-SP — 001 SD9900033
to ei
Mansour El Tahir Farah
Supervisor:
Prof. El Daw Mukhtar
Co-supervisor:
Assoc, Prof. El Tom Sirag El Bin
Khartoum -1997 r 30-36
,• v -\ :.-- DISCLAIMER
Portions of this document may be illegible in electronic image products, Images are produced from the best available original document.
Contents
Declaration I Acknowledgement , II Abstract English Ill Abstract Arabic V List of Abbreviations VII List of Tables VIII List of Figures X
Chapter I Introduction and Literature Review 1 Objectives of the Study 40
Chapter II Patients and Methods 41
Chapter III Results 45
Chapter IV Discussion ; 75 Conclusion 82 Recommendations 84
References 85
Appendices The Questionnaire 101 I would like to declare that all the research work was done by myself. I consulted all the literature included in this study .
This work has not been submitted to any other university . The information in this thesis has not been published elsewhere.
ifp I would like to express my deep gratitude to my supervisor
Professor El Daw Mukhtar whose continued enthusiasm and support had guided and encouraged me throughout the study period . This work would not been possible without the benefit of his generous help and leading advices .
I am greatly indebted to Dr. El Tom Sirag El Din for his valuable comments and leading advices , helping me alot during preparation of this thesis .
My great thanks to the staff in the diagnostic and research laboratory centre , who gave every possible help during my work .
I am greatly appreciating the help that had been provided by all doctors technicians and patients .
Finally , I am grateful to Aiman A. Al-Hamid for typing the manuscript.
II Thyroid diseases comprise a major health problem in Sudan . Although clinical diagnosis of thyroid diseases often easy , there are many diagnostic difficulties . So , laboratory investigations are essential in certain conditions .
97 Sudanese subjects were included in this study . According to the clinical features , patients were divided into three groups , either hyper or hypothyroid , and the control group .
Laboratory diagnosis of these individuals was established in the Diagnostic and Research Laboratory Centre in Khartoum Teaching Hospital. The thyroid hormones studied are T3 , T4 , FT4 (by enzyme immunoassay) and TSH (be the ultrasensitive enzyme immunoassay)..
Serum T3 concentration was found to be high in 66% of the hyperthyroid patients , and low in 75% of the hypothyroid patients , and normal in 66.7% of the control group .
Serum T4 concentration was normal in one-third of the hyperthyroid patients , and one-fourth of the Iiypothyroid patients , and 90.9% of the control eroup .
Ill FT4 was normal in the control group , low in 95% of the hypothyroid patients , and high in 66% of the hyperthyroid patients .
Signs of hyperthyroidism were associated with high honnonal levels more than symptoms do . Hyperkinesis and eye signs had a significant correlation with the hormonal levels .
No significant correlation was found between symptoms and signs of hypothyroidism and hormonal levels .
So , clinical evaluation of the patients is very important before assessing the laboratory values , and the free T4 is more specific in the diagnosis of thyroid diseases .
IV PAGES ARE MISSING IN THE
ORIGINAL DOCUMENT TRH : Thyrotrophin-Releasing Hormone
TSH : Thyroid-Stimulating Hormone.
T4 : Thyroxine.
T3 : Triiodothyronine.
FT4 : Free Thyroxine.
FT3 : Free Triiodothyronine.
VII List of Tables
Tab. (I): Age and sex distribution of hyper and hypothyroidism in 64 Sudanese patients . 51 Tab. (2) : Geographical distribution of 64 Sudanese patients with hyper and hypothyroidism . 51 Tab. (3) : Occupations of 64 Sudanese patients with hyper and hypothyroidism. 52 Tab. (4) : Symptoms of hyperthyroidism in 44 Sudanese patients. 52 Tab. (5) : Signs of hyperthyroidism in 44 Sudanese patients . . 53
Tab. (6) : Mean values (± SD) of T3 , T4 , FT4 , and TSH in 97 hyper , hypothyroid and normal individuals . 54 Tab. (7) : T3 level in 97 hyper, hypothyroidism and normal Sudanese individuals . 54 Tab. (8) : FT4 level in 97 hyper, hypothyroidism and normal Sudanese individuals . 55 Tab. (9) : T4 level in 97 hyper , hypothyroidism and normal Sudanese individuals . 55 Tab. (10) : TSH level in hyper , hypothyroidism and normal 97 Sudanese patients . 56 Tab. (11) : Mean biochemical values (± SD) in hyper, and hypothyroid 64 Sudanese patients . 56 Tab. (12) : Symptoms of hyperthyroidism and mean values of T3 , T4 , FT4 and TSH in 44 Sudanese patients . 57
VIII Tab. (13) : Signs of hyperthyroidism and mean values of T3 , T4 , FT4 , and TSH in 44 Sudanese patients . 58 Tab. (14) ; Age distribution of 64 Sudanese patients with hyper. and hypothyroidism . 59 Tab. (15) : Symptoms of hypothyroidism in 20 Sudanese patients . 59 Tab. (16) : Signs of hypothyroidism in 20 Sudanese patients . 60 Tab. (17) : Symptoms of hypothyroidism and mean values of T3 , T4 , FT4 , and TSH in 20 Sudanese patients . 60 Tab. (18) : Signs of hypothyroidism and mean values of T3 , T4 , FT4 , and TSH in 20 Sudanese patients . 6.1 Tab. (19) : T3 level in relation to presence or absence of symptoms of hyperthyroidism in 44 Sudanese patients. 62 Tab. (20) : T3 level in relation to presence or absence of hyperkinesis , exophthalmos , lid retraction and lid lag in 44 hyperthyroid Sudanese patients . 63
IX List of Figures
Fig. (I) : Sex distribution of hyper, and liypothyroidism in 64 Sudanese patients . 64 Fig. (2) : Age distribution of hyper, and hypothyroidism in 64 Sudanese patients . 65 Fig. (3) : Geographical distribution of 64 Sudanese patients with hyper, and hypothyroidism . 66 Fig. (4) : Symptoms of hyperthyroidism in 44 Sudanese patients. 67 Fig. (5) : Signs of hyperthyroidism in 44 Sudanese patients . 68 Fig. (6) : Symptoms of hypothyroidism in 20 Sudanese patients. 69 Fig. (7) : Signs of hypothyroidism in 20 Sudanese patients . 70 Fig. (8) : T3 level in hyper., hypothyroidism and normal 97 Sudanese individuals. . 71 Fig. (9) : PT4 level in hyper. , hypothyroidism and normal 97 Sudanese individuals . 72 Fig. (10) : T4 level in hyper. , hypothyroidism and normal 97 Sudanese individuals . 73 Fig, (II) : TSH level in hyper. , hypothyroidism and normal 97 Sudanese patients . 74
X
The thyroid gland was first described by Galen in 150 - 200 (1) . A further description was given by Vesalius in 1543 . In 1656 , the organ was named the thyroid or oblong shield by Wharton (1). The role of the gland in the body was the subject of pleasant, and interesting speculation . Wharton suggested that the gland was there to round out and beautify the neck , particularly , in females to whom for this reason a larger gland has been assigned . Other suggestions were that the gland was lymphatic gland , receptacle for worms , and a lubricant organ for larynx . Until 1884 , the gland was proposed as a vascular shunt cushioning the brain against sudden increases in blood flow (1). The relationship between the thyroid and various body functions was studied by experimental thyroidectomy as early as 1827 , and the concept of an internal secretory function was formulated by King , nine years later .The parathyroids were-first described by Gley in 1891 . The Reverdins and Kocher in 1883 , became aware of the similarity between myxoedema and the clinical picture which developed after successful removal of the thyroid . The injection of glycerin extract of thyroid to relieve myxoedema , and finally the feeding of lightly cooked sheep thyroid , with successful relief of the disease , completed the background for modern knowledge about thyroid function (2) . Ancient Chinese treated cretins with sheep thyroid . The association of iodine With the working of the thyroid was made in 1896 by Baumann . In 1900 , Gley and Bourcet , identified the
-1- presence of organic iodine in plasma in combination with serum protem . In 1926 and 1927 , Hamgton and Barger elucidated the chemical structure of thyroxine (T4) (3) . Later Gross and Pitt-Rivers described triiodothyronine (T3) (4) . Goitre was recognized in the earliest history and treated then by eating seaweed or burnt sponge . Hyperthyroidism was recognized first by Parry in 1825 . Graves identified the relation of the ocular complications to the disease in 1835 . De Quervain described the subacute , nonsuppurative , thyroiditis in 1936 , while chronic thyroiditis was described by Riedel in 1866 , and Hashimoto in 1912 . The carcinoma of the thyroid was described by Bums in 1811 (1).
-2- The normal adult thyroid gland weighs 15 - 20 gm . It is composed of two encapsulated lobes , one on either side of the trachea , connected by a thin isthmus which crosses the trachea anteriorly just below the cricoid cartilage . Sometimes a pyramidal lobe is found extending superiorly from the isthmus in the midline , indicating the embryological path along which the thyroid developed (5) . The thyroid volume can be measured precisely by ultrasound . It ranged from 10 to 30 ml in one study of normal individuals (6) . In the embryo , the thyroid develops as a pouch in the pharyngeal floor which elongates inferiorly as the thyroglossal duct and becomes bilobar as it descends through the neck . Rarely , one or both thyroid lobes fail to develop (7) . If migration is arrested, the thyroid may remain at the base of the tongue (Imgual thyroid ) or be found at other locations between the base of the tongue and the lower neck . Occasionally , the thyroid follows the developmental path of the thymus into the throat where decades later , it may become manifest as substernal goitre , compressing the trachea or a recurrent laryngeal nerve or even causing superior vena cava obstruction . The arterial supply of the thyroid is drived primarily from paired superior and inferior thyroid arteries . The former arise from the external carotid arteries and ths latter from the thyrocervical trunks . The venous drainage is through the paired superior , middle , and inferior thyroid veins . Normally , two pairs of parathyroid glands lie behind the upper
-3- and lower poles of the thyroid . The recurrent laryngeal nerves am along the trachea , medially and behind the lobes of the thyroid (5).
Histology:
Microscopically , thyroid tissue consists predominantly of spheroidal thyroid follicles . Each follicle consists of a single layer of cuboidal follicular cells surrounding a lumen filled' with a viscid homogeneous material called colloid . When stimulated1. the follicular cells become columnar and the follicles are depleted of colloid , when suppressed the follicular cells become flat and colloid accumulates . The luminal surface of each follicular cells is covered with microvilli extending into the colloid . The cytoplasm is filled with membrane bound microsomes on a rich endoplasmic reticulum . Near the apex of the cell are both exocytotic vesicles (secretary droplets ) and endocytotic vesicles ( colloid droplets ) , which are formed by the invagination of part of the luminai membrane . The formation of both exocytotic and endocytotic vesicles is enhanced by hormonal stimulation . Between the follicles and impinging on their surface are capillaries as well as adrenergic , cholinergic , and peptidergic nerve terminals . These abut both capillaries and follicles , their activation may alter not only thyroid blood flow but also thyroid hormone secretion (8) (9) . The thyroid also contains parafollicular or C cells in the interfollicular connective tissue and , in lesser numbers within thyroid follicles . These cells produce calcitonin .
-4- The thyroid gland produces two major active thyroid hormones . thyroxine 3, 5, 3,5- tetraiodothyronine (T4) and Triiodothyronine (T3) 3, 5, , 3 triiodothyronine (10) . The production of these hormones within the thyroid is regulated by thyrotrophin (thyroid stimulating hormone , TSH) , a glycoprotein secreted by the anterior pituitary . In turn, the production and release of TSH are controlled by thyrotrophin-releasing hormone (TRH) , a tripeptide synthesised and released from the hypothalamus . Higher cerebral centres are also known' to influence hypothalamic function . Circulating levels of T4 and T3 exert a negative feedback effect on TSH secretion via the pituitary and also the hypothalamus , whereby high levels of T4 or T3 suppress TSH, and low levels of T4 to T3 stimulate TSH secretion (10).
