Untreated Hypothyroidism - Essay Example

Hypothyroidism- Its Chemistry, Physics and Biology INDEX No. Contents Page no Introduction 3 2. Physiology of Thyroid gland 6 3. Causes of Hypothyroidism: 9 4. Nuclear medicine and Radioisotopes in Thyroid management: 10 5. Thyroid imaging: 11 6. Chemistry and therapeutic role of drugs used in thyroid treatment. 16 7. Conclusions 19 8. Bibliography 20 Introduction: Hypothyroidism is the most common pathological condition that arises due to hormone deficiency. It has diverse implication starting from asymptomatic individual to multiple organ failure that makes it most elusive disorder among all hormone deficiency related disorders (Franklyn). Hypothyroidism is found along with many other physiological disorders like neuropsychiatric complaints, hypercholesterolemia, hyponatraemia, hyperprolactinaemia, and hyperhomocysteinaemia. Untreated hypothyroidism can lead to heart failure, psychosis, and coma. Similarly, hypothyroidism in newborn leads to severe mental retardation and hampered growth. There are several causes of hyperthyroidism like congenital hypothyroidism arising due to mutation in PAX8 and TITF1 (thyroid transcription factor 1), Thyrodectomy, Radiation therapy of head and neck cancer, Autoimmunity against thyroid component (Hashimoto's thyroiditis, drug side effects (lithium, amidaron), disease of the hypothalamus or pituitary (secondary hypothyroidism) and above are all nutritional deficiency of Iodine. Hypothyroidism is a common disorder in women than men, the incidence of occurrence increases with age. Among two types of hypothyroidism primary hypothyroidism is most common. It is almost 1000 times more than secondary hypothyroidism. Around 1.7% individuals of age 65 and above in USA show overt hypothyroidism and about 13.7% have mild hypothyroidism. 21% of individual in the age group of 74 show hypothyroidism. It is also observed that there are significant variations among different ethnic groups where the white population is found to be more susceptible than Hispanic and African-Americans (Franklyn) Historically, hypothyroidism was first time reported by Gull in 1874. He observed Cretinism like symptoms in women who were previously normal. Around 4 years later Ord coined the term myxoderma for similar symptoms. Growing evidences of similar physiological disorder lead to the formation of committee by clinical society of London that had the responsibility to investigate all these observations and 5 years later committee submitted its landmark report stating role of Thyroid constituents in all these physiological disorders. In 1912, Hashimoto described autoimmune thyroiditis. In 1956, Roitt and colleague first time demonstrated antithyroid circulatory antibodies. In terms of treatment initially sheep thyroid extract was used by Murry in 1891. Thyroid hormone was crystallized by Kendall in 1914 whereas iodothyronine was discovered by Pitt-rivers and Gross in 1952. In 1963 Codliffe purified thyrotropin (thyroid stimulation hormone) which was subsequently utilized by Mayberry and Hershman for development of thyrotropin based immunoassay for diagnosis of hypothyroidism. Hypothyroidism can be classified on the basis of its time of commencement. In the case of newborn if it strikes than it is called congenital whereas if it strikes in adult it is called as acquired. Based on the functioning of endocrine gland it is further classified as primary and secondary hypothyroidism and based on its severity it is classified as clinical and subclinical. There are many symptoms and diagnostic tests available for hypothyroidism some of them are mentioned in table 1. Because hypothyroidism is associated with several other physiological disorders and very vague symptoms, the screening procedure needs to be optimized and diverse enough to identify the exact cause of particular symptoms and then establishment of hypothyroidism as primary cause. Thus, the biggest challenges in hypothyroid management are diagnosis at early stages and to pin point causative factor of hypothyroidism. Radioisotope or Nuclear medicine based imagine technique have been widely used to monitor thyroid functioning and to investigate patho- physiological condition of thyroid system. Iodine specificity of thyroid and availability of radioisotope of Iodine makes it ideal choice for these kinds of investigations. In following section radioisotope based imagine techniques and its application in thyroid management will be described in detail. Similarly, development of new synthetic thyroid component like T3 and T4 has emerged as a key candidate for hypothyroidism treatment and will be discussed in detail. Table 