The Role of Nuclear Medicine in Hyperthyroidism - Assignment Example

The Role of Nuclear Medicine and other Imaging Modalities in Hyperthyroidism Hyperthyroidism is a common ailment. The basic problem in this disorder is abnormal hyperfunction of the thyroid gland leading to excessive or larger than normal secretion of thyroid hormones, namely T3 and T4. Since the basic content of these hormones is iodine, thyroid gland has been shown to incorporate radioactive iodine into these molecules while synthesising them. Based on this principle, an external counter may detect the radioactivity and create an image of the thyroid gland. Pertechnetate is another radionuclide which can also be used in a similar fashion to detect the activity of the gland. In clinical practice different hyperthyroid conditions such as Graves’ disease, hyperthyroid goiter, and other conditions such as toxic multinodular or nodular goitre need assessment of activity of the gland. In this review, contemporary literature has been reviewed to update current knowledge on this topic. This assignment reveals that radionuclide imaging is an important diagnostic modality in the workup of hyperthyroid disorders, but despite that, in some cases the diagnostic yield is better with ultrasonography or PET scanning. In some cases, combined use of these imaging investigations pinpoints the diagnosis in a more suitable manner. Review of these articles and the knowledge apparent may be used to frame a guideline of advice regarding imaging practice in this area. Introduction The thyroid gland produces two hormones, namely, thyroxin (T4) and triiodothyronine (T3). These are known to play important physiological roles in the human body. Anatomically, the thyroid gland is located in the neck, in front of the trachea. It comprises of two lobes, right and left, connected by a narrow bridge of thyroid tissue, known as isthmus. It is a very highly vascular organ. The normal adult thyroid gland consists of follicles lined by thyroid follicular cells that contain large amount of thyroglobulin. This serves as the protein precursor of the thyroid hormones (Broome, 2006). Endocrinologically, increased need for thyroid hormone leads to a signal pathway mediated by thyroid stimulating hormone (TSH) leading to release of active hormone from a bound state with thyroglobulin to a free state, eventually being secreted into the blood stream. When there is hypersecretion of thyroid hormones due to any cause, the condition is known as hyperthyroidism. Usually hyperthyroidism is indicated by an elevated level of TSH. Therefore, in clinical practice the diagnosis of hyperthyroidism is made by finding an abnormally elevated TSH level which would indicate measurements of circulating thyroid hormone levels, ultimately confirming the diagnosis of hyperthyroidism (Flower et al., 1990). There are several interpretations of bound and unbound thyroid hormones to point to the accurate aetiological diagnosis of hyperthyroidism. However, this is not the case always. There are many physiological conditions which demonstrate higher total thyroid hormone levels due to the fact that those conditions lead to an elevated thyroid binding globulin. Likewise, there are several clinical conditions where the TSH level estimation as a screening test fails to point to the exact diagnosis of hyperthyroidism. This is more so when unbound T4 estimations are not parts of the investigative protocol (Intenzo et al., 2003). Many extrathyroid diseases may lead to an abnormal TSH level. Similar artifacts in interpretation in laboratory data may appear in certain other conditions. For example, decreased TSH, the hallmark of hyperthyroidism may be noted physiologically in the first trimester of pregnancy, following treatment of hyperthyroidism, even as a result of some medications, and more significantly in cases of hypothalamic-pituitary diseases. Certain other clinical tests are also not useful in such cases. A particular property of thyroid gland can be used to diagnose such cases. The thyroid gland is known to selectively transport radioisotopes of iodine, 123I, 125I, and 131I and 99mTC pertechnetate. This can be used to allow thyroid imaging through quantification of fractional uptake of these radioactive tracers (Wu and Weiss, 2006). This highlights one of the uses of nuclear medicine in imaging modalities used in hyperthyroidism. There are many other modalities of imaging available aside from the nuclear medicine imaging techniques, and in this assignment the relevant literature will be evaluated to