Thyroid Hormone Biosynthesis:
T4 is solely a product of the thyroid gland , whereas T3 is produced both by the thyroid and by •deiodination of T4 at extrathyroidal sites . The thyroid stores large amounts of T4 and T3 incorporated in the thyroglobulin , the unique protein within which T4 and T3 formation occurs . Because of these stores , T4 and T3 can be secreted rapidly without the need for new hormone synthesis (5) .
Iodide Economy: The major natural sources of iodine are food and water . Iodide intake varies greatly as a result both of varying iodide content of food and water and the dietary preferences , in many regions of the world iodide intake is inadequate or only barely adequate . In the United States , daily iodide intake averages about 500 ug because of the addition of iodide to salt and flour (11). The recommended minimum intake is 150 ug daily , although the amount required to prevent goitre due to iodine deficiency in adults is about 50 to 75 ug daily . After its ingestion , iodide is absorbed rapidly and is distributed in the extracellular fluid , in which the iodide concentration is about lug/dl. This pool receives not only dietary iodide , but iodide that released from the thyroid , and iodide derived from peripheral iodothyronine deiodination . Iodide leaves this pool by two major routes , transport into the thyroid or excretion in the urine , small amounts also are lost via faeces and sweat. The absolute thyroid iodide uptake rate is about 150 ug per day .
Thyroid Hormonogenesis:
Thyroid Iodide Transport:
Iodide is transported into the thyroid follicular cells against both concentration and electrochemical gradients , it then rapidly diffuses toward the follicular lumen (12) . Iodide transport is an energy dependent , requiring oxidative metabolism and phosphorylation . It is not specific for iodide , ions of similar size , shape and change , such as perchlorate ,
-6- thiocyanate and pertechnetate are transported and thus are competitve inhibitors of iodide transport. The ability of the thyroid to transport pertechnetate is used clinically for thyroid scanning . Thyrotropin (thyroid - stimulating hormone , TSH) is an important stimulator of thyroid iodide transport . In addition , the thyroid autoregulates iodide uptake independently of TSH . Iodide transport is depressed by excess, iodide and increased by iodide deficiency (13) . The gastric mucosa , salivary glands , mamary glands , choroid plexus , and placenta also transport iodide , but this transport system is not stimulated by TSH .
Tyrosyl lodination and Coupling:
In the thyroid , iodide is very rapidly oxidized and then bound (organified) to tyrosyl residues of thyroglobulin (14) . These reactions occur in exocytotic vesicles fused with apical cell membrane . Both oxidation and organification are catalyzed by thyroid peroxidase enzyme (TPO). This process results in mono- or dhodmation of about 15 of the 120 tyrosyl residues of thyroglobulin . Neither monoiodotyrosines (MIT) nor diiodotyrosines (DIT) are metabolicaliy active . This coupling reaction is aiso catalized by TPO (15) , and the metabalically active T3 , T4 or reverse T3 ( r T3) are formed . Thyroglobulin constitutes about 75 percent of the protein content of the thyroid , and is almost entirely found in the follicular lumen (16)
-7- .Tyrosyl residues in all proteins can be iodinated , but only in thyroglobulin does coupling occur to any extent. Coupling does not occur randomly . Poorly iodinated thyroglobulin has a low total iodide content, and higher MIT / DIT and T3 / T4 ratios (17) .
Colloid Endocytosis and Hormone Release :
Thyroglobulin is not only the site of formation , but also the storage form of T4 and T3 .. The process of the hormone secretion requires that thyroglobulin be taken up by the thyroid follicular cells and T4 and T3 be liberated from it . Thyroglobulin in the follicualr lumen is taken up by pinocytotic extensions of microvilli from the apoical membrane , forming endocytotic vesicles (colloid droplets) . These vesicles fused with lysosomes to form phagolysosomes . As these particles migrate towards the base of the cell , throglobulin is digested . The T3 and T4 resulting diffuse into the extracellular fluid and enter the circulation . During this process , some of the T4 is deiodinated to form T3 , so that thyroidal T3 secretion is greater than expected on the basis of thyroglobulin T3 content (18) . Uncoupled mono and diiodotyrosines are deiodmated to release tyrosine and iodide . The iodide is largely recycled in the thyroid . Some intact diyroglobulin is also released from the thyroid (19) .
Extratkyroidal Hormonogenesis:
Most of the T3 produced each day results from extrathyroidal 5 - deiodination of T4 . This reaction is catalized by thyroxine 5 - deiodinase . The liver and the kidneys have the highest T4 5 - deiodinase activity per unit tissue (18) . These tissues may be the most abundant sources of circulating T3 . However , T4 5 - deiodination has been identified in many tissues like the heart, brain , and the anterior pituitary . T4 is deiodinated either to the active metabolite T3 or to biologically inactive metabolite known as reverse T3 ( rT3) . Three types of T4 5 - deiodinase have been described . Type I is widely distributed seleno protein that is responsible for generation of majority of T3 . It has reduced activity in starvation or severe illness and is inhibited by propylthiouracil (10) . Type II is present in the brain and pituitary . It is important for local generation of T3 in these areas and has increased activity in hypothyroidism . In healthy individuals , T4 is converted equally to T3 and rT3 , but in severely ill people suffering from a variety of acute and chronic nonthyroidal illnesses , less T3 is produced and high levels of rT3 accumulate . T3 andrT3 are usually subsequently further deiodinated or' conjugated into metabolically inactive compounds (10).
Serum Binding Proteins;
Very little of T4 and T3 in the circulation is free . more than 99.95 percent of T4 , and 99.5 percent of T3 , are bound in reversible physiochemical equilibrium to serum proteins . These proteins are thyroxine-bmding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin (5) . Under physiological conditions , approximately 80 percent of T4 is bound to TBG , 15 percent to TBPA and the remainder to
-9- serum albumin . la comparison , about 90 percent of T3 is bound to TBG , 5 percent to TBPA , and 5 percent to albumin . Because so much of the T4 and T3 in serum is bound , changes in serum binding protein concentration have a major effect on total serum T4 and T3 concentrations , however, binding protein concentration changes do not alter free hormone concentrations or absolute rates of T4 and T3 metabolism . Some evidence suggests- that albumin - bound T4 and T3 and perhaps TBG - bound T3 are readily available to tissues such as the liver (19).
Regulation of Thyroid Hormone Production :
Thyroid hormone production is regulated in two ways . First, thyroidal secretion is regulated by the pituitary thyrotropin (TSH) . The secretion of TSH in turn is regulated by the circulating thyroid hormone concentrations and thyrotropin releasing hormone (TRH) . Second , extrathyroidal production of T3 from T4 is regulated by a variety of nutritional , hormonal , and illness-related factors (5) . The first mechanism provides a sensitive defense to alterations in thyroid secretion The second regulatory mechanism provides for the rapid alterations in tissue thyroid hormone availability in response to non-thyroidal illness which constitute an important adaptation to illness .
Thyroid Hormone Regulation of TSE Secretion :
T"-3 and T4 directly inhibit both TSH release and TSH synthesis . Thyrotropin secretion in normal subjects is sensitive to small changes in
-10- serum T4 and T3 concentrations when they are due to changes in thyroidal secretion , however , TSH release is not sensitive to T3 changes when they are due to altered extrathyroidal T3 production . T4 and T3 inhibit TSH secretion by decreasing the number of TRH receptors and by decreasing TSH, biosynthesis (20), (21) .
Thyrotropin Releasing Hormone:
Thyrotropin releasing hormone (TRH) is formed mainly in the hypothalamas' (22) . Lessers amounts of TRH are found throughout the central- nervous system and in the gastrointestinal tract, pancreatic islets , and reproductive tract (23) . Exogenously administered TRH causes a dose - dependent increase in serum TSH concentration in normal subjects TRH also stimulates prolactin release , and growth hormone secretion in patients with various disorders , including acromegaly , chronic liver disease , hypothyroidism , and diabetes mellitus . TRH is very rapidly metabolised . The ' half-life of exogenously administered TRH in human is 5 minutes (24). Peripheral plasma TRH concentrations in normal subjects range from 25 to 100 pg / ml, and is not altered in either hypo or hyperthroidism (25).
-11- Physiological Variables Affecting Pityitary Thyroid Function and Tests
Pregnanc"to- y :
Serum T4 and T3 concentrations increase progressively throughout the first half of pregnancy , to values about 50 percent higher than those in men and nonpregnant women . Concentrations in serum-remain constant during the latter half of pregnancy , returning to normal 4 to 6 weeks post partum (26) . This increase is due to increased TBG production (27) . There is a transient increase in serum free T4 and T3 concentrations in the first- trimester , which coincides with the period of highest serum HCG concentration , it is probably due to the weak thyroid- stimulating action of HCG (28) . During this period serum TSH concentrations and serum TSH responses to TRH are slightly decreased . While pregnancy is a period of increased demand for iodide , there is no evidence that. thyroid enlargement occurs during pregnancy in women whose iodide intake is adequate (29) .
Fetal Thyroid Function :
Thyroid functions begin at about the tenth week of fetal life , and thyroxme secretion begins soon thereafter (30) . Serum T4 concentrations are low until midgestation , and then increase progressively . At the time of delivery , serum free T4 concentrations are slightly higher . since TBG levels in fetal serum are lower than in maternal serum .
-12- Fetal serum T3 concentrations , however , are very low and serum rT3 concentrations are high . Fetal tissues have little T4 5 - deiodinase activity . Placental tissue is rich in iodothyrome 5 - deiodinase activity . T3 is deiodinated to 3,3 - Tj andT4 to rT3 very rapidly . Thus , little maternal T4 or T3 reaches the fetus . The high level of placental conversion of T4 to rT3 also may explain the high fetal serum rT3 concentrations (31) . TSH becomes dectetable in fetal serum at about the end of the first trimester , and thereafter rises gradually to levels of 5 - 15 p.U/ ml at term . Maternal TSH does not reach.the fetal circulation . TRH is detectable in the fetal hypothalamus by the end of the first trimester of gestation . However , the role of TRH in fetal pituitary - thyroid development is
Maternal TRH probably does not cross the placenta in important quantities , although large doses of TRH given to mothers shortly before delivery raise cord serum TSH concentrations (31) .
Infants and Children :
Serum TSH concentrations increase abruptly soon after birth , reaching levels from 50 - 100 p.U / ml, 1 to 2 hours after delivery , and then gradually decline to adult values by the third or fourth day of life (30) . This surge in TSH concentrations results in increased T4 secretion . Serum T4 concentrations increase 1.5 to 2 times in the first day of life and then fall .However , they remain slightly higher than m adults throughout infancy and childhood , gradually declining to adult levels by
-13- puberty (32) . Serum T3 concentrations increase 4 to 8 fold within the first day of life . Serum T3 concentrations also are slightly higher throughout childhood than in adults . Serum rT3 concentrations decline rapidly after birth .
Sex :•
There are no significant differences in pituitary-thyroid function between women and men . Thus , serum hormone concentrations do not differ . While TBG production is stimulated by estrogen , and inhibited by androgen •, serum TBG concentrations are similar in normal men and women , despite the disparties in gonadal steroid hormone concentrations
Aging:
The metabolic clearance rates of T4 and T3 gradually decrease with advancing age , as do T4 and T3 production rates'. Serum T4 , T3 , and rT3 concentrations in older adults are similar to those in younger adults , as are serum TSH concentrations . Serum TSH responses to TRH , though , decrease slightly with age , more .consistantly in men than in women (33).
