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European Review for Medical and Pharmacological Sciences 2009; 13: 341-349 function tests: a review

G. SHIVARAJ, B. DESAI PRAKASH, V. SONAL, K. SHRUTHI, H. VINAYAK, M. AVINASH

Department of Biochemistry, J. N. Medical College, Belgaum 590010, Karnataka (India)

Abstract. – In this paper, we review the combination can give comprehensive data that tests that are executed to aid the diagnosis of would enhance the diagnostic accuracy1. thyroid dysfunction. pro- vide information at physiological, pathological and anatomical levels. Along with history and Total Thyroxine (T4/TT4) physical examination they owe to many specific The concentration of total T4 in adults ranges findings that are associated with thyroid func- from 5 to 12 µg/dL (64 to 154 nmol/L)1. The con- tioning. So an attempt has been made to put for- centrations of T4 below or above this range in ab- ward a gist of thyroid function tests. Serum tests sence of thyroid dysfunction, is as a result of an ab- of thyroid function are serum total thyroxine normal level of serum Thyroid Binding Globulin (T4), serum total triiodothyronin (T3), free thyrox- ine (FT4), free triiodothyronin (FT3), reverse tri- (TBG). Such abnormally high values are observed iodothyronin (rT3), thyroid stimulating in many physiological conditions in women with (TSH), serum and thyroglobu- hyperestrogenic state of pregnancy1. Hyperthy- lin (Tg). The serological tests are antithyroglobu- roidism and can be associated with lin antibodies (ATA) and antimicrosomal antibod- abnormal menstrual cycles2. Reference ranges for ies (AMA). An invasive test for histologic exami- thyroid function tests for TT in cord- is 7.4- nation is done by fine needle aspiration cytology 4 (FNAC) and noninvasive test includes ultra- 13.1 µg/dL, 1-2 weeks is 9.9-16.6 µg/dL, 1-4 sonography, magnetic resonance imaging, and months is 7.8-16.5 µg/dL, 1-5 years is 7.3-15 positron emission tomography. Further molecu- µg/dL, and 5-10 years is 6.4-13.3 µg/dL3. Small lar study provides molecular markers for thyroid seasonal variations and changes related to high alti- cancer. These tests can provide greater sensitiv- tude, cold and heat are also seen. The variation is ity and specificity that enhance the likelihood of also related to postural changes in serum early detection of ambiguous concentration and true circadian variation. There is with only minimal clinical findings. Lastly, in vivo tests are thyroidal radioiodine and uptake increased binding to serum proteins in cases of Fa- is also done. milial Dysalbuminemic (FDH) which shows increased TBG1. Subclinical primary Key Words: hypothyroidism is more common in persons with 4 Serum total thyroxine, Free thyroxine, Thyroid stim- chronic disease (CKD) . ulating hormone, Serum , Serum calci- In thyrotoxic state serum TT4 concentration is tonin. elevated and said to be that can be caused by Graves’ disease, Plummer’s disease (toxic ), early phase of acute thyroiditis, thyrotoxic factitia, struma ovarii and normal in some cases of Luft’s syndrome (Hy- permetabolic Mitochondrial Miopathy).

Introduction In hypothyroidism serum TT4 concentration is low in case of thyroid gland failure. It can be fur- Thyroid functions have subtle clinical features ther classified into primary, secondary and tertiary. associated with some forms of thyroid dysfunc- The cause for primary hypothyroidism can be tion. The clinicians must decide which test is best gland destruction and severe inborn error of hor- suiting to diagnose or exclude disorder. It is em- monogenesis, secondary hypothyroidism is caused phasized that single thyroid function test (TFT) is by pituitary failure and tertiary by hypothalamic not absolute in diagnostic accuracy and it must be failure. Sometimes it can be subclinical if there is thus a careful selection of such tests so that their thyroid transporter defect or defect1.

