Clinical approach to thyroid disease in adults

ACHAIKI IATRIKI | 2023; 42(2):66–74


Athina-Lydia Mageiropoulou, Marina Michalaki

Endocrine Division, Medical Department of University of Patras, Patras 26504, Greece

Received: 17 May 2022; Accepted: 05 Oct 2022

Corresponding author: Marina Michalaki, e-mail address:

Key words: Thyroid, hypothyroidism, thyrotoxicosis, goiter, thyroid nodule, differentiated thyroid cancer



The thyroid gland is an endocrine organ which secretes the thyroid hormones namely thyroxine and triiodothyronine which regulate vitally important functions of the human body, such as growth and metabolism. Thyroid diseases could be classified as those affecting its function (hyperthyroidism or hypothyroidism) or/and its morphology (goiter, thyroid nodules). The present review focuses on the clinical manifestations, evaluation, diagnosis, and therapy of thyroid diseases in adults.


The thyroid gland is an endocrine organ, located in front of the trachea between the cricoid cartilage and the suprasternal notch, which secretes the thyroid hormones, namely thyroxine (T4) and triiodothyronine (T3). Thyroid hormones are iodinated tyrosine derivatives. The regulation of the synthesis and secretion of thyroid hormones is an example of negative feedback control by the hypothalamic thyrotropin-releasing hormone (TRH) and the pituitary thyrotropin (TSH) (Figure 1) [1]. Thyroid hormones are bound to plasma proteins, which are thyroxine-binding globulin (TBG), transthyretin and albumin and less than 1% of their total concentration remains free and active. Thyroid hormones act on their target tissues via TRa and TRβ nuclear receptor and promote brain and bone development in the fetus and during childhood, regulate the basic metabolic rate, appetite, heart rate, myocardial contraction, gastrointestinal motility and are involved in multiple functions of the human body [1]. Thyroid diseases could be classified as those affecting its function (hyperthyroidism or hypothyroidism) or/and its morphology (goiter, thyroid nodules). The diagnostic evaluation of thyroid diseases includes history, physical examination, laboratory measurements of thyroid hormones, TSH and antibodies against thyroid antigens and thyroglobulin in selected cases. Ultrasonography is very helpful in revealing thyroid nodules. Other imaging techniques like scintigraphy, computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) could be indicated in certain circumstances.

Figure 1. Hypothalamic-Pituitary-Thyroid axis, a paradigm of negative feedback regulation.


In hypothyroidism, the serum levels of T4 and T3 are low, due to impaired thyroid production (primary hypothyroidism) or very rarely due to hypophysis/hypothalamus defects (central or secondary hypothyroidism). The most common cause of primary hypothyroidism, in iodine sufficient areas, is the autoimmune Hashimoto’s disease and iatrogenic causes such as thyroidectomy or radioiodine thyroid ablation [2]. The clinical manifestations of hypothyroidism are atypical, including weakness, feeling cold, difficulty concentrating, constipation, weight gain with poor appetite and menstrual disturbances in women of reproductive age. Hypothyroid patients, have dry skin, puffy face with edematous eyelids, bradycardia, and slow tendon reflex relaxation (most characteristic Achille). The diagnosis is made by measuring unbound T4 (free T4, FT4) and TSH, which in the case of primary hypothyroidism is high whereas in central hypothyroidism is inappropriately low (Table 1) [2] . The measurement of antibodies against thyroid peroxidase (Ab-TPO) is helpful for the diagnosis of Hashimoto’s thyroiditis, and their levels are detectable in 90-100% of cases (Figure 2). The gold standard for the treatment of hypothyroidism of any cause, is the per os administration of levothyroxine (synthetic analog of thyroxine) pills in the morning on an empty stomach [3]. Approximately, 60-80% of ingested LT4 is absorbed in the jejunum and upper ileus. Absorption may be impaired in many circumstances, such as infection of Helicobacter pylori, atrophic gastritis, concurrent administration of certain drugs, as proton pump inhibitors, calcium and ferrum supplements and high fiber diet [4]. Recently, new forms of levothyroxine are available, like soft capsules or liquid preparations to overcome the difficulties with levothyroxine absorption [5]. The treatment goal is the replacement of the normal thyroid function which is evident when serum TSH levels are normalized in primary hypothyroidism or serum FT4 return to the upper reference range in central hypothyroidism [6]. There is a minority of hypothyroid patients, who do not feel well, despite adequate substitution of thyroid function with LT4. In those cases, the co-administration of T3 is an option [6].