Environmental Factors:
Small variations in serum T4 and / or I3 concentrations occur as a result of seasonal variation , values are slightly lower in Summer than Winter in temperate regions (34) .
-14- Cold exposure for several days raises serum T4 arid T3 concentrations . Serum TSH concentrations do increase in cold-exposed infants , and the abrupt rise in serum TSH concentrations in the first hours after birth is due to cold exposure . Exposure to extreme high altitude (above 10.000 feet ) results in small increase in serum T4 , free T4 and free T3 concentrations , and variable increases in serum TSH concentrations . In healthy subjects there is no significant impact of body weight, physical training , body habitus , posture , immobilization , exercise , or ambulatory status on thyroid function , and no significant geographic environmental variation (35). Nutrition also has a minimal impact except for variation in iodine intake . Subthreshold concentrations of iodine intake are associted with increased TSH secretion , goitre , increased thyroid iodine uptake , and rarely may lead to hypothyroidism . Excessive iodine intake can block thyroid hormone biosynthesis by inhibiting the enzymes involved in the biosynthetic process , resulting in reduced T4 secretion , increased TSH concentrations , goitre and hypothyroidism if the iodine excess is chronic (35) . If iodine excess is acute , it can inhibit thyroid hormone synthesis (Wolff - Chaikoff effect) or induce thyrotoxicosis ( Jod - Basedow Phenomenon ) (10) . Four infants with spina bifida were treated once daily with an iodine - containing ointment as a local antiseptic applied to the spina defect . All of them showed excess urinary iodine concentration . Two infants showed low serum fras thyroxin and high TSH concentrations at a mean age of four weeks (36) .
-15- Evaluation of Thyroid Function
The laboratory tests used in the diagnosis of thyroid disease can be divided into two groups : A. Those measuring the level of thyroid function . B. Those indicating the cause of thyroid dysfunction .
A. Tests Measuring the Level of Thyroid Function : 1. Thyroid iodide trap tests . 2. Thyroid hormone release tests . 3. Peripheral tissue response tests .
1. Thyroid Iodide Trap Tests : The thyroid uptake of the radionuclide is widely used test of thyroid function . In clinical practice 123I and technetium 99m ( "m Tc ) are used . The proportion of a known tracer dose of such radionuclides present in the thyroid after a given time can be used as test of thyroid function . The uptake is inversely related to the avarage iodine intake of a patient and is reduced by disorders of iodide trapping . Radioiodine uptake is increased in hyperthyroidism and decreased in hypothyroidisrn , but discimination between normal and mildly disturbed thyroid function is poor (10) . l23I has a shorter half-life than 13lI and permits less exposure to radioactivity ; technetium is tapped but not organified by the thyroid and is rarely used to assess uptake . In patients in the United States , the percentage of radioiodine taken up by the thyroid is normally 5 to 15
-16- percent in 2 to 4 hours , and 10 to 25 percent in the 24 hours after administration of the isotope (5) . Radioiodine uptake tests have been largely superseded by more precise direct hormone assays , however , they are still used in combination with thyroid scanners to provide a map of the thyroid . Scans are particularly useful when delineating areas of active and inactive tissue in the investigation of nodular goitre , toxic nodules , ectopic thyroid tissue , and thyroid carcinoma (10). 131I remains the preferred isotope to use in twenty-four-hour uptake studies before 131I therapy . The T3 suppression test was used in the past to demonstrate thyroid autonomy . A radioiodine uptake test is repeated after the patient has taken a suppressive dose of T3 ( at least 20 ug Aid for one week). In normal individuals , radioiodine uptake is suppressed to at least fifty percent of the pretreatment value . Failure of suppression occurs in thyrotoxicosis and in patients with autonomous (hot) nodules . The test is seldom necessary now , and the addition of T3 can be dangerous to patients who are already hyperthyroid (10). The TSH stimulation test .involves the administration of pharmacological doses of TSH ( 10 u/ d intramuscularly , for three days ) followed by a radioiodine uptake test (10). This test is rarely necessary since it has been superseded by more sensitive direct measures of thyroid failure such as TSH estimation . It may , however , occasionally be useful for demonstrating the presence of suppressed thyroid tissue , and may be of more interest when recombinant human TSH becomes available .
-17- 2. Thyroid Hormone Release Tests
Serum Protein - Bound Iodine (FBI)
It was one of the most useful tests of thyroid function . The test depends on the fact that thyroxine , and to a lesser extent triiodothyronine , are loosely bound to protein and are precipitated along with the plasma proteins . The PBI estimation may be invalidated by the intake of large amounts of iodine . Some X-ray contrast media contain iodine in a form that is bound to protein . Drugs such as salicylates and hydantoin group , compete with thyroxine for binding sites on thyroxine - binding proteins , and causes a lowering of the PBI . Abnormal iodoproteins and large quantities of inorganic iodide will lead to artificially high PBI values ; for these reasons , the measurement of PBI, although simple and accurate , has been superseded.
Serum Thyroxine Concentration (T4)
The best method for measuring serum T4 concentrations is radioimmunoassay (RIA) (10) . This is reliable , specific , and inexpensive test. The normal range in adults in most laboratories is about 5 to 11 ug / dl (64 - 154 nmol / L). Two major factors alts" T4 concentrations , thyroid secretion of T4 and serum concentration of thyroid hormone - binding proteins . Therefore , serum T4 concentrations are high in patients with liypertlryroidism and those with increase serum thyroxine - binding globulin (TBG) . Rare situations that result in raised T4 concentrations are the presence of binding protein with increased affinity for T4 ( familial dysalbuminemic hyperthyroxinaemia FDH), autoantibodies that bind T4 or decreased T4 clearance (5). Thus , T4 concentrations can be high in patients who are in fact euthyroid or hypothyroid . Conversely serum T4 concentrations are low in patients with hypothyroidism or decreased serum TBG concentrations ; those who are receiving drags that inhibit binding of T4 to TBG , those receiving T3 treatment and those who are seriously ill as a result of nonthyroidal illness (37) . Misinterpretation usually can be avoided by simultaneous determination of serum T4 binding capacity or direct measurement of the serum free T4 concentration .
Alterations in Serum Thyroid Hormone Binding:
Changes in serum thyroid hormone-binding proteins are important causes of altered T4 concentrations . Most important in this regard are changes in serum TBG concentration , because most of the T4 and T3 in serum is bound to TBG . An increase in serum TBG concentration , for example , alters the equilibrium between free and bound T4 , raising the bound T/i concentration and reducing the free T4 concentration . This reduction in free T4 concentration must result in transiently increased pituitary and thyroid secretion and / or decreased T4 clearance until both the free T4 concentration and the equilibrium between free and bound T4 are restored . The converse occurs when T3G production decreases .
-19- Increased Serum Binding:
Increased serum TBG concentrations are most commonly caused by increased estrogen production either due to pregnancy , administration of estrogen or oral contraceptives , or estrogen-secreting tumours . The increase is due to. increased hepatic synthesis of TBG . Serum TBG concentrations may increase in patients with several liver diseases (38) , especially , in acute hepatitis . Chronic hepatitis , and biliary cirrhosis , raise serum TBG concentrations to a lesser extend . TBG found to be high in patients receiving methadone or heroin , his may be due to the drug or concomitant liver disease . Other drugs that increase serum TBG concentrations include cloflbrate and 5 - fluorouracil (39). Other disorders that cause modest increases in serum TBG include acute intermittent prophyria , hypothyroidism , X linked inherited disorders (40) .
Decreased Serum Binding:
Decreased serum' binding of thyroid hormones , may occur as a result of decreased thyroid hormone-binding protein or competitive interactions of drugs with the T4 binding sites . The greatest deficiency in serum TBG occurs-in patients with an inherited defect in TBG production (40). v Disorders resulting in small reductions 111 serum TBG concentrations include acrornegaly , Cushing's syndrome , and hyperthyroidism . TBG production also decreased by androgens , and anabolic steriods (41) , long-term , high dose glucocorticoid therapy and asparaginase therapy (39), (42) Pateints with many acute or chronic nonthyroidal illness may have decrease TBG concentrations . TBG concentrations may decrease due to urinary loss as in patients with nephrotic syndrome (43) . Farmacologic agents that competitively inhibit T4 binding to TBG include salicylate , furosemide and heparin . Other drugs such as phenytoin, phenylbutazone and sulfonylufeas also inhibit T4 binding .
Serum T4 Binding Capacity Tj-Resin Uptake and.Free Thyroxine Index:
Since 99.9 percent of the T4 in seram is bound to TBG or other proteins , it is critical to determine the amount of protein binding to interpret properly the seram T4 concentration . This is done most simply using T3-resin uptake test , which measures the number of unoccupied protein binding sites for T4 . The test is done by mixing radiolabled T3 with seram , adding a resin or other inert substance ., and then detennining the amount of radiolabeled T3 bound to the resin (5) . In normal serum , the unoccupied protein binding sites , primarly TBG , take up about 45 to 65 percent of the radiolabeled T3 , raid 35 to 55 percent of the label is bound to the resin , the resin uptake . These percentages depend on the amount of seram and me particular type of inert substance used. Alternatively , the T3-restn uptake may be expressed as the ratio of the amount of labeled T3 bound to the resin in the presence of the test serum to that bound in the presence of normal senirn (normal range 0.8 tc 1.2). There are three conditions in which the number of T4 binding sites available in serum may be decreased , resulting in a high T3-resin uptake . 1) When more binding sites are occupied with T4 as in hyperthyroidism . •2) When binding sites are occupied by some ligand that competes with T4 for binding to TBG , such as salicylate . 3) When there is a decrease in the number of binding sites , as when TBG production is decreased . The number of unoccupied T4 binding sites in serum may be increased , resulting in a low T3-resin uptake when 1) fewer binding sites are occupied with T4 , as in hypothyroidsim or 2) there is an increase in the number of binding sites , as when TBG synthesis is increased (5). Thus , a serum T4 value must be examined in connection with the T3-resin uptake , if both are high , or if both are low , thyroid secretion is altered . If the two results are discordant, a binding protein abnormality is likely . The product of the serum T4 concentration and the T3-resin uptake yields the free T4 index . This value generally correlates with direct measurement of the serum free T4 concentration (5) .
Serum Free T./ and Tj :
Assays that measure free T4 or free T3 directly are now available and are useful in the assessment of the thyroid status of 0 patient. This single-step assays probably function effectively as a combined measure of
-22- T4 and free homone fraction , and have the virtue of simplicity . Free thyroid hormone levels should not be affected by the concentration of normal thyroid hormone binding proteins (10) .
Serum Triiodothyronine Concentrations (Tj)
Serum T3 concentrations are measured by radioimmunoassays (RIA) . Serum T3 , like those of T4 are altered by changes in' thyroid secretion , and changes in serum thyroid hormone-binding proteins . In patients with hyperthyroidism , serum T3 characteristically are increased to a greater degree than are serum T4 . In patients with hypothyroidism , they are more often within the normal range than are serum T4 . Serum T3 concentrations are low in patients with many nonthyroidal illness (37) .
Serum Reverse Tniodthyronine Concentrations (rTj) :
Serum rT3 concentrations depend primarly on the level of T4 secretion , since virtually all serum rT^ is produced from T4 at extrathyroidal sites . Elevation in serum rT3 concentrations most characteristically occur in patients with nonthyroidal illness , in whom rT3 degradation is decreased . Serum rT3 measurements are not useful clinically because: of both the wide variations that occur in patients with thyroid and-nohthyroid disorders and alterations in thyroid hormone- binding proteins .: It may be measured as an indicator of the euthyroid sick syndrome in patients with low T4 or T3 (10) .
