(EBSLN), the superior pole of the thyroid, and the superior thyroid artery. With type 1 anatomy, the nerve crosses the superior

thyroid vessels 1 cm or more above the superior thyroid pole. With type 2 anatomy, the nerve crosses the vessels less than 1 cm

above (type 2a) or even below (type 2b) the superior pole. Type 2 variants are the most vulnerable to iatrogenic injury.

Parathyroid Relationships

Parathyroid glands are encountered during thyroidectomy by virtue of their association with the thyroid

gland, however, ectopic parathyroid glands will typically not be encountered. The superior parathyroid

gland is usually located in a relatively constant area largely because of the embryologic association

between the lateral thyroid component and the superior parathyroid anlage (both associated with the

fourth branchial pouch). The tubercle of Zuckerkandl is anatomically associated with the position of the

superior parathyroid gland as well as the RLN. In relation to the point at which the RLN intersects the

ITA, a 2-cm circumscribed area on the cranial aspect will often contain the superior parathyroid gland.

It may also be found tucked posterior to the ITA or even posteromedial to the superior thyroid pole.

There is an 80% chance that a superior parathyroid gland will be found in a position similar to its

contralateral partner.

Figure 75-4. Classification scheme for regional lymph node basins in the neck.

The location of the inferior parathyroid gland is more variable. It may be found on the anterior aspect

of the inferior thyroid pole or on the inferolateral aspect. It may also be in the triangular region caudal

to the ITA and anterior to the RLN. If it is not in these locations, it is often embedded in fat and thymic

tissue within the thyrothymic tract. The symmetry of inferior parathyroid glands from side to side is

approximately 70%.

THYROID PHYSIOLOGY

Production of Thyroid Hormones

The thyroid gland produces thyroxine (T4

), triiodothyronine (T3

), and calcitonin under regulatory

mechanisms. The production of thyroid hormone by the follicular cells is ultimately orchestrated by the

anterior pituitary gland through its secretion of thyrotropin (TSH) to maintain a euthyroid state through

a feedback loop. The production of thyroid hormone by the follicular cell (thyrocyte) is depicted in

Figure 75-5. Approximately 100 to 150 μg of daily dietary iodide is required for normal thyroid

hormone synthesis to occur. In most developed regions of the world, daily intake from iodinecontaining foods is usually far in excess of this requirement and the kidneys excrete the iodide not

utilized by the thyroid. The active uptake of iodide in the thyroid occurs on the basolateral aspect of the

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follicular cells through a Na+/I− symporter which is mediated by a Na+/K+-adenosine triphosphatase

(ATPase) pump. Both TSH and the circulating concentration of iodide influence this symporter system.

TSH acts upon the thyroid gland to regulate the synthesis of thyroglobulin (Tg), the active uptake of

iodide, its incorporation with tyrosine (an oxidative reaction catalyzed by thyroid peroxidase [TPO]),

the subsequent production of T4 and T3

(and their storage bound to Tg in the colloid component of the

gland), and ultimately the release of both T4 and T3

into the circulation. Hormone release is an active

process of micropinocytosis that involves resorption of the bound Tg from the colloid compartment into

the follicular cell where enzymatic degradation releases T4 and T3

, which is released from the basal

portion of the cell into the circulation. T4

is produced in preference to T3

in the thyroid gland by a ratio

of approximately 13:1 in normal states. T4 has a relatively weak biologic action, so peripheral

conversion to the more active T3 hormone is required. Most of this takes place in the plasma and liver

by type 1 deiodinase enzymes. All of the T4

in the circulation is derived from the thyroid, whereas less

than 20% of T3

in the circulation is from the thyroid, the majority being produced enzymatically from

monodeiodination of T4

in the periphery. In circulation, most thyroid hormone (>99% of both T4 and

T3

) is bound to proteins such as thyroxine-binding globulin (TBG), albumin, and thyroxine-binding

prealbumin. Protein-bound thyroid hormones are considered biologically inert because they do not enter

cells until they are released from proteins to circulate in the very small free fraction. The half-life of T4

is approximately 7 days, whereas the half-life of T3

is much shorter – on the order of 8 to 12 hours.