Corresponding Author: Shivaraj Gowda, MD; e-mail: [email protected] 341 G. Shivaraj, B. Desai Prakash, V. Sonal, K. Shruthi, H. Vinayak, M. Avinash

Serum Total (T3/TT3) are rarely used as stand-alone tests, but are em- A normal serum TT3 concentration in adult ployed in conjunction with a binding protein esti- range from 80-190 ng/dL1. It reflects the func- mate test i.e. Thyroid Hormone Binding Ratio tional state of peripheral tissue rather than secre- (THBR) to form a Free Hormone Index i.e. FT4I 12 tory performance of the thyroid gland. Sex dif- or FT3I . ference is small, but age difference is more dra- matic. The decline of mean TT4 is also observed Free Thyroxine (FT4) in old age all though not in healthy subjects, The normal values for FT4 in adults range 1 which suggest that fall in TT3, might reflect from 1.0 to 3.0 ng/dL (13 to 39 pmol/L) .A prevalence of non-thyroidal illness rather than minute amount of thyroid hormone circulates in an effect of age alone2. Positive co-relation be- the blood in a free form, not bound to serum pro- tween serum TT3 level and body weight has teins. It is in reversible equilibrium with the been observed5. are iodothyronines bound hormone and represents the diffusible that control growth and development, as well as fraction of the hormone capable of traversing cel- function and . The T3 and T4 lular membranes to exert its effects on body tis- level were found to be significantly raised in the sues. Although changes in serum hormone-bind- moderate depression as compared to the healthy ing proteins affect both the total hormone con- controls6. centration and the corresponding fraction circu- Thyroid study on mutations in the monocar- lating free in the euthyroid person, the absolute boxylate membrane transporter 8 (MCT8) concentration of free hormone remains constant genes, located on the X chromosome (Xq13-q21 and correlates with the tissue hormone level and 13 and Xq12-q13) has established the physiological its biologic effect . Serum FT4 may be sup- importance of MCT8 as a thyroid hormone trans- pressed in the patients with thyroidal illness and porter. This syndrome combines thyroid and neu- transiently rise in acute thyroidal illness, when rological abnormalities. MCT8 gene (also known thyroid-binding protein frequently falls11. as SLC16A2 and XPCT) defect should be sus- pected in front of psychomotor impairment (se- Free Triiodothyronine (FT3) vere developmental delay, truncal hypotomia and The normal adult reference value is 0.25-0.65 1 limb spasticity) and high serum T3,low T4 and ng/dL (3.8-10 nmol/L) . Free triiodothyronine rT3 concentrations. However, the neurological (FT3) measures the very tiny amount of T3 that manifestations of this syndrome cannot be ex- circulates unbound. It is useful in looking for hy- plained by the thyroid function tests. The pheno- perthyroidism or thyroxine overplacement in type is different from that of global hormone de- women who are pregnant or taking any effective 11 ficiency or excess. Treatment with L-T4 (physio- that varies the TBG like . More logical doses) has not corrected in several pa- consistently, patients with a variety of non-thy- 1 tients the phenotype. It has been recommended roidal illnesses have low FT3 levels . This de- the use of higher doses of L-T4 during pregnancy. crease is characteristic of all conditions associat- MCT8 knockout mices have demonstrated tissue- ed with depressed serum TT3 concentrations due specific TH excess and deprivation due to differ- to a diminished conversion of T4 to T3 in periph- ent tissue dependency on MCT8 for cellular thy- eral tissues14. 7-8 roid hormone uptake . Marked elevations in both FT4 and FT3 con- The principle uses for obtaining the serum T3 centrations in the absence of are to determine the severity of hyperthyroidism, are typical of patients with resistance to thyroid 15 and to confirm the diagnosis of suspected thyro- hormone . The FT3 concentration is usually nor- toxicosis in which serum T4 levels are normal or mal or even high in hypothyroid persons living in equivocal9. In addition it may be required to carry areas of severe endemic deficiency and 16 out the test in cases of functioning thyroid adeno- their FT4 levels are, however, normal or low . In- mas, where T3 toxicosis may be present and such formation concerning this value can be the most patients may have normal or borderline elevated important parameter in evaluation of thyroid serum T4 levels along with suppressed serum function because it relates to patients status al- 10 TSH levels .Serum T3 is misleadingly elevated though other mechanisms exists for cell to con- in women who are pregnant or who take oral es- trol the active amount of the thyroid hormone by trogen, due to the high serum levels of TBG in autoregulation of receptor17 and regulation of 11 18 these conditions . TT4 and TT3 measurements deiodinase activity . Rarely, a defect in thyroid