update knowledge in this area, so this can be clinically useful. Review of Literature Appropriate recent literature was searched from databases, and for this assignment they were reviewed critically. The key words for literature search were “role”, “nuclear medicine”, “imaging”, “imaging modalities”, “hyperthyroidism”, and a combination of words with “and” or “or.” Across databases, about 76 different articles were located that included original research articles, review articles, and abstract. For the purpose of this literature review, the articles which dealt with diagnostic imaging modalities in hyperthyroidism including nuclear imaging techniques were included and reviewed, and latest were given priorities. Findings from the Literature Review Role of Nuclear Imaging in Thyroid Disease Sarkar (2006) discusses the role of nuclear medicine in benign thyroid disease. The author discusses both the diagnosis and treatment. For the purpose of this assignment, the diagnostic part is relevant. The author also comments that apart from an understanding of the pathophysiology and management, expertise in nuclear methodology is also important to be able to apply these modalities in practice. The principal nuclear tests in diagnosis of thyroid disease are assessment of thyroid uptake and imaging. This can be particularly useful in the differential diagnosis of hyperthyroidism. For example, a low uptake would indicate subacute thyroiditis, which is a self-limited but destructive disease (Sarkar 2006). Necessity of Knowledge about Thyroid Pathology As supported by other authors (Meller and Becker, 2002) on the contrary, a toxic nodular goiter and Graves disease, both forms of hyperthyroidism may present as normal or elevated uptake. Nuclear imaging of Graves disease can be pointed at an enlarged gland along with enhanced uptake of the tracer with a homogeneous distribution. Toxic adenoma which is another cause of hyperthyroidism appears in nuclear imaging as focal areas of enhanced uptake. The remainder of the gland shows suppressed tracer uptake. Toxic multinodular goiter is another cause of the same problem, the hyperthyroid picture. Anatomically toxic multinodular goitre presents as an enlarged gland with frequently associated distorted architecture. Therefore, there is no uniformity in the pattern of tracer uptake. Imaging would reveal multiple areas of relatively increased or decreased tracer uptake indicating areas of hyper or hypoactivities. One of the riddles is encountered in subacute thyroiditis, where pathologically, there is follicular cell damage and TSH suppression. Consequently, there would be very low uptake. Meller and Becker (2002) reiterates the importance of nuclear imaging as an important modality of investigation since at the molecular level, radioiodine uptake and pertechnetate would be proportionate to the sodium/iodine symporter of the thyroid gland. They have described the techniques of nuclear imaging of thyroid where both qualitative and quantitative scintigraphic analysis can be performed with the help of a gamma camera connected to an on-line computer system. This enables the estimation of iodine uptake or the uptake of technetium tracer as an equivalent of iodine clearance from the gland (Meller and Becker, 2002). Use of Imaging In Differentiation of Pathologies As indicated by Schoen et al. (2004) there remains genetic implications at the molecular level of these tracers the iodine-123 or pertechnetate scan remains one of the accurate tests for imaging of the thyroid at any location (Schoen et al. 2004). It has been also claimed that quantitative pertechnetate scintigraphy is the most sensitive and specific technique diagnosis of syndromic thyroid disease diagnosis including quantification of the autonomy of the thyroid gland (Meller and Becker, 1999). Meller and Becker (1999) have indicated the importance of these methods not only as an imaging modality, but also as an invaluable method of stratification of risks in hyperthyroidism spontaneous or due to iodine. Radioiodine therapy still remains one of the mainstays of management of these conditions, and nuclear imaging is invariably necessary to determine the target volume of the gland which would justify the dose of the ablator tracer, which is an indispensable step to ascertain the success of the treatment. Thyroid nodule may present in different forms, and a hyperactive nodule with hyperthyroidism, otherwise known as a hot nodule can be definitively ascertained by nuclear imaging to be not a cancer. Therefore, nuclear imaging