Figure 75-5. Thyroid hormone metabolism. Thyroxine (T4

) and Triiodothyronine (T3

) are produced by the thyroid follicular cell

in a complex biochemical pathway. It is dependent on the movement of circulating iodide through the follicular cell and into the

intracellular colloid space. T3 and T4 are then bound to Thyroglobulin (Tg) for eventual transport back through the follicular cell

to be released into the intravascular space.

Action of Thyroid Hormones

Thyroid hormones have many effects on various body tissues. The peripheral conversion from T4

to T3

increases the binding affinity of thyroid hormone for the nuclear thyroid receptor protein at least 10-

fold. T3 acts within the nucleus of peripheral tissues via four T3 nuclear receptor subtypes to activate T3

-

regulated gene transcription. Ultimately, the physiologic actions of thyroid hormone relate to growth,

differentiation, calorigenesis, and TSH suppression.

Calcitonin is a 32-amino-acid polypeptide that is physiologically effective in many other species, but

in humans it is apparently less important. Although exogenous calcitonin may have a therapeutic effect,

endogenous calcitonin secretion rarely results in an impact on serum calcium levels which are primarily

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mediated by parathyroid hormone.

RELEVANT LABORATORY TESTS

An understanding of the normal relationship between free T4

(FT4

) levels and TSH levels is critical for

appropriate interpretation of thyroid function tests. Thyroid function can be determined directly, by

measuring FT4

levels, or indirectly, by measuring TSH. If TSH is to be used as the primary indicator of

thyroid dysfunction, an intact hypothalamic–pituitary axis is required. Normally, a log/linear inverse

relationship between TSH and FT4

is defined by the negative feedback inhibition of TSH secretion by

circulating thyroxine levels, therefore minor perturbations of FT3 and FT4

lead to wide suppression or

elevation of TSH levels. High TSH and low T4 and T3

levels are indicative of hypothyroidism and low

TSH and high T4 and T3

levels are characteristic of hyperthyroidism. It is likely that each individual has

a genetically determined FT4 set point. Early subtle deviation from that set point will cause amplified

changes in the TSH value, thus making TSH a very sensitive and clinically useful early indicator of

thyroid dysfunction.

Thyroid-Stimulating Hormone (Thyrotropin)

As the sensitivity and specificity of current TSH assays are quite high, the indirect approach of

measuring TSH levels is the most sensitive method for detecting thyroid dysfunction. The inverse

relationship between TSH and FT4 also dictates that small alterations in FT4 will lead to a larger

response in TSH, thus adding further support to this strategy. Modern methods are generally based on

immunometric assays and are able to achieve a sensitivity of 0.02 mIU/L or less. At present, the normal

range for TSH is considered to be 0.45 to 4.12 mIU/L.10 The target range of TSH for patients treated

with levothyroxine (LT4

) for hypothyroidism during pregnancy or after thyroidectomy have a lower

target of 0.45 to 2.5–3.5 mIU/L.

Free Thyroxine and Free Triiodothyronine

Technically, it is easier to measure the total (free + protein-bound) hormone levels (measured at

nanomolar levels) as compared to the very small free hormone concentrations (measured at picomolar

ranges). Because T4

is more tightly protein bound than T3

, it is less bioavailable and, consequently, very

difficult to measure directly. Measuring FT4 or free triiodothyronine (FT3

) in preference to total

thyroxine (TT4

) or total triiodothyronine (TT3

) improves the ability to detect thyroid dysfunction in the

presence of thyroid hormone–binding abnormalities, which are relatively common. For example, some

common drugs such as phenytoin, carbamazepine, furosemide, and aspirin may compete with thyroid

hormone for binding to serum proteins.

Total Thyroxine and Total Triiodothyronine

Total hormone assays require an inhibitor to block or displace the hormone from its binding proteins.

This factor, along with large sample dilution, allows binding of the hormone to the antibody reagent.

Because of the 10-fold lower concentrations of T3

in the serum, the TT3 assay requires even greater

sensitivity and precision. Abnormal TT4 and TT3 measurements are more commonly caused by variance

in the binding capacity of serum protein rather than true thyroid dysfunction.