1: Symptoms and diagnosis of hypothyroidism (Franklyn) Physiology of Thyroid gland The first endocrine gland to mature in the human embryo is the thyroid gland. The development starts with the thickening of the floor of the primitive pharynx between the diverging aorta at about day 22 after conception. The future follicular cells acquire the capacity to form thyroglobulin at the 29th day of gestation. Ontogenesis is usually finalized after 49 days and the bilobed shape is detectable in front of the trachea and it proceeds to form follicles. The iodine concentration and the synthesis of T4 start after 11th week. The thyroid gland increases in the further course of development. (Pulzer) At the four weeks of age the fetal thyroid gland can synthesize thyroglobulin. It is after 8 weeks that the thyroid gland starts synthesizing hormones mediated by the incorporation of iodine. The early growth and development is not dependent on the TSH. When the hypothalamic-pituitary-thyroid axis matures, the TSH levels increases rapidly form about 12 weeks of gestation to late second trimester. After this period, the TSH remains relatively unchanged or increases further.(Pulzer) The thyroid hormones are unique since they contain 59-65% of the trace element iodine. These iodinated thyronines are derived from the iodination of the phenolic rings of tyrosine residues in the thyroglobuin to form mono-or diiodotyrosine, that are coupled to form T3 and T4. This is displayed in Figure 1. The synthesis of the T4 and T3 hormones in the thyroid gland involved six major steps: 1. Active transport of I- across the basement membrane into the thyroid cell; 2. The oxidation of the iodine and the iodination of the tyrosyl residues in the thyroglobulin; Figure: 1 Gross anatomy of anterior thyroid gland (Greenspan) 3. Coupling of iodotyrosine molecules within thyroglobulin to form T3 and T4; 4. Proteolysis of thyroglobulin, with the release of free iodothyronines and iodotyrosines; 5. Deiodination of iodotyrosines within the thyroid cells with conservation and the reuse of the liberated iodide; 6. Under certain circumstances, the intrathyroidal 5-deiodination of T4 to T3. (Greenspan) Figure: 2 Cross-section of the neck at level T1 showing thyroid relationships. (Greenspan) The thyroid gland influences oxygen consumption and also stimulates protein synthesis. It also facilitates growth, carbohydrate, fat and vitamin metabolism. Iodide from the dietary iodine is required for the metabolism of two hormones, thyroxine (T4) and 3, 5,3-triiodotonine (T3). T3 and T4 are stored in the body as thyroglobulin and releases through a series of peptidases and proteases. Less that 0.1% of T4 circulated as unbound (free T4). Seventy percent of T4 circulates firmly bound to throxine binding to globulin, 20% to realbumin and 10% to albumin. T3 is 3-4 times more potent as T4. (Rappley) In case of T3, 20% of T3 is secreted by the third gland whereas 80% is produced by the peripheral tissue by deiodination of unbound T3 and T4 which then enters the nucleus and binds to the hormone receptors, which are the larger class of steroid hormone receptors. A protein is secreted via mRNA which is known to be specifically secreted to the target cell in response to the process that began with contact with T4. This is the process by which T4 produces tissue specific effects in multiple organ systems. (Rappley) The thyroid gland again is regulated by the thyroid stimulating hormone (TSH, thyroptin) that is secret by anterior pituitary gland. TRH is also found in other parts of the brain and in peripheral tissue and also acts as neurotransmitter. T4 and T3 while in circulation acts a negative feedback loop to stimulate production of TRH and TSH in the hypothalamus and pituitary. This is the reason, that in the most common form of thyroidism the measured T4 levels are low and the TSH levels are high. (Rappley) Causes of Hypothyroidism: Hypothyroidim is basically, a clinically syndrome that is resultant of the deficiency of the T4 and T3 hormones. It causes to about 15/1000 in females and 1/1000 in males. The causes of this disease are listed below: Primary Thyroid Failure: The common reasons are listed below: Hashimotos thyroididtis; Idiopathic atropy; Previous treatment with radioiodine or throidectomy; Iodine deficiency; Use of antithyroid drugs; Use of drugs like lithium and aminodarone; Subacute and silent thyroididtis. The Uncommon reasons are listed below: Dyshormonogenesis; Agenesis; Infiltrative disease.