is not just another imaging technology; rather it is an imaging modality that can functionally characterise thyroid disease. The case of Graves disease may be presented as an example, where hyperthyroidism is the rule with characteristic scintigraphic imaging can be diagnostic. However a co-occurring nodule in Graves disease may have a high propensity of being a cancer, and that can be ascertained by the scintigraphy without doubts. Differentiation between hyperthyroid autoimmune thyroiditis and Graves disease may be problematic since both are hyperthyroid conditions and pertechnetate scintigraphy may of value in such cases, where other modalities of investigative imaging such as ultrasonography may be of less usefulness (Meller and Becker, 1999). Role of Different Imaging Modalities Gedik et al. (2008) investigated the diagnostic efficacy of scintigraphy combined with ultrasonography in the management of a large series of patients with thyroid and parathyroid disorders. In this series of 387 consecutive patients were subjected to scintigraphy and ultrasonography, and the results of these imaging investigations were reviewed by two independent nuclear medicine physicians, through consensus when discrepancy appeared. In thyroid diseases, ultrasonography was noted to provide additional information when more nodules than in scintigraphy was identified, when an irregular hyperactive area at scintigraphy was clearly diagnosed to be a nodule in ultrasonography, a small sized nodule of less than 1 cm missed in scintigraphy could be imaged and diagnosed with ultrasonography. All these would facilitate a USG-guided fine needle aspiration biopsy to be able to finally diagnose the condition. A combination of USG and scintigraphy could be useful in thyroid disorders. USG can be particularly useful for detection of additional nodules in glands where thyroid tissue was suppressed. Ultrasonography would also identify small nodules. In thyroid diseases, scintigraphy would be useful to diagnose a diffuse hyperfunctioning thyroid gland (Gedik et al. 2008). Specific Indications Broome (2006) defines thyroid scintigraphy as a nuclear medicine procedure that images the functional thyroid tissue due to its innate property of selective uptake of specific radionuclides. This is not only imaging, it also provides important information about anatomy and physiology of the gland, specially when some functional adenomatous tissue is responsible for the development of hyperthyroidism. It is an important modality of imaging to document the diagnosis prior to the biochemical abnormality of the gland is evident. It is also a better modality of test in hyperthyroid conditions of nonthyroid origin. This is a known additional method of diagnosis of relative severity of thyroid problems less affected by co-occurring extrathyroid disease in comparison to conventional laboratory assessments. This is an excellent method of to estimate the size of the hyperfunctional tissues (Broome, 2006). Is Imaging only Applicable to Thyroid Glands? Lass et al. (2008) discuss the use of other useful diagnostic modalities in other conditions that result from hyperthyroidism. Such conditions may be some neurological and psychiatric conditions. Hyperthyroidism is associated with psychiatric disorders such as apathetic hyperthyroidism and dementia from hyperthyroidism. Lass et al (2008) may be quoted regarding enumeration of these abnormalities, "Functional imaging of cerebral blood flow and metabolism helped establish both global and/or regional decrease of both cerebral blood flow and metabolism in hypothyroidism, particularly in regions mediating attention, motor speed and visuospatial processing. Hypothyroid dementia may be mediated by neurocircuitry different from that in major depression" (Lass et al 2008). Metabolic functional imaging of brain such as SPECT or PET imaging may be helpful in these cases to elucidate the pathologies further that may prove to establish the diagnostic background of these disorders which may be associated with hyperthyroidism (Lass et al 2008). Role of MRI or PET Imaging Schreckenberger et al. (2006) highlights the importance of PET scanning as an imaging modality in diagnosing the neuronal correlates of hyperthyroidism associated psychiatric symptoms in a cross-sectional trial. Since hyperthyroidism is associated with psychiatric symptoms, it is expected that there would be metabolic changes in the brain, specially in the limbic and paralimbic system. These can be diagnosed through imaging modalities using fluorodeoxyglucose