin; Ha Gu Chou in Cantonese) are used in TCM as an antipyretic, diuretic, astringent, and lymphatic decongestant.( n34, n38) Modern studies support selfheal's ability to reduce inflammation and modulate the immune system in vitro( n46) and to suppress antibody production in mice.( n47) No studies or abstracts in English were found documenting the flower's effect on thyroid disease in humans.

Xia Ku Cao was identified as a component in 4 of the 13 trials evaluated by the recent Cochrane review. Xia Ku Cao is included in the formula Erdong Tang with Xiaoluwan Jiawei, which was evaluated in the trial by Qiu et al (2003) enumerated above.( n44) In 1999, an unblinded parallel group trial evaluated 105 hyperthyroid patients taking methimazole plus 1 ampoule per day of an herbal formula including Xia Ku Cao, versus a control group taking methimazole alone.( n48) Outcomes included symptoms of palpitation, fatigue, emaciation and heat intolerance as well as plasma concentrations of thyroid hormones. The study found that while both groups improved with treatment, there was no statistically significant difference between the groups with regard to plasma hormone levels or symptom relief. The Cochrane review noted potential conflicts of interest in the study.

In 2001, another unblinded, parallel group trial evaluated 84 patients with hyperthyroidism identified through plasma thyroid hormone levels and clinical symptoms of palpitation, dizziness, tremor, fatigue, sweating, and emaciation.( n49) Methimazole plus an herbal formula containing Xia Ku Cao given in an unidentified dosage form and frequency were compared to methimazole alone for 2 months with 1 year of follow-up. The study found greater improvement in the treatment group compared to control with regard to the outcomes of symptom relief and plasma thyroid hormone levels at 2 months and relapse rates after 1 year. The Cochrane review notes potential conflicts of interest in the study.

Finally, Xia Ku Cao was part of a formula called Jiakang mianyi jiaonang evaluated in 2005 on 44 subjects with hyperthyroidism in a study of 86 hyperthyroid patients with diffuse toxic goiter (aka Graves' disease) or subacute thyroiditis.( n50) PTU was taken by both the treatment and control groups; the treatment group additionally took 4 capsules of Jiakang mianyi jiaonang formula 3 times daily for 90 days, while the control group took the formula jiakangning pian (the herbs in this formula were not specified in the Cochrane review) at 6 tablets 3 times per day. The study was of parallel group design and single-blinded. Outcomes included symptom relief, body weight increase, and plasma thyroid hormone levels. The study found no statistically significant improvement in treatment versus control groups for any outcome. The Cochrane review notes the herbal preparation was prepared by the authors' hospital and that this was a local government-supported project. In addition, the lack of distinction in this study between patients with Graves' disease and those with subacute thyroiditis may have impacted outcomes since, as enumerated above, neither antithyroid drugs like PTU nor antithyroid botanicals can prevent the leaking of stored thyroid hormone from inflamed tissue that causes the transient hyperthyroidism characteristic of this condition. Furthermore, the lack of distinction between these two patient groups in this study would confound any potential immune-modulating benefit of the Xia Ku Cao-containing herbal formula.

Scrophularia: Scrophularia (Xuanshen in Mandarin or Hei Shen in Cantonese) root is administered in TCM fresh or dried to "drain fire and disinhibit the throat."( n38) Scrofula is an archaic term describing tubercular swelling of the lymph nodes; its inclusion in the Latin binomial of this plant is indicative of its traditional use to treat nodules and goiter.( n32) Modern in vitro research reveals that plants in this genus contain antimicrobial,( n51) anti-inflammatory,( n52) and antitumor( n53) properties. No studies or abstracts in English were found documenting the root's effect on thyroid disease in humans. Scrophularia root or Xuanshen is included in 2 formulas evaluated in the Cochrane review of included studies of Chinese herbal medicines for hyperthyroidism. Xuanshen is included in the Qiu et al (2003) study of the TCM herbal formula Erdong Tang with Xiaoluwan Jiawei described above in the sections on prunella and fritillary.( n44) Xuanshen was also one of 10 herbs in the formula Yikang wan, given as 1 pill 3 times per day plus methimazole, versus methimazole alone in an unblinded parallel group study of 62 hyperthyroid patients.( n54) Outcomes included clinical symptom relief and thyroid function tests at 2, 3, and 4 weeks after treatment. The study found improvement in all outcomes in more individuals in the treatment group vs. control, but statistical significance is unclear. The Cochrane review concluded there was potential conflict of interest in that the herbal formula was provided by the company sponsoring the magazine in which the study was published.