(Franklyn) Nuclear medicine and Radioisotopes in Thyroid management: As per the estimation nearly 10 million people in USA are treated with nuclear medicine or radioisotopes they are widely used in diagnosis, therapy and investigations. There are hundreds of known radioisotopes which are employed for different purposes and choice of each isotope is based on its energy, half life and biological half life. Examples of some of these are 131I, 60Co, 99mTc, 137Cs etc. The major contribution of radioisotopes and nuclear medicine unlike MRI and CT is that, they provide both functional and structural details of organ systems within the body (Mcgron). Introduction of 131I as therapeutic agent in thyroid treatment in 1946 and after few years in thyroid imaging marks beginning of new era of nuclear medicine. There are mainly two types of imaging technique based on nuclear medicine or radioisotopes. 1) Single Photon; and 2) Positron Emission Topography (PET). The isotopes which are used in Positron Emission Tomography have very short half life (except 18F) and hence they need to be produced onsite, thus, making it use limited to larger hospitals and referral centers, whereas single photon imaging is widely used for routine analysis. Gamma emission imaging is successfully employed to almost all organ of body like brain, kidney, lungs, nero receptors, thyroids etc. Similarly, it was also employed to investigate inflammation, thrombosis, atherosclerosis and cancer. Biomimetic nature of radionuclide makes them ideal choice for investigating functional status of particular organ system and to investigate metabolic fate of particular compound. Easy manipulation and tagging with appropriate ligand adds additional qualification for radionuclide as tracer or imaging tool. Table 2 represents some of the most widely used isotopes for imaging Table 2: Commonly used Radioisotopes in Nuclear Medicine Imaging (Mcgron) Thyroid imaging: Literature clearly indicates early development of thyroid imaging techniques compared to other disorders, since most of the work is done during seventies, thereafter only refinement were done on fundamental techniques. There are different techniques employed for the same purpose like 1) Plain Radiography where normal X-ray is used to take image of chest along with thyroid lobe but have very limited application. 2) Ultrasound using high resolution 5-10MHz transducer is widely used to study morphology of thyroid since it has more sensitivity than Scintigraphy. Scintigraphy is also used to detect mass, solitary nodule and to examine any cystic component. 3) Computed Tomography (CT) and Magnetic resonance (MR) imaging; both techniques are used mainly to evaluate mediastinal extension of thyroid mass but are unable to give good result in case of intrathyroid lesion. 4) Radionuclide based scintigraphy is still the method of choice for thyroid functionality test. Here, mainly two isotopes are used 123I and 99mTc as pertechnetate. 99mTc is preferred over 123I in case of routine scintigraphy due to easy availability and cost, while 123I is used in case of whole body scan for thyroid carcinoma metastasis. It is also used as therapeutic agent for hyperthyroidism treatment. In recent times, other radionuclide like thallium; gallium-67 citrate; indium-labelled pentetreotide and 99mTc-labelled sestamibi, tetrofosmin and pentavalent DMSA have found an increasing role in tumor imaging due to its half life and energy contain (BURY). Among other radionuclide based imaging Thyroid uptake measurement is the primary investigation for thyroid functioning. Here thyroid uptake determination is the measurement of the fraction of administered radioactive Iodine that accumulates in thyroid in particular time interval. The efficiency of thyroid functioning is then determined by calculating percentage accumulation of radioIodine in thyroid compared to other organ or whole body. Many a times instead of 131I, 99mTc-pertechnetate is used but gives less accurate results compared to 131I. The overall procedures as follows: 1) Suitable concentration of radio iodine is administered orally in form of test solution. The dose required for uptake determination in form of different iodine compound is shown in table 3 2) Before administration of radioiodine many parameters are taken into account like patient history, food intake. Previous record of thyroid treatment, pregnancy etc is also taken into consideration. 3) The measurement of thyroid uptake is performed after 18-24 hr of administration or in some case after 2-6hr of administration using NaI crystal detector. 