-23- Serum Thyroglohulin Concentrations: Thyroglobulin is found in small amounts (5 to 25 ng / ml) in the circulation of virtually all normal subjects . Serum thyroglobulin are increased in patients with hyperthyroidism , except when hyperthyroidism is due to exogenous thyroxine administration . Thus ,serum thyroglobulin can be used to differentiate spontaneous from iatrogenic or factitious hyperthyroidism . Serum thyroglobulin also increased in some patients with endemic goitre , multinodular goitre , and benign and malignant thyroid tumours (16). Serial serum thyroglobulin determinations may be useful in the follow-up of patients who have been treated for thyroid cancer , as an indicator of tumour recurrence .
3. Peripheral Tissue Response Tests :
Thyroid hormones- alter the function of many tissues . Measurements reflecting their impact on tissues would be expected to be useful adjuncts for the diagnosis of hyper or hypbthyroidism . However , the procedures now available for this purpose , are neither sensitive nor specific indicators of thyroid hormone availability . These tests are tyrosine tolerance , serum creatine phosphokinase , tendon reflex duration , serum cholesterol, basal metabolic rate , the electrocardiogram , the red cell sodium (44) . a) Tyrosine Tolerance :
Fasting plasma tyrosine is raised in hyperthyroidism , and lowered in hypothyroidism . After a tyrosine load , plasma levels rise higher than
-24- normal in hyperthyroidism , and lower in hypothyroidism . One-third of hyperthyroid patients have normal plasma tyrosine . This test is therefore not useful in the diagnosis of hyperthyroidism , and has no value in the diagnosis of hypothyroidism (44). b) Serum Creatine Phosphokinase :
Serum enzymes have been studied in hypo and hyperthyroid patients . An inverse relationship between serum creatine phosphokinase and thyroid activity has reported . This • estimation is of little value in the diagnosis of hyperthyroidism . In hypothyroidism in addition to high serum creatine phosphokinase , serum aspartate aminotransferase and lactate dehydrogenase levels was also found to be high (45). However , serum level of all these enzymes may be high in other conditions , such as skeletal and cardiac muscles diseases and liver diseases . c) Tendon Reflex Duration :
Measurement of the duration of the achilles tendon reflex can be used as an index of thyroid function . The test is of little value in the diagnosis of hyperthyroidism . and many hypothyroid patients have results within normal range . In obvious hypothyroidisni, the tendon reflex is much prolonged (44) . This tendon prolongation may be found in other conditions such as obesity , arteriosclerosis , sarcoidosis , neurosyphilis , myasthenia , hypokalaemia , gross oedema , diabetes mellitus and Parkinson's disease .
-25- d) Serum Cholesterol:
The serum cholesterol is lowered in hyperthyroidism , and raised in hypothyroidism (46). This is not specific and has no diagnostic value .
e) Basal Metabolic Rate (BMR) :
BMR varies with plasma thyroid hormone concentrations , and its measurement was formerly used in diagnosing thyroid disease . However, the determination of BMR is rather cumbersome and imprecise , and the BMR is affected by numerous factors other than the thyroid hormones (47).
J) Electrocardiogram (ECG):
The ECG is abnormal in most severe cases of hypothyroidism , but in the mild cases no abnormality may be detected . The changes consist of bradycardia , flattening or inversion of T waves , and decrease amplitude of the R wave . These findings are often non-specific . No specific abnormalities in hyperthyroidism a part from left ventricular hypertrophy and increased QRS duration (44).
?•) Red Cell Sodium :
In hyperthyroidism the rate of exchange of sodium inside the red
cell with the potassium outside is reduced ; hence , the red cdl sodium is increased . In hypothyroidism the cell sodium is nearly normal . The test is somewhat inconvenient for routine use (44).
-26- Tests of the Thyroid-Pituitary Axis:
Currently , two tests of the thyroid-pituitary axis are used . One involves the measurement of basal serum TSH level , which provides most of the required information , and the other involves the measurement of the serum TSH response to exogenous TRH (10).
Basal TSH Estimation:
The lower limit of detection of serum TSH in most currently used sensitive RIAs is 0.05-0.1 mu / L , while some assays can detect levels as low as 0.005 mu / L . The range of basal TSH in the normal healthy population is 0.4-5 mu / L . Basal TSH is always suppressed in hyperthyroidism „ unless the hypeithyroidism is driven by the pituitary or an artifact is present in the assay (10) . TSH is usually low in hypothyroidism secondary to pituitary disease . TSH level above 5 mu / L usually indicative of some degree of thyroid failure , and in overt primary hypothyroidism , values may be in the range of 10 - 100 mu / L or higher . A normal TSH value excludes primary hypothyroidism , provided that the hypothalarno-pituitary axis is intact (10).
TSH/TRH Test:
Exogenous TRH , given intravenously in a pharmacological dose of 200 - 400 ug , induces a rise in TSH- which peaks approximately twenty
-27- minutes later and then declines , but not to basal levels , by sixty minutes in normal subjects . In hypothyroid subjects , the basal TSH elevated and the TSH response is exaggerated . In hyperthyroidism , the TSH response to TRH is suppressed . Absent response to TRH may also be found in certain patients with nodular goitre and in patients with ophthalmic Graves' disease who are borderline toxic . An absent TSH response is thus consistant with , but not diagnostic of, hyperthyroidism . A normal TSH response to TRH excludes hyperthyroidism (except that due to TSH adenoma or pituitary T4 resistance ) (10).
B. Tests Indicating the Cause of Thyroid Dysfunction :
1. Triiodothyronine suppression test . ( see p. 17). 2. TSH stimulation test. ( see p. 17 ). 3. Perchlorate discharge test. 4. Plasma proteins , flocculation tests and ESR . 5. Thyroid antibody tests . 6. Thyroid biopsy.
Perchlorate Discharge Test (PDT) :
This test is used in the diagnosis of the commonest variety of dyshormonogenesis- - the organisation defect. A similar defect is often present in Hashimoto's disease and after treatment with certain types of goitrogens including some ariithyroid drags . After administration of radioiodine , perchlorate is given and the activity over the gland followed
-28- Perchlorate blocks further trapping of iocide , and unbound radioiodide and iodide diffuse out of the gland if the organification process is deflective . A fall in radioactivity over the gland can then be detected. PDT can add useful information in the clinical evaluation of infants with congenital hypothyroidism detected by neonatal screening (48).
Plasma Protein, Floccuiation Test, andESR :
Abnormalities of serum proteins , flocculation tests , and ESR are found in Hashimoto's disease , myxoedema, and some cases of Graves' disease . The ESR is rarely raised in simple non-toxic goitre , but elevated in many patients with myxoedema and Hashimoto's disease . These tests are non specific , and rarely used .
Thyroid Antibodies:
High titrcs of antimicrosomal antibodies , and antithyroglobulin antibodies are found in the serum of most adults with Hashimoto's disease , and in many patients with primary hypothyroidism or Graves' disease (49) . In the later , die serum also contains antibodies against the TSH receptors en thyroid plasma membranes. In general, these are capable of inhibiting the receptors binding of TSH ( TSH-bmding inhibitory immunogiobulin . TBII) , and of stimulating the production of cyclic AMP therein (Thyroid Stimulating Irnmunoglobulm , TSI).
-29- In some patients analogous antibodies block the response to endogeneous TSH , and produces nongoitrous hypothyroidism . Both stimulatory and blocking anti-TSH receptors antibodies , have the ability to cross the placenta to produce transient hyper or hypothyroidism (50) . Measurement of these antibodies during the last months or pregnancy , makes it possible to assess the likelihood of the disorders developing in the neonate . • Some patients , most commonly those with autoimmune thyroid disease , develop circulating antibodies against T4 or T3 or both . The presence of thyroglobulin antibodies , and thyroid microsomal antibodies , in the first degree relatives of Graves'disease , may be an indicator of pre-Graves' disease or pre-autoimmune thyroid diseases (51).
Thyroid biopsy has limited indications , and it may be misleading in some patients . So, when carcinoma is suspected , exploration of the neck should be carried out, taking open biopsies from any suspicious areas . In solitory thyroid nodules ,. fine-needle aspiration biopsy , is the diagnostic test of choice (52) . Nodules found to be malignant on cytologic examination , should be treated with surgery . Benign nodules may be followed clinically or with levothyroxine to suppress their growth . Intermediate nodules should be excised , if ther ? is clinical suspicion of malignancy (52) .
-30- Thyroid Imaging :
With the advent of better thyroid function tests , the role of thyroid imaging studies in the evaluation of the patients with thyroid disease has diminished (53) . Current indications for thyroid imaging are the solitary or dominant thyroid nodule , an upper mediastinal mass , differentiation of hyperthyroidism , detection and staging of post operative thyroid cancer , neonatal hypothyroidism , thyroid developmental anomalies , and the thyroid mass post-tliyroidectomy for benign disease (53). Magnetic resonance imaging results can reflect thyroid function and histopathologic findings in the thyroid gland , and help discriminate malignant lymphoma from Hashimoto-thyroiditis (54). Doppler iconography of inferior thyroid artery , can supply pointers (capable of being recorded ) to the state of functioning of the thyroid , even before knowing the laboratory parameters (55). Ultrasound exploration of the thyroid gland including measuring of maximal sagittal diameter (SDm) , should.be part of every diagnostic procedure for thyroid disease , as it is precise and not time consuming (56). ;
-31- Nonthyroida! Illness ( Sick Euthyroid Syndrome )
A wide variety of abnormalities of pituitary-thyroid function , serum thyroid hormone binding , and extrathyroidal thyroid hormone metabolism , occur in patients with nonthyroidal illness (37) . These abnormalities frequently result in decrease serum T3 concentrations , less often , they lead to decrease serum T4 , and occasionally produce decreased serum free T4 concentrations . In general the degree and extent of the abnormalities, correlate with the severity of the nonthyroidal illness . The condition , considered together , mimic hypothyroidism . Some patients with nonthyroid illness have elevated serum T4 concentrations • (57) . These patients with nonthyroidal illness are frequently reffered to as the sick euthyroid syndrome (38). The frequency of these abnonnalities in hospitalized patients is high . In one study of all patients admitted to medical service on several days , 26 percent had decreased serum T3 concentrations , 19.5 percent had decreased serum T4 , 11.7 percent had decreased free T4 index values , and 6.8 percent had decreased serum free T4 concentrations (5S) . Increased serum T4 and free T4 concentrations were found in 3.9 percent and 5,4 percent respectively . Even higher frequencies of abnormal result are found in patients admitted to emergency room or intensive care unit (59) , (60).
-32- Decreased Extrathyroidal T$ Production :
Decreased serum T3 occur in patients with virtually all illnesses (38) . These include acute illnesses such as myocardial infarction , acute infections , reduced caloric intake , and the effects of trauma and surgery . Decreased serum T3 concentrations also found in patients with chronic illnesses such as diabetes mellitus , chronic liver , renal, cardiac and pulmonary disease , and neoplastic diseases . The fundamental cause of decreased serum T3 in these situations is decreased extrathyroidal conversion of T4 to T3 . Some patients have a circulating inhibitor of hepatic T4 5 - deiodinase activity (61). Serum total and free T4 concentrations are usually normal . Serum rT3 is characteristically high . Serum TSH is usually within the normal range . Serum TSH response to TRH is normal or diminished . In one study decreased serum T3 with increased serum TSH occur in critically ill patients with acquired immuno deficiency syndrome (AIDS) (62).
Decreased Serum Thyroxine Concentrations :
Both low serum T4 and low serum T3 concentrations are found in critically ill patients with various infections , cardiac , pulmonary , renal, and other diseases , bums and severe trauma (38), (53), (59). Often only the serum total T4 is decreased , and 'die free T4 and free T4 index values are normal. This change is due to diminished serum T4 binding , resulting either from decreased serum TBG , TBPA and / or Albumin or from inhibitors of T4 binding in serum , which leads to increased T4 clearance .