Figure 2. Diagnostic algorithm for evaluation of hypothyroidism.
Abbreviations: TSH: Thyroid Stimulating Hormone; Ab-TPO: antibodies against Thyroid peroxidase; T4: thyroxine.


Thyrotoxicosis is the state of excessive circulating thyroid hormones, T3, T4 either due to their over-production and secretion from the thyroid gland, namely “hyperthyroidism” or due to their release from a destructed thyroid gland in case of thyroiditis or due to exogenous administration of high doses of thyroid hormones [7]. Extreme thyrotoxicosis leading to “thyroid storm” is a life-threatening situation [8]. The most common causes of hyperthyroidism are Grave’s disease, toxic multinodular goiter and toxic adenomas [7]. The clinical manifestations of hyperthyroidism involve symptoms from multiple organs and are mostly the same regardless of the cause of thyrotoxicosis. They depend on the severity, duration, and patient’s susceptibility to thyroid hormone excess [7]. Due to the enhanced metabolic rate, thyrotoxicosis can be presented as an unexplained weight loss despite an increased appetite, heat intolerance and easy sweating which makes their skin warm and moist. From the cardiovascular system, sinus tachycardia is the most common manifestation, occasionally associated with a sense of palpitations. As a result of a higher cardiac output, patients with a preexisting either known or subclinical heart failure or angina experience a deterioration of symptoms. Atrial fibrillation is common in patients >50 years of age and in about half of them it can remit after effective treatment of thyrotoxicosis. Other features are nervousness, hyperirritability, and insomnia, consequently leading to a sense of easy fatigability and impaired concentration. Also, diarrhea and mild steatorrhea, menstrual cycle disorders in women such as oligomenorrhea or amenorrhea, gynecomastia and impaired sexual function in men could be present. Osteopenia or even osteoporosis in the elderly, can occur due to long-standing elevated thyroid hormone levels, since they have a direct effect on bone resorption. In the elderly, fatigue and weight loss are predominant, whereas the other manifestations of thyrotoxicosis are missing, a syndrome known as “apathic thyreotoxicosis” which can be mistaken for depression.

The diagnosis of thyrotoxicosis is established by measuring high serum FT4, T3 and low or undetectable serum TSH levels (Table 1). In the extremely rare situation of a TSH secreting adenoma, serum TSH levels are inappropriately high [9] (Figure 3). In the case of Graves’ disease, the measurement of thyroid stimulating immunoglobulin (TSI) can confirm the diagnosis [10].

Figure 3. Diagnostic algorithm for evaluation of thyrotoxicosis.
Abbreviations: TSH: Thyroid Stimulating Hormone; RAI- ptake: Radioactive Iodine uptake; MNG: Multinodular Goiter.

Graves‘ disease (GD)

GD is an autoimmune disease and constitutes the most common cause  of thyrotoxicosis. The disease is the result of the production of autoantibodies against the TSH receptor (TRAb), which mimic TSH action and cause hormonal hyperproduction and enlargement of the thyroid gland [11]. However, not all TRabs are stimulatory for the TSH receptor, but some are inhibitory. TRabs that stimulate the TSH receptor are also known as TSI. If TSIs predominate, then hyperthyroidism would be manifested in patients with GD. Moreover, it seems that the TSH receptor is expressed also in orbital and skin fibroblasts and orbital adipocytes thus GD can particularly be associated with Graves’ orbitopathy in 30% of patients and very rarely with thyroid dermopathy [12]. The clinical manifestations of orbitopathy are exophthalmos, an anterior protrusion of the eyeball, motility disturbances manifesting with diplopia or pain, a sense of foreign body, orbital edema and conjunctival conditions, even visual loss if the optical nerve is compressed by the excessive tissue growth [13]. The course of Graves’ disease has remissions and exacerbations. Thionamides (methimazole, carbimazole and propylthiouracil) inhibit the synthesis of thyroid hormones and are used for the treatment of GD. However, thionamides may have serious side-effects, although rare, like agranulocytosis and hepatotoxicity. Thus, more radical therapies are recommended when relapse occurs or drug therapy fails, such as, ablation with radioactive iodine or total thyroidectomy. The choice of treatment for GD depends on its activity and severity. In Graves’ orbitopathy, control of risk factors, such as smoking and thyroid dysfunction, and local treatments are recommended in all patients. In active and severe Graves’ orbitopathy, high doses of glucocorticoids or rituximab intravenously can be used. Recently, teprotumumab, an anti-IGF-1R monoclonal antibody, has exhibited very promising results [11, 13, 23].