4) Measurement is generally performed by keeping detector at distance of 25-30 cm near to the interior of the neck (experimental) and at thigh for back ground or whole body counting. In case of determination of thyroid remnant after surgery extended whole body imaging can be performed by similar way. Table 3: Radiation Dosimetry for adults (R.Balon) Calculation and interpretation: Radioiodine uptake (RAIU) is calculated by following formula For the interpretation of results many parameters taken in to consideration like reported values in literature (generally 10-35% uptakes for 24 hr is consider being normal, while for 4hr uptake 6-18% consider to be normal). Uptake rate should be correlated with thyroid functioning in lose manner as there are many factors which influence differential uptake like calibration, instrumentation, population where the patient belong to etc. Further biochemical investigation must to performed to establish abnormality in thyroid functioning and to identify exact cause of malfunctioning. The major consideration should be given to the history of patients particularly the patient's thyroid related treatment or medications. Fig 3 shows typical 99mTc uptake in different conditions Figure 3. Na 99mTc04 of four different subjects A (Graves disease), B (subacute thyroiditis), C (autonomous "hot" adenoma) are biochemically thyrotoxic. D is normal (Chatterton) The second most widely used radioiodine based imaging technique is in case of thyroid tumor or carcinoma. Papillary carcinoma is most common form of thyroid malignancy (55-75%) followed by follicular (15-20%), anaplastic carcinoma (5-15%) and medullary carcinoma (5%). At some extent ultrasound can be diagnosed with morphological variation but one cannot comment anything on malignancy. The most 131I is widely used in follow up and in establishment of metastasis in thyroid cancer. The whole body imaging with 131I administered patient gives idea of metastasis as thyroid cells migrate to different part of body where they accumulate 131I compared to normal resident cells makes it easier to identified thyroid cells against normal resident cells. Figure 4 shows whole body scan for metastatic thyroid carcinoma (Chatterton) Figure 4 Whole body images obtained 7 days after therapeutic administration of 131Iodine demonstrating uptake in regenerating thyroid tissue in the root of the neck, and metastatic deposits in the liver, left pelvic bones and upper left femur from papillary thyroid cancer. The major drawback or the matter of concern regarding radioiodine based technique is thyroid stunning. In patient with thyroid carcinoma, remnant thyroid tissue or metastases may have lower 131I uptake on post therapy images than on prior diagnostic image (Woolfenden)., This observation lead to hypothesis that effect of radiation on thyroid cells impairs its Iodine accumulation capability,a process know as stunning. To avoid this, researchers have suggested a dose of 74MBq for 131I or use of 123I, since it has low yield of conversion. Figure 5 indicates typical case of thyroid stunning where petient was administored by different doses of 131I. Figure 5: Thyroid stunning. Top: diagnostic I-131; Bottom: little or no uptake of therapeutic I-131 because the lesions were stunned by the diagnostic I-131 (The Stunning Effect in Radioiodine Therapy of Thyroid Cancer) Use of 123I for diagnosis purpose have solved stunning problem and have many advantages like lesser dose exposure of thyroid at same administered dose compared to 131I, better scintigraphic image etc but cost and salivary iodine activity in esophagus have limit its use. Chemistry and therapeutic role of drugs used in thyroid treatment. Thyroid hormone preparation have been used in the treatment of hypothyroidism since 1891, George Muray injected phenolic extract of sheep thyroid into myxedematous patient. He achieved first breakthrough in treatment of hypothyroidism which was consider to be a fetal disorder (J. H. OPPENHEIMER). After this landmark discovery he observed that direct injection of sheep thyroid extract to the patient duplicates the effect, and based on this observation, glycerol extract of thyroid was developed and extensively used for hypothyroidism treatment till seventies. (J. H. OPPENHEIMER) The synthetic preparation of L-T4 and L-T3 was developed in 1958 and 1956 respectively but therapies were more inclined toward lyophilized thyroid preparation as there was a strong belief of effectiveness of combined T3 and T4 over individual one. But soon after detailed investigation revealed that almost 80% of circulatory T3 is nothing but converted product of T4 and that is mainly occurs at peripherally. In conclusion it was established that T4 act as prohormone and is converted to T3 (Iodothyronine) which has a very high affinity towards hormone receptor than T4. The synthetic form of L-T4 is known as Levothyroxine and L-T3 is known as