-33- However , in some patients serum free T4 index value , and less often , serum free T4 are decreased (63), (64), (65). Such decreases are caused by increased T4 clearance that is not compensated by increased TSH secretion . In fact serum TSH in such patients are low normal or undetectable . Serum TSH response to TRH may be subnormal or even absent (66), (67) , and T4 production is decreased . These findings indicate more'severe adaptive hypothyroidism , designed to produce greater reduction in thyroid hormone availability than occurs in patients who have only decreased extrathyroidal T3 production , when more severe illness is present. Clinical manifestation of hypothyroidism are not usually apparent in patients with nonthyroidal illnesses who have low serum T4 concentrations. There is evidence that low serum T4 in such patients indicate a grave prognosis (68) . In two studies more than 60 percent of patients with low serum free T4 values , died (59), (69) . Undetectable free T3 concentrations at presentation , reflects severity of illness , and predicts a subsequent high mortality (70) . However , another study showed that, serum TSH , T3 , and free T4 measured witliin 3 hours'of admission to intensive therapy unit are not predictive of outcome (71). T4 or T3 treatment is of no benefit in this situation . and is potentially harmful .
-34- Increased Serum Thyroxine Concentrations:
Increased serum T4 and free T4 concentrations also may occur in patients with nonthyroidal illnesses (72) . Such findings have been reported most often in patients with psychiatric disorders /although their frequency in groups of such patients varies widely (73), (74) . Serum total T4 and free T4 concentrations are also elevated in patients with various acute and chronic medical illnesses (58), (75), (76) , although increased levels are not characteristic of any one type of illness. Serum T3 concentrations are usually within the normal range . Serum TSH , and serum TSH response to TRH also are usually normal . These patients have few clinical manifestations of hyperthyroidism , and their serum T4 concentrations decline to normal within one or two weeks .
-35- Vinous uruqs on
Many drugs can interfere with biochemical tests of thyroid function by interfering with the synthesis , transport and metabolism of thyroid hormones , or by altering the synthesis and secretion of TSH . Only rarely , however , do these effects cause overt , clinically apparent thyroid disease (77).
Glucocorticoids:
Endogenous or exogeneous glucocorticoids excess has multiple effects on pituitary-thyroid functions (38). Increased endogenous cortisol production may account for some of the changes that occur in patients with nonthyroidal illness . Glucocorticoids inhibit TSH secretion , both at the hypothalamic and pituitary levels (37), (78), (79). Large doses of glucocorticoids inhibit extrathyroidal T3 production, and can reduce serum T3 concentrations within several days . They also decrease serum TBG and increase TB.PA concentrations (42) . The net result of these actions is low normal T4 , normal free T4 . and low T3 . Serum TSH concentrations are normal, and serum TSH response to TRH decreased . Glucocorticoids also directly inhibit thyroidal T4 , T3 and thyroglobulin release in patients with hyperthyroidism due to Graves' disease or thyroiditis . High dose androgenie steroid administration leads to a relative impairment (within the normal range ) of thyroid function (41) .
-36- Adremrgic Antagonists:
The beta-adrenergic antagonist propranolol , when given in large doses , is a week inhibitor of extrathyroidal T4 conversion to T3 , therefore , it reduces serum T3 about 10 to 20 percent (38). Serum T4 modestly increase in occasional patients (80) . Other bata-adrenergic agents have a similar action (81) . The ability of bata-adrenegic antagonists to inhibit T3 production is not related to their bata-adrenergic antagonist properties .
Propylthiouracial&Methimazole:
Propylthiouracial (PTU) and methimazole (methylmercaptoimidazole MMI) are antithyroid agents . Both of these drugs inhibit thyroid hormone biosynthesis . In addition PTU rapidly inhibits the peripheral deiodination of T4 to T3 , reducing serum T3 within 24 hours - , while serum rT3 increases (82) .
Iodide:
Iodide administration , iodide formed in vivo by deiodination of various iodide-containing drugs , alters thyroid hormone production in several ways (77)... Iodides aave. limited antithyroid actions in normal subjects (83), but they may induce overt hypothyroidism in patients who previously received 131I or surgical therapy for hyperthyroidism , or who have autoimmune thyroiditis (84).
-37- Conversely , iodide administration may result in hyperthyroidism in patients with iodide deficiency or those with autonomously functioning thyroid tissue that concentrates iodide poorly (85), (86). lodinated Radiographic Contrast Agents:
Iodinated radiographic agents used for oral cholecystogram , transiently reduce serum T3 , and raise serum rT^ levels , for upto 2 weeks when given in single doses (87) . Serum T4 increase slightly in some patients .Serum TSH , and TSH response to TRH, also increase slightly . The water-soluble iodinated contrast agents used for arteriography and pyelography do not alter pituitary-thyroid functions (5) .
Amiodarone: =
This antiarrhytlimic drug , contain iodine that alters pituitary- thyroid function . In normal subjects , it inhibits extrathyroidal T3 production and rT3 deiodination , reducing serum T3 and raising serum rT3 (88) ,' (89)' -. T4 clearance decrease , and serum T4 increase . Serum TSH , and TSH response to TRH also increase slightly during this interval . After several months of therapy , serum TSH and T4 levels return to normal. • \ Amiodarone can causes either hyper or hypothyroidism in susceptible ".individuals , whose iodine intake is high , whereas , hyperthyroidism is more likely to occur in those whose iodine intake is limited (90).
-38- Lithium:
Lithium is concentrated by the thyroid and inhibits the release of thyroid hormones (91). It is thus goitrogenic . Lithium therapy causes overt hypothyroidism in 5 to 15 percent of patients , and goitre in up to 37 percent (77).
Phenytoin:
Phenytoin (Diphenylhydontoin ) accelerates clearance of T4 and perhaps T3 . As a result , serum T4 and free T4 decline by about 25 percent , while serum T3 do not change . Serum TSH increases very slightly (92) .
-39- Objectives of the Study
The objectives of this study are as follows :
* To assess the laboratory values of the thyroid function tests in Sudanese patients . * To compare the Sudanese laboratory values of thyroid function tests with the international values . * To study the relation between different symptoms , signs of the thyroid diseases and tho hormonal levels.
-40- -I-'"'
ter Patients and Methods
97 Sudanese subjects were studied in the Diagnostic and Research Laboratory Centre in Khartoum Teaching Hospital, in the period between August 1996 to January 1997 . The patients were referred from different parts of Sudan , since all the laboratories for thyroid function tests are located, in Khartoum , and this centre is one of the main centres receiving cases of thyroid diseases in Sudan .
. Only Sudanese patients were included in this study , both males and' females of different age groups .
The selection of the patients in this study was based on the following criteria: 1. Should be newly presented to the hospital. 2. Should not have taken any specific treatment for the disease e.g. glucoconticoids , propranolol and amiodarone . 3. Should have . symptoms and signs of either hyper or hypothyroidism .
Patients were excluded if they were : . 1. Very ill and debilitated . 2, Had past history of thyroid disease . 3, Received any treatment which may affect the thyroid functions .
-41- The 97 subjects were divided into 3 groups according to the clinical presentation :
Group I ( 44 patients ):
This include patients who presented with symptoms and signs of hyperthyroidism.
Group II ( 20 patients ):
Those patients had symptoms and signs of hypothyroidism .
Group III (33subjects):
These were healthy individuals , randomly selected from general population . They served as a control group for the laboratory tests . ' Detailed history was taken from the patients including age, sex. residence , and original home . The main presenting symptoms were reported according to the patients complaints , and detailed symptoms related to thyroid diseases were reported using data sheet including all the symptoms expected to be found in patients with thyroid disease .
History from all patients was reported by one observer ( the researcher ) to circumvent any inter observer variation in the evaluation of symptoms .
-42- Clinical examination of all the patients was performed and reported by the same observer ( the researcher ) , looking for the signs of hyperthyroidism ( such as tachycardia , fine finger tremors , worm and sweaty hands , enlarged thyroid glands with thrills and bruit over it, eye signs of Graves' disease , peritibial myxoedema and other signs ) and signs of hypothyroidism ( such as bradycardia coarse features , thick rough skin , harsh voice , delayed relaxation, phase of tendon jerk and other signs ). Fundal examination was done for all the patients .
All the patients were followed in the out patient clinic , except those presented with cardiovascular complications such as heart failure , ischaemic heard disease and atrial fibrillation .
The laboratory diagnosis of all patients enrolled in this study was established in the Diagnostic and Research Laboratory Centre in Khartoum Teaching Hospital , by enzyme immunoassay for the quantitative determination of T3 , T4 and FT4 in the serum . The reference ranges are 0.8
- 2 ng/ml % 40 - 120 ug/1 and 7-17 ng/1 respectively.. Thyroid stimualting hormone (TSH) was done by ultrasensitive enzyme immunoassay for quantitative determination of TSH in the serum . The reference range is 0.25 - 4 juU/ml.
Other investigations were done in the Central Laboratory in Khartoum Teaching Hospital . These include fasting blood sugar , fasting serum
-43- cholesterol , blood urea and electrolytes , haemoglobin percent, total white blood count, ESR , and electrocardiogram (ECG).
Analysis of the data was carried out using the SPSS ( Statistical Packing for Social Sciences ) . Computer oriented programme . Chi square test (X2) was used for comparison .
-44- er Results
97 Sudanese individuals were studied . 44 patients had symptoms and signs of hyperthyroidism , and 20 patients were diagnosed clinically as having hypothyroidism . 33 normal individuals were taken as control group for the laboratory tests .
Patients presented with symptoms and signs of hyperthyroidism . In these patients ,84.1 % were females , and 15.9 % were males , with male to female ratio of 1:5.3 . The mean age was 35.9 (± 11.5) years . (Table 1, Figl). :,;:.
The patients came from all over the country , with 61.2% coming from central part of Sudan , mainly Khartoum (55%) (Table 2, Fig 3) . They have different: occupations , but most of them (63.6%) were housewives . (Table 3). -
The frequency of symptoms in the 44 hyperthyroid patients is shown in (table 4 , Fig 4). The commonest symptoms are cold preference (79.5%), anxiety 75% , fatigue and palpitation 72.7% , weight loss andhottness (70.5%) • These symptoms are common to both sexes , at different age groups .
-45- The presence of palpaole thyroid gland was a common sign in all patients (100%), and all the patients had tachycardia .
Fine finger tremor was found in 72.1 % of the patients hyperkinesis in 65.9% , proximal myopathy in 59.1% . 40.9% had moist hands , and 34.1% had hot hands . Other signs are shown in table (5) fig.. (5) .
Table (6) shows the mean values of T3 , T4 , FT4 and TSH in the hyperthyroid patients . No clear difference between these levels in male and females , and no age difference . .
66% of the hyperthyroid patients had high T3 level (above 2 ng/ml) .
(table 7 , fig 8 ), and high FT4 above 17 ng/ml (table (8), fig. (9) .34% of them had normal T3 and FT4 .
• 68.2% of the patients with symptoms of hyperthyroidism had high T4 (above 120 ug/L) , while 22.7% of them had normal T4 (range 40-120 ug/L) . (Table 9, Fig. 10) .
TSH level was low in 66% of the hyperthyroid patients , (less than 0.25 ill/ml) , and normal in 31.8% of them (range 0.25-4 iiU/mi) . (Table 10, Fig 11).
Fasting blood sugar was found to be high in 90% of the thyrotoxic patients , with no male to female difference . Other chemical and
-46- haematological investigations of the hyperthyroid patients were found to be within normal limits . (Table 11).
ECG was found to be normal in 80% of the hyperthyroid patients . 20% had atrial fibrillation .
