Physiology

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2 Thyroid Gland Anatomy andPhysiology

– Most RLN injuries are temporary (>80%). – Surgeon volume has been shown to have an inverse correlation with risk of

injury to the RLN [4].

• Non-recurrent laryngeal nerve is rare (<1.0% of patients) but much more com-

mon on the right side of the neck [1].

• Superior laryngeal nerve: also a branch of the vagus nerve, it has two subdivi-

sions, the internal and external branches. The external branch of the superior laryngeal nerve must be protected during mobilization of the upper pole of the thyroid. Injury causes hoarseness, decreased pitch and/or volume, and voice fatigue; of particular concern when operating on opera singers and stage actors [1, 5].

Other Surrounding Structures (Fig.2.1)

• Parathyroid glands.

• Common carotid artery.

• Internal jugular vein.

• Esophagus.

• Trachea.

• Manubrium and clavicular heads.

• Hyoid bone.

Physiology

Thyroid Cell Types [6]

• Follicular cells—originate from embryonic endoderm and produce thyroglobu-

lin and thyroid hormone; in the mature thyroid gland, follicular cells form into a single layer to create sphere-shaped follicles that are lled with colloid. The major component of colloid is thyroglobulin.

• Parafollicular C cells—originate from embryonic neural crest and produce

calcitonin.

Thyroid Hormone [6] (Fig.2.3)

• Thyroxine (T4) : T4 is a prohormone and requires conversion to triiodothyronine

in order to act on peripheral tissues. T4 makes up 90% of secreted thyroid hormone.

Fig. 2.3 The hypothalamicpituitary-thyroid axis. Source: Sorensen and Gauger [6]

Anterior pituitary

Negative

eedback

T4/T3

Hypothalamus

Thyrotropin-releasing hormone (TRH)

gland

Thyroid-stimulating hormone (TSH)

Thyroid

gland

F. T. Drake

• Triiodothyronine (T3): T3 is the biologically active form of thyroid hormone and

makes up 10% of secreted thyroid hormone.

• Thyroglobulin (TG) is one of the largest proteins in the human body; it is synthe-

sized by follicular cells in a process regulated by thyroid-stimulating hormone (TSH) and other transcription factors.

• Role of iodine:

– Iodine can only be acquired in the diet. – The thyroid contains >90% of the total iodide in the body. – The sodium-iodide symporter (rst cloned in 1996) allows iodide to enter the

thyrocyte against its concentration gradient, which enables storage of high levels of iodide in the thyroid gland.

– Iodide then crosses the apical cell membrane into the lumen of the follicle

where it undergoes organication and coupling, which are key steps in thyroid hormone formation. Both processes are catalyzed by thyroperoxidase (TPO).

• Organication is the process by which oxidized iodide is joined to tyrosyl resi-

dues located on the TG molecule; each tyrosyl may accept one or two oxidized iodide ions, resulting in either monoiodotyrosine (MIT) or diiodotyrosine (DIT) , respectively. DIT and MIT remain integrated within the TG molecule. Although there are over 100 tyrosyl residues on each TG molecule, only a fraction are available for iodination.

• Coupling is the process by which two DITs form T4 or one MIT and one DIT

forms T3. Again, these thyroid hormones remain as an integrated part of the TG molecule. Similar to organication, this process is catalyzed by TPO.

• Mature, iodinated TG is stored in the follicular lumen.

• To be released into the blood stream, TG has to cross back into the thyrocyte

cytoplasm from the follicular lumen; once in the cytoplasm, T3 and T4 are liberated from TG via several mechanisms. Both thyroid hormone and very small

2 Thyroid Gland Anatomy andPhysiology

amounts of TG are released into the blood stream. Thyroid hormone enters the circulation via passive diffusion from the follicular cell and via an active transport system across the cell membrane.

• Very little thyroid hormone circulates freely. The remainder is bound to carrier

proteins (mostly, thyroid-binding globulin, transthyretin, or albumin). Thyroid hormone’s half-life is 6–7days, which is the longest of any human hormone.