PET scan. This study also reports that hyperthyroid patients may have elevated anxiety levels showing hypermetabolism of the sensory association cortex bilaterally. These may be detected by functional MRI imaging studies. Metabolically this can be explained by increased cerebral blood flow yet normal oxygen consumption in regional areas of brain in patients with hyperthyroidism (Schreckenberger et al. 2006). Studies that Indicate a Guideline Prvulovich and Bomanji (1998) in their review on the role of nuclear medicine in diagnostic imaging reviews evidence in favour of this imaging modality in clinical practice. In the section of thyroid diseases, the usage of radionuclide imaging has been summarised. The scintigraphy in thyroid diseases has been used with pertechnetate or radioiodine. The commonest reason for imaging is to determine the nodules which would necessitate biopsies. This is of use in order to differentiate Graves disease and Plummers disease. Hasimoto thyroiditis with hyperthyroid symptoms also can best be imaged and diagnosed with this modality. A nonsuppressed thyroid trap may be imaged best with this. The usefulness of this investigation in calculating the optimal dose of radioiodine as a therapeutic agent has been mentioned earlier and the role is insurmountable (Prvulovich and Bomanji, 1998). Intenzo et al. (2003) indicates hyperthyroidism is due to over activity of the thyroid gland with an increased thyroid hormone synthesis. Despite in some cases, the diagnosis being straightforward and imaging apparently being unnecessary, clinically imaging is advised in the form of a RAIU, mainly in a pretherapeutic anticipation of radioiodine therapy. Sometimes imaging is necessary for further workup of the condition. In many cases, development of Graves disease is progressive, and in these cases, thyroid enlargement is not universal, nor invariable. Thus despite the diagnosis is Graves disease, the gland remains normal in size early in the course of the disease. RAIU and scintigraphy would be helpful in such cases, specifically allowing differentiation from various stages of thyroiditis or from factitious hyperthyroidism. The authors have briefly described the technique of pertechnetate scintigraphy. The findings as indicated by the authors were occasional rapid iodine turnover with enlarged thyroid gland. The radioiodine activity or pertechnetate activity would be increased globally across the gland relative to the background. This finding was ascribed to both increased function and increased stimulation of the gland (Intenzo et al. 2003). Flower et al. (1990) performed comparative studies of 41 hyperthyroid patients, who had clinically two types of diagnoses, namely, Graves disease and multinodular goiter. The interventions performed in all patients were sequenced with ultrasonography, PET using 124I, followed by gamma camera pinhole imaging scintigraphy subsequent to 131I therapy. The last was not performed with a diagnostic intent, but the findings correlated well with 124I PET imaging that would determine the relative size of the lobe. In this way, any of these imaging modalities could be utilised to indicate the relative dose of radiation applicable to each lobe of thyroid. High resolution ultrasonography images correlated well with the PET images while elucidating the gland morphology. However, in terms of image quality and diagnostic yield, these images did not correlate well with the 131I pinhole image. It was concluded that if the goal is to acquire anatomical and physiological detail, the choice of imaging modality would be a PET imaging than a 131I pinhole imaging. In about two-thirds of the cases, despite the pinhole image showing uniform radioisotope distribution, the PET image yielded better spatial resolution. This indicated despite being apparently uniform, there had been a nonuniform distribution of the tracer across the gland (Flower et al. 1990). Studies that Summarise the Findings To summarise this review, reference to Meier and Kaplan (2001) may be made where following a review, the authors have concluded that radioactive iodine uptake and thyroid scintiscan has important role in diagnosis of hyperthyroidism. The main usage is in identification of the cause of hyperthyroidism and to ascertain the dose of 131I in its treatment. To be able to interpret this information in order to be able to reach a diagnosis, the factors that may be associated with alteration of uptake must be known. Although there is a possibility that its use is no longer that rife, increasing knowledge