The relation between the level of the thyroid hormones (T3 , T4 , FT4) and different symptoms and signs of hyperthyroidism, was studied statistically , High hormonal levels was found in patients complaining of increased appetite , and weight loss (table 12 ). They are also found to be high in patients with enlarged thyroid glands with bruit, tachycardia , fine ringer tremors , exophthalmos , lid lag , lid retraction and hyperkinesis . (Table 13).
Group II: Patients with symptoms and signs of hypothyroidism.
In these patients 95% were females and 5% were males , with male to female ratio of 1:19. (Table 1, Fig 1) .
Hypotnyroidism was found m different age groups , with peak incidence occurring in the fifth decade of life 45% . (Table 14, Fig. 2) . The mean age wa> 43 -v± 1 I) years .
-47- Patients were coming from different parts of the country , but 60% of them coming from central part of Sudan , mainly from Khartoum (58%). (Table 2, Fig. 3) .
Most of the patients were housewives (58%). (Table 3 ). The frequency of symptoms of the 20 hypothyroid patients is shown in table (15) .. The commonest symptoms are intolerance to cold (90%)., constipation (70%) . 57.9% of the patients had excessive somnolence .
Only 15.8% of the females had normal menstrual cycles . The majority had either amenorrhea (45%) or menorrhagia (36.8%). No marked difference in frequency of symptoms between males and females.
The commonest physical signs ofhypothyroidism were bradycardia (75%), harsh voice and delayed relaxation phase of tendon jerk (70%) . 63.2% of the patients have coarse features and dry rough skin , (table 16, fig. 7) .
Most of the hypothyroid patients had anaemia , with mean haemoglobin 54.6 (±9.1)%. Other haematological indices of these patients were normal .
95% of the patients had normal blood sugar , with mean value of 125 (± 23.7 mg/dl). (Table 11) .
-48- Fasting serum cholesterol was found to be high in most of our hypothyroid patients , with mean value of 320 ± 33 mg/dl. (Table 11).
Table (6) shows the mean values of T3 , T4 , FT4 , and TSH . The mean T3 was 0.57 (+ 0.4) ng/ml, and the mean FT4 was 3.4 (± 2.9) ng/L . No marked difference in values between males and females .
75% of the hypothyroid patients had T3 level less than 0.8 ng/ml (table 7 , fig. 8), and TSH level more than 4 jiU/ml. (Table ,10, Fig. II ) and T4 level less than 40 ug/L (table 9, fig. 10) . 20% of the patients had normal T3 and TSH values .
95% of the hypothyroid patients had low FT4 (less than 7 ng/L). (Table 8, Fig. 9) .
The relation between the level of the thyroid hormones and the different symptoms and signs of hypothyroidism was studied statistically , but no significant correlation was found .
Low levels of T3 and FT4 was found m patients with menorrhagia and cold intolerance (Table 17), also these hormones were found to be low in patients with bradycardia and delayed relaxation phase of tendon jerk . (Table 18) . 50% of the hypothyroid patients had ECG changes in the form of bradycardia , flat T wave and decrease R wave amplitude .
Group III: Control group.
In the control group , the 33 individuals were healthy , the biochemical and haematological investigations were normal.
The hormonal levels were as follows , 66.7% of them had normal T3 ,
30% had high T3 level. (Table 7, Fig. 8) .
81.8% had normal TSH . 15.1% had low TSH (table 10, fig. 11 ). 90.9% had normal T4 (table 9, fig. 10), but all of the patients had normal
FT4 (table 8 , fig 9) . •
-50- Table (1)
AGE AND SEX DISTRIBUTION OF HYPER AND HYPOTHYROIDISM IN 64 SUDANESE PATIENTS
Patients Hyperthyroidism Hypothyroidism Number of patients 44 20 Mean age (years) 35.9 43.3 (±S:D) (±11.5) (±11.3) Male: female 1 :5.3 1 : 19
Table (2)
GEOGRAPHICAL DISTRIBUTION OF 64 SUDANESE PATIENTS WITH HYPER AND HYPOTHYROIDISM IN K . T . H .
Residence Number of Number of • hyperthvroid patients hyDOihvroid patients ! Central 27 12 North 9 West- 6 2 ; East 2 lm 1 _ — South Total 44 20 i
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ORIGINAL DOCUMENT Table (5)
SIGNS OF HYPERTHYROIDISM IN 44 SUDANESE PATIENTS
Signs Frequency % Tachycardia 100% Palpable Thyroid gland 100% Fine finger tremor 72.1% Hyperkinesis 65.9% Proximal myopathy 59.1% Lid lag 54.5% Moist hands 40.9% Hot hands 34.1% Onycolysis 29.5%
Lid retraction 29.5% • Exophthalmos 22.7%
Bruit over thyroid gland 22.7% Table <6)
MEAN VALUES (± SD) OF T3 , T4 , FT4 AND TSH IN HYPER , HYPOTHYROIDISM AND NORMAL SUDANESE INDIVIDUALS
Hormones Hyperthyroidism Hypothyroidism Control T3 (ng/ml) 4.2 0.57 2 (mean ± SD) (±3.7) (± 0.4) ±(1.6)
T4 (ug/L) 150 38 83.2 (mean ± SD) (±10.2) (± 9.2) (±11.5)
FT4 (ng/L) . 27.4 3.4 11.4 (mean ± SD) (±12.5) (±2.9) (±2.3) TSH (ulu/ml) 0.8 19.8 1.3 (mean ± SD) (±0.5) (±18) (±1)
Table (7)
T3 LEVEL IN HYPER , HYPOTHYROIDISM AND NORMAL SUDANESE INDIVIDUALS
T3 level Number of Patients (ng/ml) Hvperthvroidism Hvpothvroidism Control i <0.8 0 15 1 0.8-2 15 A > 2 29 1 '0
= 00
-54- Table (8)
FT4 LEVEL IN HYPER , HYPOTHYROIDISM AND NORMAL SUDANESE INDIVIDUALS
FT4 level Number of Patients ng/L Hyperthyroidism Hypothyroidism Control < 7 0 19 0 7-17 15 1 33 • > 17 ' 29 0 0 p =00 X2 =135
Table <9>
T.4 LEVEL IN HYPER , HYPOTHYRGIDISM AND NORMAL SUDANESE INDIVIDUALS
T4 level Number of Patients (ug/L) .Hyperthyroidism Hygothyroidism Control
< 40 4 15 1 40 - 120 10 | 5 30
-55- Table (10)
TSH LEVEL IN HYPER , HYPOTHYROIDISM AND NORMAL 97 SUDANESE INDIVIDUALS
TSH level Number of Patineis QiU/m!).
Hyperthyroidism L Hypothyroidism Control <0.25 > 29 1 5 0.25-4" 14 4 27 >4 1 15 1
P - 000 X 2 81.65
Table(W
MEAN BIOCHEMICAL VALUES ± SD IN HYPER , HYPOTHYROID 64 SUDANESE PATIENTS
Hyperthvroidism Hvpothvroidism ; Fasting blood glucose 205 (±5.7) 125 (±23.7) 1 mg/dl (mean ± SD) Fasting serum cholesterol 177 (-33) '• 320 (+33) 1 Blood area 25 (+3) /4(+2) ! Serum sodium j 140 (±5) ; 138 (±8) '' Serum potassium 4.2 (±1.2) 3.9 (±0.5)
-56- Table (12)
SYMPTOMS OF HYPERTHYROIDISM AND MEAN VALUES OF T3 ,
T4 , FT4 AND TSH IN 44 SUDANESE PATIENTS
Symptoms Mean T3 Mean T4 Mean FT4 TSH
(+SD) (± SD) (+SD) (+SD)
Cold preferance 2.0 ±1.5 130 ±5 17.5 ±2 1.3 ±0.2
Anxiety 1.44 ±1.2 135 ±2 14.1 ±3 2.1 ±0.9
Fatigue 1.35 ±0.9 133 ±0.3 17.2+1.3 2.5 ±0.8
Palpitation 2.32 ±1.5 150 ±9 18.3 ±2 1.5 ±0.2
Weight loss 2.2 ±1.02 165 ±5 18.7 ±3.1 0.25 ±0.1
Hottness 0.29 ±0.01 'llO ±3 15 ±2.1 1.2 ±0.3
Insomnia 2.3+0.2 170 ±2 19.9 ±2.1 • 0.51 ±0.2
Increase appetite 2.3 ±0.1 173 ±2 19.3 ±2 0.72 ±0.1
Headache 1.76+ 1.5 155 + 3.1 17.2 + 3 1.2 + 0.2 i
Sweating 1.34 + 0.2 150 ± 2 16.3 ±0.2 0.93 ±0.21
Diarrhea 0.58 ± .007 145 ± ] 17.1x5..! 3.3±0.9 !