Liothyronine which are widely used in hormone replacement therapy of hypothyroidism. L-T4 or Levothyroxine: In 1927, Charles Robert Harington and George Barger have chemically synthesized thyroid hormone T4 or thyroxin in laboratory the chemical name of this compound was found to be 3,5,3',5'-tetraiodothyronine. Figure 6 shows chemical structure of Levothyroxine. Inside the body it is synthesized via iodination of tyrosine molecule which subsequently coupled with diiodotyrosine. Almost 80% of total thyroxine in blood circulation is thyroglubulin and when requirement arises, proteolytic cleavage takes place that leads to release of thyroxin. All kind of hypothyroidism response to this drug like congenital and acquired hypothyroidism, autoimmune hypothyroidism, and in case of surgical removal of thyroid gland. The main function of Levothyroxine is to regulate TSH level in blood, thus constant monitoring of TSH in blood gives good indication of overall effectiveness of treatment. Figure: 6 3, 5, 3', 5'-tetraiodothyronine (Levothyroxine) Since T3 is generated for prohormon T4, it is widely accepted that use of T4 is more favorable over T3 and determination of T4 titer in blood facilitates accurate dose calculation. Half life of T4 in blood is 7days while T3 has half life of 1 day. There is some controversy over dose of T4, the range is from 127 microgram to 300 microgram and thus the decision should be taken on case basis and the disease history of patient. Liothyronine or T3: Liothyronine is the L iso-form of hormone triiodothyronine or T3, which is an active form of thyroid hormone responsible for regulation of basic metabolism in body. It also play a key role in carbohydrate and protein metabolism. It have a shorter half life than it pro hormone form T4, due to its less binding to plasma proteins. Figure 7 shows chemical structure of Liothyronine Figure 7 The structure of Liothyronine. Being highly active molecule it has many side effects including life threatening toxicity. It should always be taken with proper diagnosis and prescriptions. Conclusion: Hypothyroidism is one of the most common hormone mediated pathological condition. There are different causes for hypothyroidism starting from genetic defect to surgical removal of thyroid gland. Advancement of imaging technique along with biochemical and immunological diagnosis has made this disease quite treatable. Radioisotope particularly radioiodine have central role in diagnostic imaging due to its selective accumulation in thyroid There are certain limitations and disadvantages of radioisotope based imaging like patient expose to radiation. This may leads to other complications and phenomenon like thyroid stunning gives false negative results. Problem of stunning can be taken care by use of 123I but cost and availability has to be taken in to consideration. Treatment of hypothyroidism has achieved significant success in recent past particularly after development of synthetic T3 and T4. Still there is some controversy over use of T4 or T3 is persisting along with dose requirements. But generalize consensus are emerging for dose requirement. There are some reports, in which the combination of Liothyronine and Levothyroxine was advocated but statistical analysis revealed no significant advantages over treatment of Levothyroxine alone and till further investigation, should be employed (Hector F. Escobar-Morreale). Bibliography: 1. BURY, K. S. NAIK and R. F. "Imaging the Thyroid ." Clinical Radiology ( 1998): 630-639. 2. Chatterton, Barry E. A Doctor's Guide to Nuclear Medicine. 14 may 2008 . 3. Franklyn, Jayne A. "Hypothyroidism." Medicine (2005): 27-29. 4. Greenspan, Francis S. "Thyroid Gland." Francis S. Greenspan, David G. Gardner. Basic & Clinical Endocrinology. London: MacGrawHill-Professional, 2001. 214-265. 5. Hector F. Escobar-Morreale. "REVIEW: Treatment of Hypothyroidism withCombinations of Levothyroxine plus Liothyronine." The Journal of Clinical Endocrinology & Metabolism (2005): 4946-4954. 6. J. H. OPPENHEIMER. "A THERAPEUTIC CONTROVERSY Thyroid Hormone Treatment: When and What" Juurnal uf' Clinical Endocrinology and Metabolism (1995): 2873-2883. 7. Mcgron, Anthony J. "radioiotop in nuclear medicine." (n.d.). 8. Pulzer, Juergen Kratzsch and Ferdinand. "Throid Gland development and Defects." Best Practice & Research Clinical Endocrinology & Metabolism (2008): 57-75. 9. R.Balon, Helena. "Society of Nuclear Medicine Procedure Guideline for Thyroid Uptake Measurement." Guidline. 2006. 10. Rappley, Marsha D. "Hypothyroidism." Medical Update for Psychiatrists 1996: 64-66. 11. The Stunning Effect in Radioiodine Therapy of Thyroid Cancer. 14 may 2008 . Read More