342 Thyroid function tests: a review

hormone transport in the cells would abolish the rT3 concentration in serum reflects both tissue 7 free hormone and metabolic effect co-relation . supply and metabolism of T4 and identify condi- The free hormone concentration is high in thyro- tions that favor this particular pathway of T4 toxicosis, low in hypothyroidism,and normal in degradation. The normal range in adult serum for 19 1 euthyroidism . rT3 is 14-30 ng/dl (0.22-0.46 nmol/L) although varying values have been reported. It is elevated

Triiodothyronine Resin Uptake Test (T3RU) in subjects with high TBG and in some individu- Values correlate inversely with the concentra- als with Familial Dysalbuminemic Hyperthyrox- 1 2 tion of unsaturated TBG . A high resin uptake is inemia (FDH) .Serum rT3 levels are normal in seen with hyperthyroidism and with chronic hypothyroid patients treated with T4, indicating disease, nephrotic syndrome, anabolic ad- that peripheral T4 metabolism is an important 20 ministration, and high dose admin- source of circulating rT3 . Values are high in istration, indicating low amounts of thyroid bind- thyrotoxicosis and low in untreated hypothy- ing proteins (TBP) or high levels of T4 in the pa- roidism. High values are normally found in cord tient’s serum. circulate mainly blood and in newborns21. bound to serum binding proteins (TBP). Changes in TBP concentrations will acutely modify the Thyrotropin or Thyroid Stimulating concentration of free hormones with a conse- Hormone (TSH) quent new equilibrium. Therefore, the aim of Likely to all pituitary hormones, TSH is se- TBP is to maintain a constant serum free hor- creted pulsately and has a . mone concentration. Three TBP are prevalent: Serum TSH concentrations are highest in the thyroxine-binding globulin (a 54 KD glycopro- evening at 23 hours, during the first hours of tein synthesized by the liver whose gene resides sleep. The serum TSH values vary as the age on the long arm of the X chromosome), changes. (RET) a 55 KD synthesized by the Normal range is approximately 0.5-4.5 mU/L1. liver and in the chorioid plexus. It is a tetramer The American Association of Clinical Endocri- whose every single polypeptide contains 125 nologists (AACE) has revised these guidelines amino acids. The RET gene proto-oncogene as of early 2003, narrowing the range 0.3-3.0 codes for a kinase membrane . mU/L. The majority of practitioners including Germline point mutations of the RET proto- endocrinologists and the physicians who special- oncogene were demonstrated as causative of ize in thyroid disease rely solely on the TSH test MEN 2 and of nearly 50% of the sporadic as the primary test, for diagnosing and managing Medullary Thyroid Carcinoma with a very high most thyroid conditions22. Moreover, to mini- specificity; (a 66.5 KD, 585-amino acid mize the cost of a TFT the study was aimed to protein synthesized by the liver). A low resin up- determine if TSH or FT4 alone as a first-line test take (high TBP) is seen with estrogen therapy, would be adequate in assessing the thyroid hor- pregnancy, acute hepatitis, genetic TBP increase, mone status of patients. Analyzed TFT records and hypothyroidism. A low resin uptake with low from January 1996 to May 2000 in the Port TBP may be seen in severe illness11. Moresby General Hospital was done. The bio- chemical status of 95% of patients will be ap- Free Thyroxine and Free Triiodothyronine propriately categorized as euthyroidism, hy- Index (FT4I, FT3I) pothyroidism or hyperthyroidism with only 5% This FT4/FT3 index can be obtained by deter- discrepant (i.e., normal TSH with abnormal FT4) 1 mination of TT3 and TT4 .The FT4 elevated in results. In contrast, using FT4 alone as a first- euthyroid patients with FDH. This is the benign line test correctly classifies only 84% of TFTs. autosomal dominant trait in which an abnormal Euthyroid status is observed in 50% of patients albumin molecule binds T4 with much greater and FT4 assays on these samples will be exclud- 11 affinity than T3 . ed appropriately if a TSH-only protocol is adopted. This will save a quarter of the yearly