-o/- Table (13)
SIGNS OF HYPERTHYROIDISM AND MEAN VALUES OF T3,T4,FT4 AND TSH IN 44 SUDANESE PATIENTS
Signs Mean T3 Mean T4 Mean FT4 TSH (±SD) (±SD) (± SB) ' (±SD) Tachycardia 4.08 + 3.7 200 ±3 43 ±5.6 1.8 + 6.1
Palpable thyroid 4.67 + 0.2 210 ±3.1 26.2 ±4.4 1.87 ±0.8 gland
Fine finger tremor 4.77 ±0.4 205 ±5 25.2 ±5.5 0.36. ±0.1
Hyperkinesis 4.95+4.2 245.4 ±4.4 35.4 ±4.4 0.15 ±0.01
Proximal myopathy 3.1 ±1.2 166 ±0.15 17.5 ±0.12 2.1 ±0.3
Lid lag 5.3 ±4.5 223 ±9 34.6 ±6.9 0.17 + 0.38
Moist hands 3.95 ±1.92 199 + 2 18.1 ± 3 1.11 ±0.3
Hot hands 5.34 + 4.1 •201 ±3 17.3 ±3.1 0.50 ±1.2
Onycolysis 5.81 ±5.6 212 + 15 42.94 + 9.0 0.10 + 0.02
Lid retraction 5.76 + 4.2 230 ± 25 31.38 ± 12 0.08 ±0.19
Exophthairnos 7.9 ±5.9 300 + 28 52.94 0.10 ±0.25
Bruit over thyroid 4.23 ± 1.1 210± 10 55.1+8.3 0.02 ±0.01 gland Table AGE DISTRIBUTION OF 64 SUDANESE PATIENTS WITH AND HYPOTHYROIDISM Age (years) Number of Patients Hyperthyroidism Hypothyroidism Under 20 1 20-30 12 1 31-40 15 5 . 41-50 11 9 Over 50 3 4 Total 44 20 Table (15) SYMPTOMS OF HYPOTHYROIDISM IN 20 SUDANESE PATIENTS Symptoms j Frequency Cold intolerance 90% |i Constipation 70% ! Excessive somnolence 57.9% Weight gain 45% ! Amenorrhea 45% Fatigue 40% j Menorrhagia 36.8% Depression | 25% -59- Table (16) SIGNS OF HYPOTHYROIDISM IN 20 SUDANESE PATIENTS Signs Frequency Bradycardia 75% Harsh voice 70% Delayed relaxation phase of tendon jerk 70% Rough skin 63.2% j Coarse features 63.2% Table (17) SYMPTOMS OF HYPOTHYROIDISM AND MEAN VALUES OF T3,T4,FT4 AND TSH IN 20 SUDANESE PATIENTS Symptoms Mean T3 Mean T4 Mean FT4 Mean TSH (±SD) (±SD) (±SD) (+SD) Cold 0.19 ±0.1 35 ± 0.2 2.85 ± 1.5 22.5 ±17.5 intolerance i Constipation 0.72 ±0.01 39 + 7.1 3.15 ±1.5 ! 17.1 ±7.9 Excessive 0.46 ±0.2 35.1 ±6.1 2.2 ±1.4 \ 32.1 ±16.3 somnolence Weight gain 0.40 ±0.01 30.2 ±2.5 ' 2.27 ±1.5 32.5 ± 15.9 | Amenorrhea | 0.25 ± 0.015 29.9 ±7.5 3.1 ±1.3 i 25.5 ±0.25 Fatigue 0.25 ±0.1 33.1 ±7.1 3.3 ±2.1 20.1 ±1.0 Menorrhagia 0.16 ±0.2 33.1 ±5 3.8 ± 3.5 25 ±11.5 Depression 0.32 ±0.1 40 ±11.1 3.03 ±1.5 34.3 ± 17.5 1 -60- Table (18) SIGNS OF HYPOTHYROIBISiVI AND MEAN VALUES OF T3,T4,FT4 AND TSH IN 20 SUDANESE PATIENTS Signs Mean T3 Mean T4 Mean FT4 Mean TSH (±SD) (± SD) (±SD) (±SD) Bradycardia 0.2 ±0.1 25.1 ±3 2.3 ±1.2 21.3 ±5 Harsh voice 0.8 + 0.5 30.3 ±5.1 •2.91 ± 1.4 21.5 ± 18.4 Delayed relaxation 0.2 ±0.12 29.9 ±1.2 2.86 ±1.7 14.5 ±7.8 phase of tendon jerk Rough skin 0,84±0.6 39 ±7 2.91 ±1.4 22.4 ±1.9 Coarse features . 0.7 ±0.6 38.8 ± 11 3.1 ±1.5 21.4.+ 18.0 -61- Table (19) T3 LEVEL IN RELATION TO PRESENCE OF SYMPTOMS OF HYPERTHYROIDISM IN 44 SUDANESE PATIENTS Variable Percentage of cases Palpitation Present 2.32 (±1.5).* 72.7 Absent 2.1 (±1.3) . 27.3 Anxiety Present 1.44 (± 1.2) ** 75 Absent 1.4 (±1.1) 25 Insomnia Present 2.3 (±0.2)*** 65.9 Absent 2.1 (±0.1) 34.1 Hottness Present 0.29 (±0.01) **** 70.5 Absent ' 0.20 (±0.1) 29.5 Excessive Present 1.34 (±0.2) ***** 38.6- Sweating Absent 1.2 (±0.5) 61.4 * p = 0.0001 **p = 0.001 AAA "p = 0,009 AAAA p = 0.001 A A A A A p = 0.009 -62- Table (20) T3 LEVEL IN RELATION TO PRESENCE OR ABSENCE OF HYPERKLNESIS , EXOPHTHALMOS , LTD RETRACTION , AND LID LAG IN 44 HYPERTHYROE) SUDANESE PATIENTS Variable T3±SD Percentage of cases Hyperkinesis Present 4.95 (±4.2)* 65.9 Absent 3.6 (±2) 34.1 Exophthalmos Present 7.9 (±5.9)** 22.7 Absent 4.2 (±1.2) 77.3 Lid Retraction Present 5.76 (±4.2)*** 29.5 Absent 3.7 (±2.1) 70.5 Lid Lag Present 5.3 (±4.-5) **** 54.5 Absent 4.2 (±2.2) . 45.5 * p = 0.009 ** p = 0,001 *Vc* p = 0.007 it-kick p = 0.009 -63- Fig. 1 Sex Distribution of Hyper and HvDothvroidism in 64 Sudanese Hyperthyroidism Hypothyroidism Males 5% -64- Fig: 2 Age Distribution of Hyper and Hypothyroidism in 64 Sudanese Patients Hyperthyroidism n = 44 Hypothyroidism n = 20 50% 40% 0%-i Under 20 20-30 31-40 Over 50 Age Groups (Years) -65- Fig: 3 Geographical Distribution of 64 Sudanese Patients with Hvper and Hypothyroidism • Hyperthyroidism n = 44 HI Hypothyroidism n = 20 70% 61.4% 60% 60%- 50%™ 40%- 30% 20.5% 20% 13.6% 10% 10%- 0 0 0% Central North West East South -66- Fig: 4 in 44 Sudanese Cold 79.5% prefereiu >. Anxiety 75% Fatigue 72.7% Palpitation! '"•*.• '2.7% Weight los.s 70.5% Hottness 70.5% Insomnia. 65.9% Increase appetite Sweating 38.6% Diairhoeai 25% 0% 10% 20% 30% 40% 50% 60% 70% 80% Fig: 5 Signs of Hyperthyroidism in 44 Sudanese Patients Tachycardia 100% Palpable Thyroid gland 100% Fine finger tremoi 72.1% Hyperkinesis 65.9% Proximal myopathy 59.1% Lid lag 54.5% Moist hands Hot hands 34.1% Onycolysis 29.5% Lid retraction 29.5% f Excphthaimos IIRIfttl 22.7% Bruit over thyroid? 22.7% gland 1 i 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Fig: 6 in 20 Sudanese patients Cold intolerance 90% Constipation 70% Excessive 57.9% somnolence Weight gain Amenorrhea Fatigue Menorrhagia 36.8% Depression 25% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% !{)()%, - 69- Fie : 7 Signs of Hypothryoidism in 20 Sudanese Patients Bradycardia 75% Harsh voice ; 70% Delayed relaxa- tion phase of 70% tendon Jerk Rough skin J,,:.. Coarse features 63.2% 0% 10% 20% 30% 40% 50% 60% 70% 80% - 70- Fis: 8 '.?2 Level in Hyper, Hypothyroidism and Normal 97 Sudanese Individuals Hyperthyroidism n = 44 Illl Hypothyroidism n = 20 III Control n = 33 32.12 * ng/ml ioo%- 90%- 75% E* ""3 70%- "I 66.7% .60%-- P•A S 50%- - 40%- - J1 s 34.1% 30.3% 30%- •III iilii 20%- jiililj 10%- illll 0.8 * 0.8-2 * >2 * - 71- FIs: 9 ^ Level in Hyper, Hypothyroidfom and Normal 97 Sudanese Individuals Hyperthyroidism n= 44 HI Hypothyroidism n= 20 III Control n= 33 P = 00 X2 = 135 * ng/L 100% 100% - - 95% 90%-. 80%.. 70%- • 66% 60%-- 50%- 40% - 34.1% 30%- 20% ' 10% - 0% 0 0 0 < 7 * 7 - 17 * > 17 - 72- Fig: 10 T/i Level in hyper,, hypothyroidism and normal 97 Sudanese individuals Hyperthyroidism n= 44 1 Hypothyroidism n= 20 11 Control n= 33 * ug/L 100% - 90.9% 90%- 80%- | 75% 70.%- HHf 68.2% 60%- 50%- 1 : 40% - \ ! i 1 • •saps [ ! 30% - { : 22.7 r .rr~n : 20% - m 3 | 1 m 3 10% ~ 6.1% 0% H 0 liiifi <40 " 40 - 120 =• > 120 - 73- Fii: 11 TSH level in hyper ., Hvpothroidism and Normal 97 Sudanese individuals Hypeithyroidism n= 44 Hypothyroidism n= 20 Control n= 33 P = 000 X2 = 81.65 * uU/ml 100%-I • 90%- 81.8% 80% 1- 75% 70% 4 66.% 50% H- 40% - 31.8% 20% 20% - 15.2% iilil liili 5% 1111 2.3% 0%_, <0.25% * 0.25-4 * >4 * - 74- Chapter IV sseussu Discussion In the 64 Sudanese patients who presented with symptoms and signs of hyperthyroidism (44 patients) or hypothyroidism (20 patients), the female predominate the population studied (table 1 , fig 1) . In hyperthyroidism the male to female ratio was 1 : 5.3 , (fig 1), which is similar to the known international ratio (5), and almost similar to the ratio in the previous Sudanese studies (93) . In hypothyroidism , the male to female ratio was 1 : 19 (fig 1) , the mark decrease in the number of hypothyroid males in our study may be due to small number of the patients studied. Hyperthyroidism was found to be affecting different age groups , with peak incidence occurring in the fourth decade of life 34% (fig 2, table 4) , which is nearly similar to the previous Sudanese studies (93) . Hypothyroidism had peak age incidence in the fifth decade of life (fig . 2) The 64 Sudanese patients were coming from different parts of Sudan . Table 2 , Fig 3) 60% of these patients came from central part of Sudan mainly from Khartoum . This could be explained by the fact that, it is easy for these patients to reach the referral thyroid centres in Khartoum -75- Although thyroid diseases , especially endemic goitre , are common in western Sudan (94), only 13% of the hyperthyroid patients came from the west . This may be due to the recent mass displacement of the people from west to the capital (Khartoum ) , due to the drought and famine in their original home . None of our patients were coming from the south , although southern inhabitants were well represented in Khartoum in the displaced camps , due to civil war . Because thyroid diseases are common in females , most of our patients were housewives (table3) . No special occupation was detected in our patients . More than 70% of our hyperthyroid patients presented with preference of cold weather , anxiety , fatigue , palpitation , weight loss and hottness (table 4 , fig 4). To diagnose thyrotoxicosis from patient's symptoms only , is very difficult, because most of the European scores of the symptomatic diagnosis is not applicable in Sudan . For example , symptoms which were given high scores (95) like cold preference , weight loss , increase appetite are considered as vague symptoms . In such perennial hot country like Sudan , everyone would prefer cold weather . The majority of Sudanese patients believe that weight loss is essential accompaniment of ill health , so , this complaint is a -76- manifestation of any disease . Furthermore , patients will deny any increase in appetite , even if it is present. Signs of thyrotoxicosis are more reliable in clinical suspicion of the disease , especially those related to increase thyroxine level in the blood like tachycardia (which is present in all our patients 100%) , fine finger tremor , and excessive sweating , Nevertheless , any patient with anxiety state and sympathatic over activity , may frequently lead to mistakes in the diagnosis of hyperthyroidism . Other frequent signs essential for the diagnosis of hyperthyroidism , according to the Newcastle thyrotoxicosis index (44), are present in our patients like palpable thyroid gland with bruit, eye signs (exophthalmos , lid lag and lid retraction ....), hyperkinesis and other . (table 5 , fig 5) . Many of the common symptoms and signs of hypothyroidism frequently occur in euthyroid patients . Fatigue , lethargy , constipation and dry skin , have limited diagnostic value . The most discriminating symptoms and signs are slow movement, coarse skin , decrease sweating , harsh voice , cold intolerance and delayed relaxation phase of tendon jerks(5). Most of our hypothyroid patients had these symptoms and signs like cold intolerance (70%) , harsh voice (70%) , rough coarse skin (63.7%) and delayed relaxation phase of tendon jerk (70%) (Fig. 6,7, -77- table 15,16) , which fit with the clinical diagnostic criteria for hypothyroidism (96) . Hormonal studies for the thyroid functions were done . In group I (the hyperthyroid patients): 66% of these patients had high T3 level (more than 2 ng/ml) . (table 7, fig. 8), and high FT4 level (more than 17 ng/L) . (table 8, fig. 9) . Significant correlation was found between thyrotoxic patients and the T3 level. X2 = 32.12 . P = 00 . (table 7). Serum T3 concentration is a sensitive test and it is usually high in hyperthyroid patients , even if the serum T4 concentration is normal (5). A study in Zaire concluded that serum T3 level should be considered as an accurate and alternative test for the assessment of thyroid functions in Zairian people (97). Serum T4 concentration was found to be high in 68.2% of the hyperthyroid patients . Significant correlation was found between the hyperthyroid patients and the T4 level . P = 00 (table 9, fig. 10). The normal or even low T4 in the remaining 31.9% hyperthyroid patients could be due to any factors which may affect the TBG levels in these patients , or they may have T3 toxicosis .In our patients 75% of those with normal T4 , have T3 toxicosis . 