Thyroid Hormone Regulation [6] (Fig.2.4)

The hypothalamic-pituitary-thyroid (HPT) axis is a negative feedback system in which neurons in the hypothalamus sense circulating levels of thyroid hormone. Thyroid hormone receptors (specically the beta-2 isoform) in the paraventricular nucleus of the hypothalamus are bound by thyroid hormone and release thyrotropinreleasing hormone (TRH) . This is a negative feedback system; thus when thyroid hormone levels are high, TRH secretion is low, and when thyroid hormone is low, TRH secretion is high. Thyrotropin- (another name for TSH) releasing hormone stimulates the pituitary gland to release TSH.TSH released from the pituitary gland stimulates follicular cells to secrete thyroid hormone via activation of adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP) to stimulate essentially every step in the process of thyroid hormone production. (As will be discussed later, a mutation that effects cAMP is thought to be important in the formation of toxic follicular adenomas.)

Action ofThyroid Hormone

• Once inside of target cells in peripheral tissues, T4 is deiodinated by three types

of iodothyronine deiodinase:

Inner ring

3’

5’

Outer ring

Inner ring

Thyroxine (T4) Triiodothyronine (T3)

3’

5’

Outer ring

Fig. 2.4 Molecular structure of T3 and T4. Source: Sorensen and Gauger [6]

F. T. Drake

– Type 1 is primarily expressed in thyroid, liver, and kidney. – Type 2 is located in the endoplasmic reticulum and exclusively catalyzes T4

to T3. It is primarily located in brain, pituitary gland, thyroid gland, skeletal muscle, and brown adipose tissue.

– Type 3 is the major thyroid hormone deactivating enzyme and produces the

inactive metabolite “reverse T3”. With the exception of brain, skin, and gravid uterus, type 3 deiodinase is not active in normal adult tissues (but is present in some cancers) [6].

• Thyroid hormone can act within the nucleus, which is called genomic action, and

it can act at the plasma membrane, in the cytoplasm, and on the mitochondria, which is called nongenomic action. In genomic action, thyroid hormone (T3) binds to thyroid hormone receptors that upregulate the expression of certain genes. Different tissues express different thyroid hormone receptors [6].

• Cardiovascular system: T3 has an important role in cardiac development. In the

mature heart, T3 increases heart rate and myocardial contractility via direct genomic action on nuclear thyroid hormone receptors within myocytes and also by increasing myocardial sensitivity to catecholamines [7, 8].

• The urologic system: T3 helps regulate kidney development, renal hemodynam-

ics, and glomerular ltration rate. T3 also has a direct impact on a number of co-transport systems in the renal tubule [8].

• Musculoskeletal system: T3 is necessary for bone development. In adults, bone

mass maintenance and bone mineralization both involve thyroid hormone. Skeletal muscle contractile function and growth are regulated by T3; specically, skeletal muscle is stimulated to grow by T3, which increases the number and diameter of muscle bers [8].

• Nervous system: T3 is crucial in brain development, including differentiation of

neural and glial cells, development of synapses, and myelination. Thyroid hormone deciency during fetal development can lead to neurologic and cognitive defects. T3 increases the sensitivity of the sympathetic nervous system to catecholamines [7, 8].

• Overall metabolism: T3 increases the basal metabolic rate, increases oxygen

consumption, increases synthesis of certain proteins, and stimulates lipolysis, glycogenolysis, and gluconeogenesis [7].

Surgical Diseases of Disordered Thyroid Hormone

There are many clinical conditions that arise from or are manifested by disorders in the production or regulation of thyroid hormone. Most of them are non-surgical; however, endocrine surgeons do have an important role in the management of several disease states that arise from disorders of thyroid physiology. Three examples that may be encountered during a surgical clerkship are listed below, and are covered in much more detail in other chapters:

2 Thyroid Gland Anatomy andPhysiology

• Iodine deciency: TSH secretion is stimulated by low iodine, and increased TSH

promotes follicular growth and goiter formation. Although benign, these goiters can grow so large they have signicant and deleterious mass effect on the patient’s cervical and upper mediastinal structures [6].