Toxic multinodular goiter (TMNG) and toxic adenoma 

Nodular thyroid disease commonly occurs in adults either as solitary or multiple nodules, which may be functional or not. Therefore, we can classify multinodular goiter in two categories, toxic multinodular goiter and non-toxic [14]. Toxic adenoma is a solitary functional thyroid nodule. Toxic multinodular goiter or toxic adenomas are characterized by functional autonomy caused mostly by activating mutations of the TSH receptor or the Gsa protein [14]. The clinical presentation of toxic MNG can be described as mild thyrotoxicosis. The treatment of toxic MNG is quite challenging [7]. Surgery is the definitive treatment of both nodular goiter and thyrotoxicosis. However, it is not the first treatment choice as the patients are usually elderly. Antithyroid drugs and beta blockers are usually used to control the symptoms of hyperthyroidism. Ablation with radioiodine could be a therapeutic option for elderly in whom thyroidectomy is contraindicated due to co-morbidities whereas it is the treatment of choice for toxic adenomas [7].


Thyroiditis is the inflammation and destruction of the thyroid gland and constitute a group of heterogenous diseases. The most common one is the “subacute granulomatous thyroiditis or de Quervain’s thyroiditis” which is of uncertain origin [15,16]. A possible history of upper respiratory tract infection a few weeks prior to the onset of thyroiditis is usually reported.  More frequently, it affects women of 30-50 years of age. The thyroid is painful and enlarged accompanied with fever and malaise. However, last year’s many cases of painless subacute thyroiditis (SAT) have been reported, up to 6,25% in one series [16], thus the diagnosis is delayed. The course of thyroiditis follows 3 phases: a) a thyrotoxic phase due to the damage of follicular cells and the release of pre-formed thyroid hormones and thyroglobulin, b) a hypothyroid phase caused by depletion of pre-formed thyroid hormones and the inability of the destructed gland to synthesize new and finally, c) the euthyroid phase during which the thyroid gland recovers, and its function is restored. Depending on the phase of illness, symptoms of thyrotoxicosis or hypothyroidism can occur. The diagnosis is confirmed by a high erythrocyte sedimentation rate (ESR) and low radioiodine uptake (<5%) in the face of thyrotoxicosis (T3 & T4 and TSH). White blood cell count is increased.  Antibodies are negative. If there is a diagnostical doubt, FNA (fine needle aspiration) biopsy can be useful. Aspirin and NSAIDs (nonsteroidal anti-inflammatory drugs) could be used but in most cases high doses of glucocorticoids are indicated. The disease subsides in most cases, but a few patients may experience relapses and a prolonged course over many months. Permanent hypothyroidism occurs in about 15% of cases [17]. In addition, SAT has been described within two weeks of SARS-CoV-2 infection [16, 17].

“Acute thyroiditis” is rare and is caused by the suppurative infection of the thyroid, caused by gram-positive or gram-negative organisms [18,19]. It commonly occurs in children and young adults mostly when a piriform sinus, a remnant of the fourth branchial pouch that connects the oropharynx with the thyroid is present. Moreover, it is prevalent in immunosuppressed patients, such as those with the acquired immunodeficiency syndrome (AIDS) [18]. The patient exhibits acute thyroid pain and a tender goiter. Fever, dysphagia, and erythema over the thyroid are common, as are systemic symptoms of a febrile illness and lymphadenopathy. The erythrocyte sedimentation rate (ESR) and white cell count are usually increased, but the thyroid function usually is normal. FNA biopsy shows thyroid infiltration by polymorphonuclear leukocytes. Drainage is recommended and intravenous antibiotic therapy according to the analysis of the fluid obtained from the neck mass or of blood cultures [19].

Silent thyroiditis either postpartum or sporadic is painless, without fever and malaise and with a similar clinical course to subacute thyroiditis. This condition concerns 5% of women 3-6 months after delivery and has an autoimmune origin. A brief phase of mild thyrotoxicosis of 2-4 weeks is followed by a 4-12-week phase of hypothyroidism. Radioactive iodine uptake is suppressed whereas ESR is normal and there is a presence of TPO antibodies. The disease is mild and transient, and no treatment is needed. Beta-blockers can be used during the thyrotoxic phase to control adrenergic symptoms.  An annual follow up is recommended thereafter because there is a possibility of the development of permanent hypothyroidism [18].

Several drugs can cause silent destructive thyroiditis, such as lithium, interferon alfa, interleukin-2, tyrosine kinase inhibitors, immune check point inhibitors and amiodarone.