66% of the thyrotoxic patients had low TSH level (less than 0.25 uU/ml) . There is a significant correlation between hyperthyroid patients and TSH level. X2 = 81.65 . P = 000 (table 10, fig. 11). Table (19) showed significant correlation between T3 level in hyperthyroid patients and anxiety (P = 0.001) , insomnia (P = 0.009), palpitation (P = 0.0001), hottness (P = 0.001 ) and excessive sweating (P = 0.009) . This could point to the importance of these symptoms in diagnosing hyperthyroidism in Sudanese patients . High T3 level was also found to be significantly related to hyperkinesis (P = 0.009) and eye signs (exophthalmos (P = 0.001) lid lag (P = 0.007) and lid retraction (P = 0.009) in hyperthyroid patients . (table 20) . FT4 was found to be high in all patients who had these signs . So , these features could have increase weight in diagnosing thyrotoxicosis . Fairly similar results was found in the previous Sudanese patients (93) . In group II who were clinically hypothyroid . 75% of them had serum T3 concentration (less than 0.8 ng/ml), and TSH level more than 4 uU/mi . (table 7 , table 10). Significant correlation was found between hypothyroid patients and T3 level. X2 = 32.12 . P = 00 -79- Although 25% of the hypothyroid patients had normal T3 level, only 5% of them had normal FT4 . This could be explained by the fact that FT4 is very sensitive test, (not affected by any factors ) . Serum T4 concentration was found to be low in 75% of hypothyroid patients . 25% had normal T4 level. A significant correlation was found between hypothyroid patients and T4 level (table 9) . P = 00 . The mean value of the thyroid hormones was studied in relation to the different symptoms and signs • of hypothyroidism . T3 , T4 and FT4 were found to be low in relation to most of them . (table 17 , 18) . Non of these relations was found to be statistically significant. This may be due to small number of hypothyroid patient studied . In group III (the control group): These individuals were randomly selected , but, they were similar to the patients studied in the age , sex and geographical distribution . They were healthy , and on no drug treatment for any disease . All of the control group had normal FT4 level (7-17 ng/L) . 90.9% had normal T4 level . 66.7% had normal T3 level. Significant correlations were found between these individuals and T3,T4,FT4, and TSH (tables 7,8,9,10). -30- 33% of the normal individuals had high T3 level. This could be explained by the fact that, T3 like T4 is affected by changes in binding proteins . Early thyrotoxicosis may cause high T3 level. Provided that no technical problem in doing the test. The mean values of the hormonal level in the control group were as follows T3 = 2 ± 1.6 ng/ml, T4 was 83.2 ±11.5 ng/L , FT4 was 11.4 ± 2.3 ng/L and TSH was 1.3 ± 1 juU/ml. All these values were normal. ' This fairly similar to the previous mean values for Sudanese individuals which was done in different parts of the country .(94). Table (11) shows the mean biochemical values in hyper and hypothyroidism . The mean fasting blood sugar was in a diabetic range in the hyperthyroid patients (205 (± 5.7) mg/di), and normal in hypothyroid patients in whom mean fasting serum cholesterol was found to be high (320 ± 33 mg/dl). Other biochemical values like blood urea , serum sodium and potassium were found to be normal in both hyper and hypothyroidism . These values were similar to the previous Sudanese studies .(93) . -81- This study had shown that thyroid diseases in Sudanese patients occur in females more than males , with male to female ratio 1 : 5.3 in hyperthyroidism , and 1 : 19 in hypothyroidism . The peak age incidence was found to be in the fourth decade in hyperthyroidism , and in the fifth decade in hypothyroidism . Patients were coming from different parts of Sudan , mainly from Khartoum . The diagnosis of hyper and hypothyroidism was based on the clinical features and confirmed by the level of the thyroid hormones . The serum T3 concentration was found to be high in two-thirds of the hyperthyroid patients , and low in three-quarters of the hypothyroid patients , and normal in two-thirds of the normal Sudanese individuals . The serum T4 concentration was normal in one-third of the hyperthyroid patients , and one-fourth of the hypothyroid patients , and most of the normal subjects . -82- The FT4 was found to be consistent with clinical features in two- thirds of hyperthyroid patients , and 95% of the hypothyroid patients . It is normal in all normal subjects . Some features should be considered in the diagnosis of hyperthyroidism . For example , anxiety , insomnia , palpitation , hottness and excessive sweating were found to be significantly related to the hormonal level . On the other hand , hyperkinesis and eye signs were found to be associated with high hormonal levels . So , clinical evaluation of the patients is very important before assessing the laboratory values , and the free T4 is more specific in the diagnosis of thyroid diseases . -83- Recommendations Thyroid diseases comprise a major health problem in Sudan. It affects young subjects in different parts of Sudan . So , early and perfect diagnosis and management is essential through : # Improving the medical' services and diagnostic facilities , by well-equipped laboratories and competent pathologists in different parts of Sudan especially in the rural areas for early diagnosis . # Taking good history from every patient , paying due attention towards other diseases and pharmacological agents which may affect thyroid functions , giving false positive or negative results . # Formation of Sudanese clinical index for diagnosis of thyroid diseases . This can be achieved by proper diagnosis of each symptom and sign , relating them to thyroid hormones level , then a score must be given for each symptom ad sign according to its importance . # Additional studies of thyroid diseases in larger group of patients , with proper management and follow up , for further confirmation of the diagnosis of the disease especially in borderline cases . # To reduce the cost of the laboratory services . -84- References Referenc es 1. Sidney C.W. ( 1971 ). Historical Resume' _. The Thyroid . A Fundamental and clinical text . 3rd edition . P. 5 - 7 . Editors Sidney C.W. and Sidney H.I. Harper and Row Publishers . New York . 2. Howitz F. , cited by Vermeulen F. (1893 ) .Treatment of myxoedema by feeding with thyroid glands . Brit. Med. J. 1, 266 - 270 . 3. Harington C.R. ( 1926 ) . Chemistry of thyroxine . I . Isolation of thyroxine from the thyroid gland . Biochem . J. 20 , 293 - 298 . 4. Harington C.R. and Barger G. (1927 ). Chemistry of thyroxine . 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Revue Zairoise de sciences Nucleaires . 1 , 118 - 126 . -100- Appendices The Questionnaire Assessment of Laboratory Values Of Thyroid Function Tests ( T.F.T ) In Sudanese Patients (1) Name :- (2) Age : (3) Sex: (l)Male (2) Female . • (4) Occupation : - (5) Original Home (1) North (2) South (3) East (4) West (5) Central • (6) Residence (1) Urban (2) Rural (3) suburban • (7) Tribe: (8) Marital Status (1) Married (2) Single • (9) Children (1) Yes (2) No ' • Clinical Features: Symptoms (10) fever (1) Yes (2) No • (HHottness (1) Yes (2) No • (12) Weight. (1) Increased (2) Normal (3) Decreased D (13) Sweating (1) Yes (2) No • (14) Fatigue (1) Yes (2) No • (15) Diarrhea (1) Yes (2) No • (16) Constipation (1) Yes (2) No LJ (17) Headache (I) Yes (2) No • (18) Sense of swelling on swallowing (1) Yes (2) No L_! (19)Dysphagia (l)Yes (2) No D -101- (20) Periods (1) Heavy (2) Normal (3) Scanty (4) Absent • (21) Impotence (1) Yes (2) No • (22) Eye Complains (1) Pain (2) Protrusion (3) Blurring of vision (4)Double vision (5) None • (23) Sleep (1) Insomnia (2) Excessive somnolence (3) Normal LJ (24) Cough (l)Yes (2) No D (25) Chest pain (1) Yes (2) No • (26) Palpitation (l),Yes (2) No D (27) Symptoms of heart failure (1) Yes (2) No D (28) Tremor (1) Yes (2) No • (29) Weather preference (1) Hot (2) Cold (3) Indifferent • (30) Anxiety (1) Yes (2) No • (31) Depression (1) Yes (2) No • (32) Appetite (1) Normal (2) Increased (3) Depressed El (33) Pain in the gland (1) Yes (2) No • (34) Neck pain (1) Yes (2) No • (.35) Chocking (1) Yes (2) No • (36) Change in voice (1) Yes ' (2) No D (37) psychatric symptoms (1) Yes (2) No LJ (33) Loss of consciousness (i)Yes (2) No L_3 (39) Past history (1) Irradiation (2) Drugs (3) Surgery (4) Negative LJ Examination (40) Hyperkinetic rnovment (l)Yes (2) Mo LJ (41) Fine finger tremor (1) Yes (2) No • -102- (42) Hands (1) Palmar erythema (2) Hot (3) Cold (4) Moist (5) Normal • (43) Nails (1) Clubbmg (2) Onychi sis (3) Normal • Eyes (44) Lid retraction (1) Yes (2) No • (45) Lid lag (l)Yes (2) No • (46) Exophthalmos (1) Yes (2) No • (1) Unilateral (2) Bilateral • (47) Squint (1) Yes (2) No • (48) Ophthalmoplegia (1) Yes (2) No • (49) Periorbital oedema (1) Yes (2) No • (50) Conjectival oedema (1) Yes (2) No • (51)Papilloedema (1) Yes (2) No • (52) Corneal ulcers ' (1) Yes (2) No • (53) Panophthalmitis - (1) Yes; (2) No • (54) Coarse facial features (1) Yes (2) No • (55) Harsh voice (1) Yes (2) No • (56) Skin (1) Rough (2) Pigmentation (3) Vitiliigo (4) Normal !Z3 (57) Legs Pretibial myoedema (1) Yes (2) No D (58) Pitting oedema (1) Yes (2) No • Thyroid Gland (59) Size (1) Visible (2) Visible & palble (3) Visible at distance (4) Monstous C3 (60) Consistancy (1) Soft (2) Firm (3) Hard (4) Cystic • -103- (61) Mobility (1) Mobile (2) Fixed • (62) Character (1) Diffuse (2) Nodular • (63) Tenderness (1) Yes (2) No D (64) Retrosternal extension (1) Yes (2) No D (65) Scars (1) Yes (2) No • (66) Thrills (1) Yes (2) No • (67) Bruit (1) Yes • (2) No . • (68) Cervical lymphadenopathy (1) Yes (2) No • (69) Trachea (1) Central (2) Deviated • CVS Pulse (70) Rate (1) Tachycardia (2) Bradycardia (3) Normal • (71)Rhytham (1) Sinus (2) AF (3) Extrasystoli • (72) Character (1) Callapsing (2) Normal • (73)B.P (1) Normal (2) High (3) Low • (74) Apex beat Site (1) Normal (2) Deviated D (75) Character (1) Normal (2) Forceful (3) Heavy • (76) Thrills (1) Yes (2) No • (77) Murmurs (1) Yes (2) No • (78) Heart Failure (1-) Yes (2) No • Abdomen (79) Splenomegaly (1) Yes (2) No • (80) Hepatomegoly (1) Yes (2) No • (81)Ascites (1) Yes (2) No • -104- CNS (82) Cranial nerves (1) Yes (2) No • (83) Tendon jerk (1) Normal (2) Brisk (3) delayed relaxation phase • (84) Proximal weakness (1) Yes (2) No • (85) Peripheral neuropathy (1) Yes (2) No • Chest (86) Chest examination (1) Normal (2) Abnormal • Specify Investigation (87) Hb (88) TWBC (89) ESR (90) Fasting serum cholestrol (91)R.B.S (92) ECG (93) T3 (94) TSH (95) FT4 . (96) T4 -105-