Enforcement

31 2.4.1 ANATOMY OF THYROID GLAND

The thyroid gland is the body’s largest single organ specialized for endocrine hormone production.

It is highly vascular, situated at the front and sides of the neck and consists of right and left lobes connected across the midline by a narrow portion, the Isthmus. It weighs about 25-30g.⁽²⁴⁾

2.4.2 STRUCTURE OF THE THYROID GLAND

The thyroid gland is invested by a thin capsule of connective tissue, which projects into its substance and imperfectly divides it into masses of irregular forms and sizes. A cross section shows a brownish-red color, seen to be made up of a number of vesicles containing a yellow fluid. The vesicles are of various sizes and shapes, and contain as a normal product a viscid, homogenous, slightly yellowish colloid material. The thyroid gland synthesizes and releases into the vascular channels a substance formed under normal conditions in the outer pole of the cell and excreted directly without passing through the follicular cavity. In addition to this direct mode of secretion, there is an indirect mode which consists of condensation of the secretion into droplets, having high content of solids and an extension of these droplets into the follicular cavity.⁽²⁵⁾

2.4.3 SYNTHESIS OF THYROID HORMONES

The synthesis and storage of thyroid hormones occur between follicular cells and the colloid.

Different follicles may be in different stages of activity. The less active follicles cells have a more cuboidal appearance, while the active follicles have columnar cells. Sodium-Iodide Symporter (Na-I Sympoter) which spans the cell basal membranes actively transports iodide from the blood.

At the thyrocyte’s apical border, a second iodide transport protein, pendrin, transports iodide to the membrane-colloid interface, where it becomes a substrate for thyroid hormogenesis. Once inside the follicular cell, iodide is oxidized to active iodine by hydrogen peroxide generated by a

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NADPH oxidase in the presence of calcium cations, a process catalyzed by the heme-containing enzyme Thyroid Peroxidase (TPO).⁽²⁶⁾

At the apical-colloid interface, iodine is immediately incorporated into the tyrosine residues of the large glycoprotein thyroglobulin molecules. Once iodinated, thyroglobulin is taken up into the colloid of the follicle where while still incorporated in the protein, a coupling reaction between pairs of iodinated tyrosine molecule occurs. This coupling of two tyrosine residues, each iodinated at two positions (di-iodotyrosine, DIT) produces tetra-iodothyronine or thyroxine (T4) while the combination of DIT with mono-iodotyrosine (MIT) produces tri-iodothyronine (T3). This coupling is catalyzed by TPO. Thyroid hormones are stored in this state and only released when the thyroglobulin molecule is taken back up into the follicular cells. Stimulated by Thyroid Stimulating Hormone (TSH), thyroglobulin droplets are captured by the follicular cells by a process of pinocytosis. Fusion of the droplets with lysosomes results in hydrolysis of the thyroglobulin molecules and release of T4 and T3. Approximately 100µg of the thyroid hormones are secreted from the gland each day, mostly in the form of T4 with about 20% as T3.

Eighty percent of T4 undergoes peripheral conversion to the more active T3 in the liver and kidney (T3 is ten times more active than T4) or reverse T3 (rT3) that has little or no biological activity.

Very small quantities of other iodinated molecules such as MIT and DIT as well as thyroglobulin are also measurable in the circulation.⁽²⁶⁾

2.4.4 TOTAL AND FREE THYROID HORMONES

Thyroid hormones circulate in the blood bound to carrier proteins with only 0.04% of T4 and 0.4%

of T3 unbound or free and consequently available for entry and action in target tissues. There are three major thyroid hormone transport proteins: Thyroxine Binding Globulin (TBG), Transthyretin

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and Albumin. The plasma protein binding permits delivery of thyroid hormones which are otherwise poorly soluble in water and also creates a large pool of circulating thyroid hormone with a stable 7-day plasma half-life ensuring homogenous distribution of thyroid hormones.⁽²⁷⁾

Only free (unbound) portions of thyroid hormones are believed to be responsible for biological actions. The concentrations of carrier proteins are altered in many clinical conditions including HIV/AIDS.^(28-29) In normal thyroid function, as the concentrations of the carrier proteins change, the total thyroid hormone level also changes, though the free hormone concentrations remain constant. Measurement of free thyroid hormone concentrations (free T3and free T4) therefore correlate more reliably with a patient’s clinical status.⁽³⁰⁾

2.4.5 THYROID AUTOANTIBODIES

Anti-thyroid autoantibodies (anti-thyroid antibodies) are targeted against one or more components of the thyroid gland. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (Anti-TPO antibodies), thyrotropin receptor antibodies (TRAbs) and thyroglobulin antibodies (Anti-TG antibodies).⁽³¹⁾

Graves’ disease has in recent times been described as a form of Immune Reconstitution Inflammatory Syndrome (IRIS) when found among HIV-infected patients who are on HAART.⁽³²⁾ It is however pertinent to screen patients for anti-thyroid antibodies while being evaluated for thyroid function abnormalities especially when on HAART.

Samad et al⁽³²⁾ in a study on Immune Reconstitution after initiation of HAART in patients with HIV/AIDS reported four cases of Graves’ IRIS out of the fifty subjects studied with markedly elevated thyroid autoantibodies (anti-TG and anti-TPO). It was suggested that HIV-infected individuals on HAART who present with weight loss and other signs and symptoms of

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hyperthyroidism despite adequate and sustained immunological and virological control should have anti-thyroid antibodies assayed to rule out possibility of Graves’ IRIS. However, another study did show that elevated levels of anti-thyroid antibodies are non-specific consequences of increased B-cell activation seen in the clinical course of HIV infection.⁽³³⁾

Salvatore et al⁽³⁴⁾ investigated thyroid function in 102 asymptomatic HIV-infected patients alongside a control group of in-patients. Values of FT3, FT4 and TSH were found to be similar to those of controls. Elevated anti-TG and anti-TPO were seen in 28% of the HIV-infected group.

They attributed the occurrence of elevated anti-thyroid autoantibodies to previous thyroiditis and possibility of opportunistic pathogens.⁽³⁴⁾

Studies on prevalence of thyroid abnormalities among blacks suggest that blacks tend to have lower prevalence of thyroid dysfunction.⁽³⁵⁾ Sichieri et al⁽³⁵⁾ in 2007 studied the prevalence of hypothyroidism among three different races resident in Rio de Janeiro, Brazil and reported that while the overall prevalence of hypothyroidism among whites were 16.7%, it was 8.8% among mulattos and 6.9% among blacks. Also Kanaya et al⁽³⁶⁾ in 2002 reported that blacks in San Francisco, California had a lower prevalence of thyroid dysfunctions compared to whites in the same locality. Both studies looked at people from the general population of residents in their respective localities without regards to their HIV status.^(35-36)