Reverse Triiodothyronine (rT3) cost of Thyroid Function Test (TFT) on reagents Reverse T3 (rT3) is principally a product of T4 alone by performing TSH only. Hence TSH degradation in peripheral tissues. It is also secret- alone is an adequate first-line thyroid function ed by the thyroid gland, but the amounts are test, when it is normal no further FT4 test is nec- practically insignificant. Thus measurement of essary unless clinically indicated23.

343 G. Shivaraj, B. Desai Prakash, V. Sonal, K. Shruthi, H. Vinayak, M. Avinash

TSH’s production is controlled by thy- mediated and in TSH nonmediated (Graves’ dis- rotrophin-releasing hormone (TRH), a tripeptide ease & trophoblastic disease)1,39. A combined (pyroglutamyl–Histidyl–Proline amide) produced Tg-antithyroglobulin antibody is more valuable in peptidergic of the hypothalamic par- than measuring only Tg for recurrent and persis- aventricular nuclei. TSH release is controlled tent diseases with differentiated thyroid disease27. through by the thyroid hor- Detectable levels of thyroglobulin are commonly mones. TRH test may be needed to diagnose hy- observed in patients who had undergone incom- perthyroidism in a hospitalized patient with a plete and 131I remnant ablations. basal sensitive TSH level of less than 0.1 mi- The baseline or stimulated serum Tg levels when croU/ml because a detectable TRH response con- greater then or equal to 2 ng/mL specifies the traindicates hyperthyroidism whereas hyperthy- need for neck ultrasound and further scanning. In roid patients with nonthyroidal illness have the certain series of patients of differentiated thyroid expected absent response. cancer following , about 21% of Hypothyroidism must be diagnosed on the ba- incidence of metastases showed serum Tg less sis of both a high TSH level and a low FT4I be- then 1 ng/mL (while receiving thyroxine for TSH cause an isolated high TSH value may merely re- suppression), so stimulated serum Tg must be al- flect the recovery phase of a nonthyroidal illness. ways used with neck ultrasound11. Patients with No clinical urgency exists for subclinical hy- undetectable serum Tg levels without receiving pothyroidism24. Serum thyrotropin measurements therapy may be considered free of in the community were studied that showed most disease28. abnormalities of serum thyrotropin concentra- tions are transient. This showed variation of TSH Radio Iodine Uptake (RAIU) study different at different times hence diagnosis can- This assay is used to measure the ability of the not be totally relied upon value of TSH25. The pit thyroid gland to trap iodine. A number of ra- falls of TSH measurements are nonthyroidal ill- dioisotopes are now available for investigative ness (sick euthyroid syndrome), changing thyroid procedures and provision of more sophisticated status, central hypothyroidism, hyperthyroidism and sensitive detection devices has substantially associated with inappropriate TSH secreation, decreased dose and radiation exposure required and central resistance to thyroid hormone9. for studies. 131I an average dose given for scan- ning purposes is 50 µCi. Isotopes with slower Serum Thyroglobulin (Tg) physical decay, such as 125I and 131I, are particu- Tg is the principal iodoprotein of the thyroid larly suitable for long-term studies. Conversely, gland, that is produced by normal thyroid tissue isotopes with faster decay, such as 123I and 132I, and also by neoplastic follicular cells; then it is usually deliver lower radiation dose and are ad- released into the circulation. Hence serum Tg vantageous for short term and repeated studies29. measurement can be used in clinical practice as a Normal values of RAIU uptake will depend on specific and sensitive tumour markers of differ- Iodine content in geographic region and also re- entiated thyroid cancer26. Tg concentration in lated to age (children having higher iodine up- serum of normal adults range from less than 1 to take than adults)30. RAIU is the measure of the 25 ng/mL (<1.5 to 38 pmol/L), with the mean avidity of the thyroid gland for iodide and its rate levels of 5 to 10 ng/ml.Values are slightly higher of clearance relative to kidney, but the results of in females than in males. In neonatal period and this test does not equate with the hormone pro- during the third trimester of pregnancy, mean duction or release. Disease states like hyperthy- values are approximately two fold to fourfold roidism (Graves’ disease, Plummer’s disease, tro- higher. The gradual decline is seen from infancy phoblastic disease, resistance to thyroid hor- to . Pituitary TSH regulates the se- mone, TSH-producing pituitary adenoma), non- cretion of Tg as the serum Tg is in positive corre- toxic goiter (endemic, inherited biosynthetic de- lation with TSH. Elevated serum Tg reflects in- fects, generalized resistance to thyroid hormone, creased secretory activity by stimulation of thy- Hashimoto’s thyroiditis) and excessive hormonal roid gland or damage to thyroid tissue, whereas loss (nephritis, chronic diarrhea, hypolipidemic values below or at the level of detectability indi- resins, diet high in ), decreased renal cate a paucity of thyroid tissue or suppressed ac- clearance of iodine (renal insufficiency, severe tivity. Serum Tg increases in early phase of suba- failure), recovery of suppressed thyroid cute thyroiditis, TBG deficiency which are TSH (withdrawal of thyroid hormone and antithyroid