Amiodarone’s effects on the thyroid gland

Amiodarone is an antiarrhythmic drug type III, which influences the thyroid gland in many ways [20]. The chemical structure of amiodarone is related to thyroid hormones and contains two iodine atoms. Amiodarone metabolism in the liver releases approximately 3 mg of inorganic iodine into the systemic circulation per 100 mg of amiodarone ingested, meaning that the administration of a regular dose of 200-400 mg of amiodarone per day loads the body with pharmacological doses of iodine. Furthermore, amiodarone alters thyroid hormone metabolism, may be toxic for the thyroid gland and is stored in adipose tissue and for this reason high levels of plasma iodine can persist even for more than 6 months following drug withdrawal. Normally, the first few weeks after the administration of amiodarone a transient slight elevation of serum TSH and FT4 occurs while T3 drops. However, when an underlying thyroid disease exists, amiodarone can cause either thyrotoxicosis or hypothyroidism. There are, two different types of thyrotoxicosis (AIT – amiodarone induced thyrotoxicosis); the first one is related to already existing thyroid disorder (Graves’ disease or multinodular goiter), in which the synthesis of thyroid hormones becomes excessive as a result of increased exposure to iodine (Jod-Basedow phenomenon); the second one appears in patients without any thyroid disorder and is a result of a drug induced lysosomal activation which causes destructive thyroiditis. The differential diagnosis between the two types is challenging and crucial because treatment completely differs between the two types of thyrotoxicosis [20]. The diagnosis is based on history of any thyroid disease, colored doppler and iodine uptake on scintigraphy, because unlike type 2, type 1 is characterized by increased vascularity and iodine uptake. The treatment of type 1 is antithyroid drugs whereas in type 2 high doses of glucocorticoids are given. Frequently, both treatments are used because the differential diagnosis between the two types is uncertain or mixed types exist. Rarely, drug therapies fail, and total thyroidectomy is indicated. The withdrawal of amiodarone is a matter of debate but in most cases is desirable. Additionally, the decision to withdraw is not urgent since the half-life of amiodarone is 100 days [20].

Non-thyroidal illness syndrome 

An interesting phenomenon found in patients with an acute severe non-thyroidal disease or fasting is the alterations in thyroid function tests namely “non-thyroidal illness syndrome” or “euthyroid sick syndrome” [21, 22]. The syndrome does not have any deleterious consequences in these patients, so it does not need treatment, and it seems that it is an adaptation of the organism to inhibit catabolism and save energy. The pathogenesis is not clearly described yet, but inflammatory cytokines such as IL-6, and drugs are involved. The most common pattern in the non-thyroidal illness syndrome is a decrease in total and free levels of T3 with normal levels of T4 and TSH. The severity of illness can correlate to the magnitude of fall of T3 levels. Peripheral deiodination of T4 to T3 is impaired leading to an increase of (inactive) reverse T3 (rT3), due to the inactivation of DI and DII deiodinase isoenzymes. In very severe disease or critical illness, patients may exhibit low T4 and TSH levels, associated with poor prognosis [22].

Goiter, thyroid nodular disease and thyroid carcinoma

Goiter is the enlargement of the thyroid gland due to the irregular growth of follicular cells [14]. Iodine deficiency, autoimmune disease or dyshormonogenesis cause hypothyroidism which in turn increases TSH secretion to restore normal thyroid hormone levels but concurrently TSH has trophic effects on the follicular cells. However, in most of the goiters no cause is identified. Long-standing goitrogenesis gives rise to the development of focal or nodular hyperplasia [14].  Nodular thyroid disease commonly occurs among adults either as solitary or multiple nodules, which may be functional or not, as mentioned above.

Thyroid nodules are common radiological findings, depicted as a discrete lesion in the thyroid gland that is radiologically distinct from the surrounding parenchyma [23]. The major clinical concerns related to nodules are the exclusion of malignancy (4-6,5% of thyroid nodules), evaluation of functional status and assessment for the presence of pressure symptoms [23]. Non-functioning benign nodules could be a colloids, Hashimoto’s thyroiditis, cysts, and more rarely follicular adenomas [24]. Papillary thyroid cancer is the most common type of thyroid cancer representing approximately 95% of all cases [25]. It originates from the epithelial follicular cells, is well differentiated and in most cases mortality is nearly zero. Other types of thyroid cancer are follicular and Hurthle Cell (oncocytic) carcinomas also derived from follicular cells with less favorable prognosis (10 years mortality around 10%) [25, 26]. Approximately 1-2% of thyroid cancers are medullary carcinomas, which originate from c-cells thus producing calcitonin which serves as a marker. It can be either sporadic or familial (MEN 2A, MEN 2B, familial MTC with other features) in 25% of cases and thus all patients diagnosed with medullary thyroid cancer (MTC) should be tested for RET (Ret Proto-Oncogene) mutations, pheochromocytoma, and hyperparathyroidism [25]. MTC has less favorable prognosis depending on the stage of the disease with mortality rate ranging from 0% to 100% from stage I to stage IV [27]. Finally, anaplastic carcinomas are rare (<1%), poorly differentiated, very aggressive with a poor prognosis. They spread locally into surrounding tissues like trachea, larynx, and laryngeal nerves. Also, thyroid lymphomas or metastases from other primary tumors such as renal carcinomas and melanomas could be detected [25].

