Many cases of TNG are detected during routine screens of asymptomatic patients. Thus, the following applies to symptomatic TNG patients. Upon query and physical examination of apparently healthy individuals, mild but characteristic findings may also be revealed.

TNG is typically developed by patients with a long medical history of goiter. Symptoms may be caused by metabolic disturbances due to increased serum levels of thyroid hormones and by local mass effects exerted by space-occupying nodules.

With regards to the former, patients may present characteristic symptoms and signs of hyperthyroidism, i.e., anxiety, irritability, intolerance to heat, tremor, arrhythmias, hypertension and weight loss despite an increased appetite. However, loss of appetite has been reported in elderly patients. Also, instead of frequent bowel movements and diarrhea - which are manifestations of hyperthyroidism observed in younger individuals - constipation may occur.

A single palpable mass or multiple nodules in the anterior neck region is generally noted. In a case of considerably enlarged thyroid glands, hoarseness, dyspnea and dysphagia may be triggered by growing nodules compressing larynx, recurrent laryngeal nerve, trachea, and esophagus. Such symptoms and signs are less common than those related to hyperthyroidism.

Because most TNG patients are older than 50 years, comorbidities are generally present and may dominate or complicate the clinical picture. This particularly applies to cardiovascular symptoms and osteoporosis.

Laboratory analyses of blood samples are first-line diagnostic measures applied in symptomatic patients and are in fact the source of a tentative diagnosis of TNG in many asymptomatic individuals. Serum levels of TSH are the most sensitive parameters and many patients show decreased concentrations of TSH accompanied by only minor increases in thyroid hormone levels. Although the diagnosis of primary hyperthyroidism is largely facilitated by detection of elevated concentrations of free or total T4 and T3, only reduced TSH levels are required for a diagnosis of TNG.

Certain pathologies and drugs may interfere with thyroid hormone metabolism, and this fact should be considered in multimorbid older patients who receive, for instance, amiodaron, other iodinated compounds, propranolol or thyreostatics like propylthiouracil [9] [10]. If peripheral conversation of T4 to T3 is inhibited, T4 concentrations rise and T3 levels diminish.

Scintigraphy with iodine-123 or technetium-99m may be performed subsequently to assess the condition of thyroid tissue, to evaluate whether the whole organ presents pathological alterations or there are demarcated nodules, and to distinguish autonomously functioning "hot" nodules from non-functional ones. Both types may coexist. In TNG patients, one or more hot nodules are depicted by scintigraphy.

Nodules may also be visualized by sonography. This technique is often applied to guide fine-needle aspiration biopsies, which are required to characterize functional thyroid nodules suspicious for thyroid cancer. Only histopathological analysis of such specimens allows for a distinction between TNG and distinct types of neoplasms. Although it has long since been assumed that cancerous tissue usually corresponds to cold nodules, 10% of TNG patients have been diagnosed with thyroid cancer in recent studies [11]. If patients present with multinodular disease, it may be necessary to obtain several samples since different nodules don't necessarily behave identically.

Although patients may be reluctant to accept radioiodine therapy or thyroidectomy as treatment options, sole drug therapy is no longer recommended for TNG. A great advantage of radioiodine therapy and surgery is that they are also effective against distinct types of thyroid cancer. The fact that TNG-associated mortality mainly results from malignant degeneration of thyroid cells should seriously be considered when deciding on a therapeutic approach [3]. Antithyroid drugs and symptomatic medications are of great value though when preparing a patient for radioiodine treatment or thyroidectomy. Methimazole, carbimazole, propylthiouracil, as well as beta blockers, are most commonly administered to this end.

Radioiodine therapy is preferred over thyroidectomy. Only patients who present large tumors, symptoms of mechanical obstruction, or who did not respond well to radioiodine treatment should be referred for surgery. Near-total or total thyroidectomy is generally realized.

TNG is generally related with a good prognosis. The outcome worsens if hyperthyroidism is inadequately controlled - a condition that should be prevented by regular blood sample analyses and, if there is a need, adjustment of drug therapy - or if surgery is not performed despite cancerous tissue being present [7]. Indeed, a reduced life expectancy due to TNG is primarily associated with cancer [8]. About 20% of patients may develop hypothyroidism after successful treatment of TNG, but thyroid hormones can be substituted.

When considering TNG etiology, both components of the disease have to be contemplated. TNG patients primarily present goiter that is most commonly associated with iodine deficiency. If follicular cells are unable to synthesize adequate amounts of thyroxine (T4) and triiodothyronine (T3), a release of TSH by the pituitary gland increases. The latter stimulates thyroid cell hyperplasia, which provokes goiter [4]. This is essentially a physiological mechanism, although the thyroid gland may not be able to compensate for iodine deficiency despite induction of growth.

In TNG, thyroid follicular cells produce T4 and T3 independent of TSH levels, i.e. the afore-described process cannot be interrupted by supplementation of iodine. In healthy individuals, TSH binds to a G protein-coupled receptor expressed by follicular cells. Upon ligand binding, the α subunit of the Gs protein mediates activation of adenylyl cyclase and generation of cyclic adenosine monophosphate. The latter accounts for the induction of several downstream events and thereby causes thyroid hormone production. If TSH levels decrease, this pathway becomes less and less active. In contrast, constitutive activation of this cascade causes autonomous hormone production in toxic nodules of TNG patients.

The latter occurs due to de novo mutations of those genes encoding for the TSH receptor or the adenylyl cyclase-activating α subunit of the aforementioned Gs protein [5]. Hyperplasia is associated with enhanced cell division and thus, the risk of gene mutations is augmented. A sustained proliferation of degenerated cells then leads to the formation of one or more toxic nodules. Of note, non-toxic nodules may coexist with toxic ones. If cells obtained from non-toxic nodules are analyzed, distinct gene defects may be revealed.