344 Thyroid function tests: a review administration, subacute thyroiditis, iodine ma (MTC). is clinical manifesta- induced myxedema), Iodine insufficiency (en- tion of MTC that is either single or multinodular demic and sporadic dietary deficiency, excessive goiter, so the routine measurement of sCT is use- iodine losses in pregnancy or in dehalogenase de- ful for evaluating thyroid nodule(s) which will fect), and TSH administration, the RAIU is ele- facilitates the diagnosis of MTC. sCT measure- vated. But in case of hypothyroidism (primary or ment is far more sensitive than cytology in find- secondary), syndromes of TSH resistance, thy- ing MTC. The major benefits is of this clinical roid dysgenesis (hypoplasia, ectopy or agenesis), practice is that it alerts surgeon for the need to Na/I symporter defect, defect in iodide concen- perform total thyroidectomy and central com- tration (inherited trapping defect, early phase of partment lymphadenectomy, being the minimal subacute thyroiditis, transient hypothyroidism), surgical treatment for MTC and outcome of suppressed thyroid gland caused by thyroid hor- MTC is favourably affected because it is usually mone (hormone replacement, thyrotoxicosis fac- identified at a less advanced stage. However, oth- titia, struma ovarii), and iodine excess (dietary, er non-MTC causes of hypercalcitoninaemia and drugs) the RAIU is decreased1. false sCT positivity do exist and must be recog- nized33. If basal sCT exceeds 10 pg/ml, then it is Iodide Uptake Study Using Radionucleides analyzed by pentagastrin stimulation testing, af- The use of 99mTc is ideal for ter renal insufficiency and proton pump inhibitor studying the trapping of iodide by thyroid. It is have been ruled out. Thyroidectomy available easily in all nuclear medicine laborato- is advised in the individuals MTC which CT val- ries and low of cost. It gives information regard- ues >100 pg/ml. If stimulated CT exceeds 200 ing anion trapping. The administration amount pg/ml, thyroidectomy and lymphadenectomy is ranges from 2 to 10 mCi (74 to 370 MBq) and strongly recommended. Pentagastrin-stimulated imaging of thyroid is usually began 15 to 30 CT values <100 pg/ml are associated with a low minutes after i.v. injection31.This was followed risk of MTC, or very rarely, non-metastasizing by a single daily intake of 2 µg/kg of L-thyrox- micro-MTC (size <10 mm). Therefore, regular ine, for 10 days. Thyroid imaging and uptake clinical and biochemical follow-up is the pre- were then repeated. 99mTc pertechnetate uptake ferred treatment in such patients, unless thyroid after L-thyroxine suppression had a mean reduc- malignancy is suspected otherwise34. Certain tion of 58-87% in comparison to the baseline studies indicate the use of routine calcitonin level. In trials all subjects were euthyroid by screening for detection of medullary thyroid can- clinical and laboratory criteria and none com- cer (MTC) in patients with thyroid nodules that plained of side-effects, despite significant sup- may improve patient outcomes. However, routine pression of TSH levels. This method was effi- sCT screening in patients for thyroid nodules cient for demonstration of autonomous thyroid evaluation appears to be cost-effective, compara- tissue, since none of the patients showed signifi- ble to the measurement of thyroid stimulating cant reduction of thyroid uptake after L-thyrox- hormone, colonoscopy, and mammography ine suppression compared with the control screening35. However, initial examination includ- group. This test was effective as that of the origi- ed thyroid examination, thyroid scans or ultra- nal T3 suppression test and more convenient to sonography, measurements of serum free tri- the patient with no side-effects, easy hormonal iodothyronine (T3), free thyroxine (T4), thy- intake, low dosimetry and short stay in the nu- rotropin (TSH) levels, and antithyroid autoanti- clear medicine laboratory32. bodies. Fine needle aspired cytology (FNAC) The thyroidal uptake of Thyroid suppression was performed in all patients with palpable or 99mTc is approximately 10 times lower for 123I visible thyroid nodule in ultrasonography, and (0.4 to 4%). 123I images of gland may be obtained pentagastrin stimulation test36. any time between 4 hours and 24 hours after ad- ministration31. Fine Needle Aspiration Cytology (FNAC) FNAC are viewed as ‘gold standard’ for diag- Calcitonin (CT) nosis in most cases, as they play a vital role in Calcitonin is secreted by parafollicular C cells selection of patients for surgery. The diagnostic having low or barely detectable level of serum accuracy is nearly 98%, with fewer than 2% false CT (sCT) in normal subjects. Increased sCT lev- positives and false negatives. Miller et al37 com- els highly suggests of medullary thyroid carcino- pared FNAC and cutting needle biopsy. FNAC