During the initial evaluation a detailed history assessing risk factors, such as: head or neck radiation during childhood, total body irradiation for bone marrow transplantation, exposure to ionizing radiation in young age, family history of papillary or medullary carcinoma or thyroid cancer syndromes, presence of rapidly enlarging nodule or fixed nodule to surrounding tissues and pressure symptoms such as vocal cord paralysis and hoarseness is required [23].

Laboratory assessment should begin with the measurement of TSH levels. Low serum TSH suggests an overt or subclinical hyperthyroidism (Figure 4). A radionuclide thyroid scan should be performed next to determine the functional status of the nodule. Nodules may appear ‘hot’, ‘warm’ or ‘cold’ depending on whether they absorb radioisotopes more, less than or equally to the remaining normal thyroid tissue. Only non-functioning/cold nodules have a malignancy possibility, and these nodules should be punctuated to obtain specimens for cytological examination (FNA) [26]. The indication for the FNA of a cold thyroid nodule depends on its size and sonographic features (hypoechogenicity, irregular margins, shape with vertical bigger than transverse dimension, microcalcifications are indicative of malignancy). The cytological diagnosis is mostly reported according to the “2017 Bethesda System” [24]. There are six diagnostic categories and each one predicts the risk of malignancy: (i) nondiagnostic or unsatisfactory (5-10%.); (ii) benign (1-3%); (iii) atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) (15%); (iv) follicular neoplasm or suspicious for a follicular neoplasm (10-40%); (v) suspicious for malignancy (50-75%); and (vi) malignant (99%). The clinical management of non-functioning thyroid nodules depends on the cytopathological findings and the implying risk of malignancy. Thus, we do not operate on benign nodules which do not pressure adjacent vital structures, but we periodically evaluate them with ultrasound. For the unspecified categories (iii and IV), there are several options: where available, mutational analysis should be performed or repeat FNA after 6 months or lobectomy. Patients with cytological findings suggesting thyroid carcinoma should be referred for surgery. The gold standard for the treatment of differentiated thyroid carcinoma (DTC), which accounts for approximately of 90% of thyroid cancer, is total thyroidectomy followed by radioiodine therapy [26]. More recently, it became clear that the mortality rate is not parallel to the morbidity for DTC. New staging systems have been developed to predict disease persistence or recurrence which is independent of death. For example, DTC patients with small infiltrated cervical lymph had 10year survival nearly 100%, especially if they were younger than 55 years old. Thus, the American Thyroid Association (ATA) in 2015 categorized DTC patients as low, intermediate, and high risk for recurrence based on their clinicopathological characteristics. For low-risk patients, alternative therapeutical options are lobectomy instead of total thyroidectomy, avoidance of radioiodine therapy and even active surveillance without surgery for micropapillary (<1cm) thyroid carcinomas especially for elderlies with several co-morbidities [28]. In contrast, for high-risk patients with advanced DTC or MTC or anaplastic carcinomas besides total thyroidectomy, tyrosine kinase inhibitors can be used and seem very promising [27,29].

Figure 4. Clinical approach to thyroid nodule.
Abbreviations: TSH: Thyroid Stimulating Hormone; FNA: Fine Needle Aspiration

Conclusions and Future directions

Thyroidal diseases are complex including either functional or morphological or both disorders of the hypothalamic-pituitary-thyroid axis. The differential diagnosis in most cases is difficult and demands a thorough history and physical examination, targeted laboratory tests, ultrasonographic examination of the gland and in selected cases scintigraphy, CT, MRI or PET scans. Most of thyroidal diseases are treated successfully, however there are still unmet therapeutic needs especially for patients with Graves’ orbitopathy and advanced thyroid cancer. Furthermore, issues remain regarding the quality of life of patients even with mild thyroid diseases such as hypothyroidism. Novel diagnostic tools and treatments are expected in the near future.

Conflict of interest disclosure

None to declare

Declaration of funding sources

None to declare

Author Contributions

Athina- Lydia Mageiropoulou: data collection & drafting of the article & final approval of the article; Marina Michalaki: data collection & drafting of the article & critical revision of the article for important intellectual content & final approval of the article.


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