Some TNG patients may be predisposed to thyroid disorders after having inherited certain germline mutations that affect the gene encoding for the TSH receptor. These mutations are, however, not a prerequisite for TNG.

TNG incidence varies largely among developed and developing countries, or more explicitly, between geographical regions where iodized salt has been introduced years ago and those where this product is not used. Nevertheless, TNG is still considered the second most common cause of hyperthyroidism in industrialized nations. Here, higher incidence rates are only reported for Graves disease, an autoimmune thyroid disorder. With regards to the developing world, TNG is the most common trigger of hyperthyroidism. Of note, voluntary diet restrictions may also lead to TNG and are more frequently observed in developed countries [6].

TNG is typically diagnosed in older women. Females are affected five to ten times more often than men and the likelihood of developing TNG increases with age. The majority of TNG patients are older than 50 years.

TNG may be caused by a one or more functional nodules; in a case of the latter, the patient is diagnosed with toxic multinodular goiter. Generally, each nodule consists of monoclonal cells that present any of the aforementioned genetic defects. Distinct nodules may differ regarding their genome and behavior. This partially explains the increased risk of thyroid cancer in patients suffering from multinodular goiter. A recently published case report relates toxic multinodular goiter and anaplastic thyroid carcinoma and although this combination is very rare, this work highlights the possibility of toxic nodules to be malignant [7]. However, the pathophysiology of thyroid carcinoma in TNG patients is still a matter of debate. Neoplasms may arise from toxic nodules themselves or develop independently and in a case of functional tumors, a clear distinction may not be possible at the time of diagnosis.

According to data provided by the World Health Organization, about a third of the world's population ingests insufficient amounts of iodine. In the Americas, only 10% of the population consume less than 100 µg iodine per day; in Europe and the Eastern Mediterranean, this share rises to almost 60%. Sufficient iodine intake is the most efficient way to avoid goiter and because goiter is part of TNG pathogenesis, this measure can also be considered preventive against TNG. Consuming of iodized salt is therefore highly recommended.

Toxic nodular goiter (TNG) refers to the combined presence of goiter and one or more nodules that produce thyroid hormones in an autonomous manner and. Thus, TNG develops from a previously existing goiter and may be considered a late complication of the latter.

TNG is typically diagnosed in the elderly; because prevalence rates of goiter have been decreasing in developed countries after the introduction of iodized salt, TNG incidence is low in these geographical regions. However, iodine deficiency is still a major health concern in developing countries [1]. This condition does not only predispose for goiter, but also for follicular thyroid carcinoma.

Goiter does not necessarily result in TNG. A variety of gene mutations have been identified that render thyroid follicular epithelial cells insensitive to regulatory mechanisms mediated by varying concentrations of thyroid-stimulating hormone (TSH). Constitutive activation of determined intracellular pathways causes a continuous production of thyroid hormones despite low serum levels of TSH.

Consequently, TNG patients show symptoms characteristic for hyperthyroidism. They are irritable, nervous, unable to tolerate heat and suffer from tremor, arrhythmias, hypertension and weight loss. A thyrotoxic crisis constitutes an acute, life-threatening aggravation of hyperthyroidism. Here, patients show severe cardiovascular symptoms, vomiting, and diarrhea, subsequent dehydration, and finally reduced awareness. If not treated adequately, they may fall into a coma and die. Thyrotoxic crises rarely occur spontaneously, but they may be induced by TNG treatment [2].

Malignant degeneration of toxic nodules poses another threat to human health. However, it may not always be possible to distinguish between thyroid cancer due to TNG or concomitant neoplasms. Anyway, at least 3% of TNG patients develop thyroid cancer and this share may even be highly underestimated [3]. Patients who suffer from toxic multinodular goiter are more likely to develop neoplasms of the thyroid gland than those presenting a single nodule.

Thyroidectomy and/or radioiodine treatment are recommended for TNG patients. Both methods are also effective against possible thyroid neoplasms.

Toxic nodular goiter (TNG) is a thyroid disorder characterized by an enlargement of this endocrine gland and by the presence of one or more hormone-producing nodules.

In order to understand the pathophysiology of TNG, basic knowledge regarding regulatory mechanisms is required: In healthy individuals, production of thyroid hormones is strictly regulated. The key event is thyroid cells dispose of receptors for thyroid-stimulating hormone (TSH), the main inducer of hormone production. TSH serum concentrations diminish as soon as sufficient thyroid hormones are available and thyroid activity decreases. In turn, lack of thyroid hormones causes elevations of TSH levels and induction of hormone synthesis.

Patients who present with goiter may suffer from iodine deficiency. The thyroid gland is unable to produce adequate amounts of thyroid hormones, TSH levels rise and stimulate the proliferation of thyroid cells. This results in an overall enlargement of the thyroid gland.

In TNG patients, cell division during goiter development is related to gene mutations. These mutations render minor shares of thyroid cells insensitive to TSH regulation. These cells form nodules and produce abnormally large quantities of thyroid hormones. This leads to hyperthyroidism.

Consequently, TNG patients may note palpable masses in their anterior neck region and may suffer from anxiety, irritability, intolerance to heat, tremor, arrhythmias, hypertension and weight loss despite an increased appetite. Gastrointestinal disturbances may also be experienced.

Administration of radioactive iodine (radioiodine therapy) and surgical removal of altered thyroid tissue are effective treatment options that are generally related to a good outcome.

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