345 G. Shivaraj, B. Desai Prakash, V. Sonal, K. Shruthi, H. Vinayak, M. Avinash examination could detect majority of carcinomas, Positron Emission Tomography (PET) whereas additional procedure done by cutting PET is a diagnostic technique which has be- needle biopsy especially for larger nodules (more come an important method in oncology. The ba- then 2-3 cm) helped in diagnosis. FNAC is per- sis for this test is the injection of a positron-emit- formed with guidance of ultrasound especially in ting radionuclide that localizes in cancers and al- smaller or partially cystic nodule and non palpa- lows imaging. The most exclusively used is 18F ble of 0.5 cm could be biopsied using this tech- –Fluorodeoxyglucose (18FDG) and it is a radiola- nique. FNAC is a minimally invasive, highly ac- beled analogue of , actively concentrated curate and cost-effective procedure for the as- in variety of malignant tumors including carcino- sessment of patients with thyroid lesions38. ma44. PET plays an important role in the manage- FNAC can also be performed both as therapeutic ment of patients. It may be in- technique and as diagnostic tool if the nodule is volved in initial, sometimes inadvertent, diagno- cold and cystic, that will detect the percentage of sis, in postoperative evaluation, in detection of cystic adenocarcinomas. If the nodule is cold and occult metastases, in the evaluation of thyroid totally or partially solid, the therapeutic decision nodules, and also in prognosis of metastatic dis- will depend on results of FNAC39. Molecular ease45. testing of thyroid nodules enhances the accuracy of FNAC cytology and is of particular value for Molecular Basis of Thyroid Cancer: thyroid nodules with indeterminate cytology. So Diagnostic and Therapeutic Implications far thirty-two mutations were found, including 18 Thyroid cancer though uncommon it is esti- BRAF, 8 RAS, 5 RET/PTC, and 1 PAX8/PPAR40. mated lifetime risk of 0.8% for women and 0.3% for men. The incidence appears to be increasing Ultrasonography and now it is currently the eighth commonest The technique is noninvasive, involves less cancer in women46. Fagin47 reported MAP ki- time, less expensive and more sensitive than nase-signaling cascade in thyroid cancer. He re- scintiscanning. It was popularly known to be first ported on studies using various inhibitors of thy- line evaluation of thyroid nodules. It is the good roid oncogenes RET, RAS, MAPK and BRAF can technique which indicates cystic areas capsule be beneficial in subjects with radioiodine refrac- around the nodule and lobe size39. tive papillary thyroid cancer and other inhibitors are mammalian target of rapomycin (mTOR) act Magnetic Resonance Imaging (MRI) as a distal effector of TSH and of signaling sys- MRI images are generated by computer – as- tems that involves the phosphoinositide cascade. sisted analysis of the interaction of electromag- Similarly Williams47 reported on the genetics of netic waves of a specific frequency and hydrogen thyroid tumors in the context of the occurrence in patients body. The two properties of of multiple tumours. He also mentioned that in MRI are termed as T1 and T2. The hydrogen 1965 about 10% of medullary thyroid cancer was atoms of various tissues have specific T1 and T2 thought to be genetically mediated while today properties, differences in T1-weighted and T2- this figure has increased to about 25-30%. Hence weighted images can be used to identify the thy- up to 70% of non-medullary thyroid cancer is roid gland, skeletal muscle, blood vessels or thought to be genetically mediated. He empha- lymph nodes41. In general, normal thyroid is sized the importance of studying gene involve- slightly more intense than muscle on a T1- ment in tumors such as Cowden’s or familial weighted image whereas thyroid tumor appears adenomatous polyposis (FAP) and also of the dif- still more intense or brighter42. The scintigraphy ficulty of determining the multiplicity of papil- and ultrasonography are the primary imaging lary thyroid cancers. The Author also comment- modalities for investigating thyroid disorders ed that thyroid carcinoma can be resulted from whereas MRI is used for specific indications, that the interaction germline mutations and environ- evaluate the extent of substernal goiters, thyroid mental factors such as radiation or iodine defi- carcinomas, and localizing recurrent sites of thy- ciency with consequent TSH hyperstimulation. roid neoplasia. MRI investigation is also done for Recently Dumont47 reported on the application of congenital disorders of the thyroid gland, even microarray technology to the study of gene ex- evaluation of diffuse thyroid disease, such as pression in various thyroid regulatory pathways Graves’ disease, Hashimoto’s thyroiditis, Riedel and even regulatory pathways common to all tu- thyroiditis and hemochromatosis43. mours, whereas Fusco47 described altered expres-