• Graves’ disease: This is an autoimmune disorder caused by thyroid-stimulating

immunoglobulins (TSI) that bind to TSH receptors on thyroid follicular cells and cause hyperthyroidism that is resistant to the normal feedback control mechanisms of the HPT axis. These antibodies are also known as thyrotropin receptor autoantibodies (or TRAbs). Common signs and symptoms are tachycardia, diffuse goiter, tremors, weight loss, heat intolerance, palpitations, and nervousness or anxiety. About 25% of patients have ocular involvement, which is caused by the binding of TSIs to TSH receptors in the retrobulbar and periorbital tissues. Initial treatment is via antithyroid medications such as methimazole or propylthiouracil. Beta-blockers also play an important role. Surgery is one of two forms of denitive therapy and is favored in patients with severe eye disease, large goiters, co-existing thyroid nodules, or cancers, among other indications [9].

• Toxic thyroid nodule: These are adenomas that synthesize and secrete thyroid

hormone in an autonomous fashion, free from TSH regulation; indeed, TSH is generally suppressed in these patients. Recent data suggests that a mutation in the TSH-receptor gene may be related to the development of toxic nodules. This mutation activates the cAMP cascade in the thyrocyte leading to autonomous secretion of thyroid hormone and adenomatous growth. Most toxic nodules are follicular adenomas. Hyperfunctioning carcinomas are rare [10].

References

1. Mohebati A, Shaha AR.Anatomy of thyroid and parathyroid glands and neurovascular relations. Clin Anat. 2012;25(1):19–31. https://doi.org/10.1002/ca.21220.

2. Amdur RJ, Mazzaferri EL. Basic thyroid anatomy. In: Amdur RJ, Mazzaferri EL, editors. Essentials of thyroid cancer management. Boston, MA: Springer; 2005. https://doi.org/10.100

7/0- 387- 25714- 4_1.

3. Durán M, Sañudo J, Sancho JJ, Wojtczak B, Maranillo E, Sitges-Serra A.Recurrent laryngeal nerve branching. In: Randolph G, editor. The recurrent and superior laryngeal nerves. Cham: Springer; 2016. https://doi.org/10.1007/978- 3- 319- 27727- 1_8.

4. Adam MA, Thomas S, Youngwirth L, Hyslop T, Reed SD, Scheri RP, Roman SA, Sosa JA.Is there a minimum number of thyroidectomies a surgeon should perform to optimize patient outcomes? Ann Surg. 2017;265(2):402–7. https://doi.org/10.1097/SLA.0000000000001688.

5. Marchese-Ragona R, Restivo D, Mylonakis I, etal. The superior laryngeal nerve injury of a famous soprano, Amelita Galli-Curci. Acta Otorhinolaryngol Ital. 2013;33:67–71. PMID:

23620644.

6. Sorensen M, Gauger P.Thyroid physiology. In: Pasieka J, Lee J, editors. Surgical endocrinopathies. Cham: Springer; 2015. https://doi.org/10.1007/978- 3- 319- 13662- 2_1.

7. Cohen MS, Brunt LM.The endocrine system. In: O’Leary JP, Tabuenca A, editors. The physiologic basis of surgery. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

8. Brtko J.Thyroid hormone and thyroid hormone nuclear receptors: history and present state of art. Endocr Regul. 2021;55:103–19. https://doi.org/10.2478/enr- 2021- 0012</div>.

9. Burch HB, Cooper DS.Management of Graves’ disease: a review. JAMA. 2015;314(23): 2544–54. https://doi.org/10.1001/jama.2015.16535.

10. Patel K.Hyperthyroidism and thyroiditis. In: Pasieka J, Lee J, editors. Surgical endocrinopathies. Cham: Springer; 2015. https://doi.org/10.1007/978- 3- 319- 13662- 2_1.

11. Stathatos N. Anatomy and physiology of the thyroid gland. In: Luster M, Duntas L, Wartofsky L, editors. The thyroid and its diseases. Cham: Springer; 2019. https://doi.

org/10.1007/978- 3- 319- 72102- 6_1.

12. Martini FH, Nath JL, Bartholomew EF.Fundamentals of anatomy and physiology. 10th ed. NewYork, NY: Pearson Education; 2015.

F. T. Drake

Chapter 3

Hyperthyroidism: Differential Diagnosis andSurgical Management

JessicaM.Fazendin

Overview

• Hyperthyroidism results from increased production of thyroid hormone and

occurs in 1.2% of the US population.