Thyroglobulin

The primary clinical use of thyroglobulin (Tg) measurement is as a tumor marker, which serves as an

index of the amount of DTC present (assuming that all normal thyroid tissue has been removed with

total thyroidectomy with or without radioiodine ablation). Tg is measured in the serum by

radioimmunoassay methods or by immunometric assays. The latter is more susceptible to competitive

interference by thyroglobulin autoantibodies (TgAbs), which cause an artifactual decrease in the

measured levels. TgAbs may be present in approximately 3% to 10% of the general population, 20% of

patients with differentiated thyroid carcinoma and 80% to 100% of patients with Hashimoto thyroiditis.

Sensitive quantitative TgAb determination is a critical accompaniment to serum Tg measurement

because the presence of these antibodies prevents the use of Tg as an accurate tumor marker for thyroid

cancer. The particular assay utilized must be sensitive enough to detect Tg levels at the lower end of the

reference range (1 to 3 μg/L). Elevated TSH levels typically stimulate higher levels of Tg, therefore

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interpretation of Tg levels require TSH determination at the time of measurement.

Thyroid Autoantibodies

Thyroid peroxidase autoantibodies (anti-TPOab) and antithyroglobulin autoantibodies (anti-Tgab) are

elevated in Hashimoto thyroiditis. A significant fraction (up to 12%) of people with no apparent thyroid

disorder may also have positive anti-TPOab titers. TSH receptor autoantibodies (anti-TSHRab) are

heterogeneous and may mimic the action of TSH to cause hyperthyroidism as in Graves disease or,

conversely, may block the action of TSH and cause hypothyroidism as occurs in neonates of a mother

with thyroid autoantibodies. Thyroid-stimulating immunogloblin (TSI) elevations suggest graves

disease.

Calcitonin

Basal calcitonin levels are generally less than 16 pg/mL for healthy people and for nearly all patients

with thyroid disease, other than medullary thyroid carcinoma (MTC). Therefore, calcitonin serves as a

very specific tumor marker for MTC. Basal calcitonin levels are useful for diagnosis and observation of

MTC patients.

THYROID IMAGING TECHNIQUES

Ultrasound (US) is the most useful imaging test for evaluation of structural thyroid pathology. Various

other imaging modalities may be useful in specific circumstances.

Ultrasonography

3 US is the imaging technique of choice to evaluate the thyroid gland and its surrounding structures. It

is best performed using a high-frequency “small parts” probe (7.5 to 15 mHz). As with any imaging

technique that depends on individual performance of the test, a user-dependent factor exists. US can be

especially useful when performed by the surgeon and allows appropriate preoperative planning. US is

the most sensitive and specific technique to determine the size, number, and distribution of thyroid

nodules. US often detects very small, subtle nodules that are not otherwise clinically evident. Studied

prospectively, the prevalence of asymptomatic thyroid nodules (thyroid incidentalomas) detected by

ultrasonography is approximately 67%, whereas physical examination identifies thyroid nodules in

approximately 5% to 8%.11 Hyperechoic nodules are often benign, whereas thyroid malignancies,

regardless of cell type, are often hypoechoic. Irregular margins between the nodule and surrounding

tissues raise concern for malignancy. An anechoic rim around the nodule is referred to as a “halo” sign

and is more likely to be associated with a benign nodule (Figure 75-6A). Larger macrocalcifications with

posterior acoustic shadowing are usually indicative of chronicity and are more likely associated with a

benign nodule, whereas subtle microcalcifications, which cause a “twinkling” or “stars in the sky” effect

when the transducer is moved across the nodule, are correlated with malignancy (Figure 75-6B). In

practical terms, selective FNA biopsy is indicated for nodules greater than 1–1.5 cm, those with

concerning US features, or those that have increased in size under serial US measurement.12 Because US

can detect nodules at a preclinical stage, it follows that proper perspective about the significance or

insignificance of these nodules must be maintained. US has an important role in the preoperative staging

and postoperative follow-up of patients with differentiated thyroid carcinoma and evaluation of the

cervical lymph nodes with ultrasound should be considered mandatory prior to surgery. In experienced

hands, it is a very sensitive technique for detecting abnormally enlarged lymph nodes or tumor

recurrence within the thyroid bed, and for guiding subsequent confirmatory biopsy. It is especially

important for identifying sites of recurrent thyroid cancer in those patients with negative radioactive

iodine (RAI) scans or in dedifferentiated tumors that are no longer iodine avid.

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