346 Thyroid function tests: a review sion of micro RNA (miRNA) in differentiated 30% of Graves’ disease patients. Autoimmune and undifferentiated thyroid cancer. MicroRNAs thyroid disease (AITD) is commonly seen in (miRNAs) is a recently identified class of small women between 30-50 yrs of age. It can cause endogenous non coding RNAs that act as nega- several forms of thyroiditis ranging from hy- tive regulators of the protein-coding gene expres- pothyroidism (Hashimoto’s thyroiditis) to hyper- sion that may impact on cell differentiation, pro- thyroidism (Graves’ disease). Graves’ disease is liferation and survival, a fundamental cellular one tenth as common as hypothyroidism and processes implicated in carcinogenesis. miRNA common in younger individual. Autoimmune expression is deregulated in many types of hu- thyroid disease is the result of a complex interac- man cancers, that can also include thyroid can- tion between genetic and environmental factors. cer. Hence the findings of miRNA in deregula- Genetic factors lies in HLA complex (HLA DR- tion in thyroid tumors can show a potential role 3) and the T cell regulatory gene (CTLA 4) and in thyroid cancer biology and molecular diagnos- environmental factors like viral infection, smok- tics48. Haugen47 described the possible thyroidal ing, stress and iodine intake are associated with side effects of new therapeutic agents such as ty- the disease progression. The main hallmarks of rosine kinase inhibitor (TKI). AITD are antibodies to Follicular Variant of Papillary Thyroid Carci- (TPO), thyroglobulin (Tg) and Thyroid stimulat- noma (FVPTC) has become a diagnostic chal- ing (TSH R)53. In case of at- lenge for clinicians and pathologists. Molecular rophic thyroiditis, the major antibody is the TSH- features of FVPTC may be similar in both patho- R blocking antibody. This results in diminished logic features as well as in clinical behavior of thyroid hormone output, atrophy of thyroid gland follicular adenoma or carcinoma and histopatho- and the clinical state of hypothyroidism. Other logical diagnosis is difficult49. Elastography is a antibody is Na+/I-symporter (NIS) which is the newly developed technique that uses ultrasound fourth major thyroid autoantigen54. to provide an estimation of tissue stiffness, to dif- ferentiate malignant from benign lesions, to diag- nosis of thyroid cancer, especially in indetermi- nate nodules on cytology