• Hyperthyroidism can be attributed to both thyroid [toxic adenoma (TA), toxic

multinodular goiter (TMNG), Graves’ disease, subacute thyroiditis], and nonthyroid [i.e., medications (amiodarone, lithium, etc.)] etiologies.

• Clinical presentation and manifestation range from subclinical to overt thyro-

toxicosis and even thyroid storm, if not treated appropriately.

Evaluation

History

• Patients with hyperthyroidism present with a wide variation of symptoms that

include anxiety, irritability, insomnia, hyperactivity, lethargy and muscle fatigue, palpitations, heat intolerance, diarrhea, +/− weight loss.

Physical Examination

• Varies depending on the etiology and severity of disease.

J. M. Fazendin (*) University of Alabama at Birmingham, Birmingham, AL, USA e-mail: jmfazendin@uabmc.edu

Switzerland AG 2024 R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_3

• Tachycardia, tremulousness, rapid speech, hair thinning, sweating, eyelid retrac-

tion and/or proptosis (Graves’), single palpable nodule (TA), multiple palpable nodules (TMNG), and uniformly enlarged goiter (Graves’), neck pain and swelling (subacute thyroiditis).

• Overt thyroid storm is a life-threatening condition, with patients presenting with

AMS, fever, tachycardia, CHF, and/or other end-organ dysfunction.

J. M. Fazendin

Laboratory Tests

• Low serum TSH (less than 0.05mU/L).

• If TSH is low, elevated free thyroxine (T4) and triiodothyronine (T3) levels dif-

ferentiate between subclinical and overt hyperthyroidism.

• Based on clinical picture and presence/absence of nodule(s), thyrotropin recep-

tor antibodies [TRAb, (TSI or TBI)] can be ordered to assess etiology. Ex. Elevated TRAb may indicate Graves’ disease.

Imaging (Fig.3.1)

• Thyroid scan and radioactive iodine uptake test can differentiate between TA,

TMNG, and Graves’ disease, with preferential uptake in areas of greatest hormone production in the gland. Graves’ disease will show diffuse uptake while TA and TMNG will demonstrate nodular uptake.

• A thyroid scan can be deferred if the clinical picture of Graves’ disease is strong.

Treatment

• Medical

– Antithyroid agents (methimazole, propylthiouracil), beta-blockers, steroids,

and other medications (SSKI, Lugol’s solution, calcium channel blockers, lithium, and plasmapheresis).

– Up to a third of patients may have long-term remission on antithyroid medica-

tions and the rest will require denitive therapy. – Recommended short-term use only. – Complications of antithyroid medications include agranulocytosis and

hepatotoxicity.

• Denitive

– Radioactive Iodine

3 Hyperthyroidism: Differential Diagnosis andSurgical Management

Fig. 3.1 Thyroid scan showing toxic multinodular goiter with increased uptake within hot nodules

Contraindicated in pregnancy, smoking, very large glands with risk of tracheal compression, patients with thyroid eye disease (TED), and in pediatric patients. Delayed effect (weeks–months) to achieve cure, may require a second dose. Very small risk of secondary malignancy.

– Surgery

Preparation to achieve a euthyroid state prior to operation is preferred. Oral calcium supplementation before surgery to avoid hungry-bone syndrome postoperatively.

Type ofOperation

• Based on the etiology of hyperthyroidism:

– Toxic adenoma → lobectomy. Thyroid radiofrequency ablation or other abla-

tive techniques may also be a treatment option for certain single toxic

adenomas. – TMNG (if bilateral lobes involved) and Graves’ → Total Thyroidectomy. – Medical (i.e., amiodarone-induced thyrotoxicosis) → Total Thyroidectomy.

J. M. Fazendin

Surgical Complications inHyperthyroidism

• Complication rate (nerve injury, hypocalcemia, hematoma) no higher than thyroidectomy performed for other disease processes.

• Temporary hypocalcemia rates are increased in this population postoperatively, thought to arise from hungry bone syndrome (thyrotoxic osteodystrophy).

Physiology

Thyroid Cell Types [6]

Surgical Diseases of Disordered Thyroid Hormone

References

Overview

Evaluation

History

Physical Examination

Laboratory Tests

Treatment

Further Readings