Rehmannia: Rehmannia (Shengdi in Mandarin) prepared or cured root or rhizome is considered in TCM to be nourishing to the liver and blood and also to have heat-clearing properties. Its use in thyroid formulas stems from the idea in TCM that thyroid disorders are ultimately rooted in liver and kidney disorder.( n34) Modern in vitro studies reveal that extracts of the plant may have antioxidant( n55) and anticancer( n56) activity. A study in mice suggested a hepatic protective effect.( n57) No studies or abstracts in English were found documenting the root preparation's effect on thyroid disease in humans. Rehmannia rhizome or Shengdi is part of the herbal formula Erdong Tang with Xiaoluwan Jiawei evaluated by Qiu et al (2003) discussed previously.( n44) It is also part of the formula Yikang wan evaluated by Huang (2003) as summarized above for the herb scrophularia.( n54) A third study included Shengdi as one of 12 herbs, also including prunella flower.( n49) A fourth study included in the Cochrane systematic review examined Shengdi as one of 4 herbs of a formula used in a parallel single-blind study of 93 patients with Graves' disease.( n58) The herbs were made into granules, and 1 ampoule per day was given for 8 weeks to the treatment group along with PTU, while PTU alone was used by the control group. Outcomes included plasma thyroid function tests. Free T3 and free T4 of both treatment and control groups were improved at 8 weeks; statistical significance is unclear. The Cochrane reviewers concluded there was potential conflict of interest in the study.

Conclusion
Herbal medicines may be used as adjunct treatments for autoimmune thyroid diseases such as hypothyroidism and hyperthyroidism, the physical abnormalities (often referred to nonspecifically as "goiter," "nodules," or "thyroiditis") that can result from or precipitate the physical symptoms of these diseases, and for the malignant nodules that characterize thyroid cancers. However, large, randomized, double-blind, well-controlled studies in humans for their efficacy in any of these disorders are lacking. Most of the studies of botanical medicines for the treatment of thyroid disease have centered on hyperthyroid conditions. For herbs used to treat hyperthyroidism in TCM, a recent systematic review of 13 trials that met reviewers' inclusion criteria suggests that some herbal formulas used in conjunction with pharmaceutical antihyperthyroid drugs may provide marginal improvement over antihyperthyroid drugs alone with regard to symptom relief, thyroid hormone function tests, and relapse rates.( n33) However, reviewers evaluated these studies as low quality due to small sample sizes, unblinding or single blinding, and potential for conflicts of interest. The authors of the systematic review have 52 more studies to evaluate, which may yield more information. Currently there is scant published information supporting use of TCM herbal formulas alone for treating hyperthyroid conditions.

Therefore, initiation of treatment with any herbs for any type of thyroid disorder should be considered only under the supervision of a healthcare provider well trained in the use of herbs or TCM for thyroid disease. Such treatment is best done using information obtained with some tools of conventional medicine--blood chemistry analysis, FNAB, ultrasound, and radionuclide imaging--which can give the practitioner and patient an idea about the possible source, characteristics, and progress of thyroid disease. Because disorders of the thyroid are complex, idiosyncratic, and impact other body systems, courses of treatment with either alternative or conventional regimens (or both) must be carefully tailored to the individual, with assiduous attention to the individual's symptoms and plasma thyroid function analysis.

DIAGRAM: Illustration of the location and parts of the thyroid. Illustration by Robert Morreale/Visual Explanations, LLC. ©2008 American Society of Clinical Oncology Background photo: Kelp Laminaria spp. ©2008 Steven Foster

DIAGRAM: Illustration of the location and parts of the thyroid. Illustration by Robert Morreale/Visual Explanations, LLC. ©2008 American Society of Clinical Oncology

DIAGRAM: Chemistry of thyroxine (T4) and triiodothyronine (T3) formation: Most hormone released from the thyroid gland is in the form of thyroxine (T4); however, enzymes remove an iodine atom from about half the thyroxine molecules released, to form additional triiodothyronine (T3), which is the most active form of the hormone utilized by cells.

PHOTO (COLOR): Bugleweed Lycopus virginicus ©2008 Steven Foster

PHOTO (COLOR): Lemon Balm Melissa officinalis ©2008 Steven Foster

PHOTO (COLOR): Rehmannia Rehmannia glutinosa ©2008 Steven Foster

PHOTO (COLOR): Chinese Yam Dioscorea oppositifolia ©2008 Steven Foster

PHOTO (COLOR): Kelp Laminaria spp. ©2008 Steven Foster

PHOTO (COLOR): Prunella Prunella vulgaris ©2008 Steven Foster

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By Katie Welch, Pharm D

Katie Welch is an herbalist and pharmacist currently practicing at an independent compounding pharmacy in Portland, Oregon. Welch earned her PharmD at Oregon State University in 2007 and was the 2007 recipient of the Natural Medicines Comprehensive Database Award, which is presented to an outstanding pharmacy school graduate who has shown an interest in evidence-based approach to patient care with regard to natural medicines. In 2006, she spent part of her fourth-year pharmacy-school curriculum as an intern at the American Botanical Council, where she broadened her knowledge of, and consolidated her research skills in, botanical medicine. A survivor of papillary thyroid cancer, Welch is especially interested in alternative treatment of thyroid disorders.

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