with more accuracy50. Thyroid-stimulating hormone receptor mes- References senger ribonucleic acid is a useful marker circu- lating in cancer that helps in diagnosis and man- 1) ROY EW, SHARON YW, SAMUEL R. Diagnostic Tests of agement of differentiated cancer (DTS). When the Thyroid, In: DeGroot LJ, Leslie J, Jameson JL TSHR mRNA measured with fine needle aspira- et al, eds. , volume 2, 5th edition. tion (FNA) promotes preoperative detection of USA: Elsevier Saunders, 2006, pp 1899-1913. cancer in patients with thyroid nodules, reducing 2) KOUTRAS DA. Disturbances of menstruation in thy- unnecessary surgeries, and immediate postopera- roid disease. Ann NY Acad Sci 1997; 816: 280- tive levels can predict residual/metastatic 284. disease51. 3) CARL AB, EDWARD RA, DAVID EB. Reference infor- In human thyroid papillary carcinoma, follicu- mation for Clinical Laboratory. Table 56-1 Refer- lar or classical variant it shows that level of the ence intervals and values, In: Burtis, Carl A, Ash- wood, Edward R et al, eds. Tietz textbook of Clini- P2X7 receptor (P2X7R) much higher level than cal Chemistry and Molecular diagnostics, 4th edi- normal thyroid tissue. Hence it is a new potential tion. USA: Elsevier Saunders, 2006, p 2298. 52 marker of the disease . 4) CHONCHOL M, LIPPI G, SALVAGNO G, ZOPPINI G, MUGGEO M, TARGHER G. Prevalence of subclinical Serological Tests for Specific Disorders hypothyroidism in patients with chronic kidney dis- Circulating antithyroid antibodies, specifically ease. Clin J Am Soc Nephrol 2008; 3: 1296-1300. Antimicrosomal (AMA) and Antithyroglobulin 5) WELLE S, O’ CONNELL M, DANFORTH E JR, CAMPBELL R. (ATA) antibodies are usually present in patients Decreased free fraction of serum thyroid hor- with autoimmune thyroid disease. Anti-TPO was mones during the overfeeding. Me- tabolism 1984; 33: 837-839. formerly known as Antimicrosomal antibodies. Anti-TPO autoantibodies are found in over 90% 6) DAS BK, BARAL N, SHYANGWA PM, TOORA BD, LAMSAL M. Altered serum levels of thyroxine, triiodothyroi- of patients with autoimmune hypothyroidism and nine and thyroid stimulating hormone in patients Graves’ disease. TgAb are found in less than with depression. Kathmandu Univ Med J 2007; 5: 60% of patients with lymphocytic thyroiditis and 330-334.

347 G. Shivaraj, B. Desai Prakash, V. Sonal, K. Shruthi, H. Vinayak, M. Avinash

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