about the pathogenesis of hyperthyroidism indicates that nuclear scintigraphic imaging of the thyroid gland may substantially contribute to therapeutic decision making and in cases where deemed essential, these imaging modalities may be priceless in clinical management of such diseases. One such example may be planning of 131I therapy in postoperative recurrence of goiter (Meier and Kaplan 2001). Wu and Weiss (2006) summarise the findings in a succinct manner. In the preliminary care setting RAIU or thyroid scan is seldom advised. In hyperthyroidism, the initial test should be TSH assay. However, when the diagnosis between thyroiditis and Graves disease as a cause of hyperthyroidism is not clear, this imaging may be advocated. The primary indication for a scan can be a suppressed or low TSH level (Wu and Weiss 2006). Lastly, Canbaz et al. (2004) highlighted the role of scintigraphy or nuclear imaging in the diagnosis of subclinical hyperthyroidism. These cases often present as low TSH levels along with normal free T4 and free T3. Although named subclinical, many affected individuals can have nonspecific symptoms suggestive of hyperthyroidism. Standard methods of radionuclide imaging using pertechnetate may be useful in diagnostic imaging of such conditions. In order to establish their hypothesis, the authors investigated 52 patients with the above defining criteria for inclusion into the study. All patients who had thyroid influencing medications, thyroid surgery, or extrathyroid diseases were excluded from the study. Imaging from scintigraphic studies was evaluated visually. This modality was able to diagnose both hyper and hypoactive nodular goiter, hyperactive multinodular goiter, and diffuse hyperactive glands. Mild to moderate hyperplasia was another finding, although encountered in a small proportion of patients. Most of the patients demonstrated multinodularity (Canbaz et al. 2004). Summary of Findings and Conclusion To summarise, this literature review indicates, there are many modalities of imaging of the thyroid gland is available. The most prominent of them are radioiodine tracer scintigraphy or pertechnetate nuclear imaging. Other than that ultrasonography and PET imaging are also available. While the most commonly advised imaging modality is radioactive iodine uptake test, scintigraphic imaging still holds good as the prime modality advised in diagnosis of hyperthyroidism. Comparative studies indicate PET imaging can demonstrate better resolution comparable to ultrasonographic scanning, scintigraphy is more commonly advocated. The usage have been elucidated to be diagnosis of the cause of hyperthyroidism, specially Grave’s disease, diagnosis of thyroiditis, aid in determination of radioiodine thyroid ablation, imaging of a multinodular goiter with or without a nodule, and diagnosis of subclinical hyperthyroidism. Ultrasonography has been advocated before fine needle aspiration biopsy cytology, but accuracy of determination of a multinodular goiter with hyperthyroid symptoms is more easily accomplished with PET scanning. Some hyperthyroid patients have psychological symptoms due to thyroid induced hypermetabolism in the brain in specific areas. The diagnosis of these conditions can best be accomplished with SPECT or PET scan of the brain. Despite progress in laboratory technology and endocrinological assays, where advice for nuclear imaging should come to nominal numbers, even now scintigraphy with radioiodine or pertechnetate remains the gold standard, and even in cases of obvious diagnosis, these are advised. However, from the clinical standpoint, in the conditions mentioned above, nuclear imaging scintigraphy of the thyroid is still a valuable imaging modality. In some studies a judicious combination of both these modalities have been tried to make a better diagnostic yield, where for example scintigraphy had been used to diagnose a nodule which was later subjected to fine needle biopsy under ultrasonographic guidance. Whatever may be the modality, knowledge on the part of physicians of nuclear imaging and on the part of nuclear physicians about the pathology of hyperthyroidism is necessary to pinpoint the best imaging investigation and interpret it. Reference List Broome, MR., (2006). Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract; 21(1): 10-6. Canbaz, F., Basoglu, T., Kececi, D., Yapici, O., and Alkurt, M., (2004). Scintigraphic patterns in patients with subclinical hyperthyroidism. Hell J Nucl Med, 7(3): 203-5. Flower, MA., Irvine, AT., Ott, RJ., Kabir, F., McCready, VR., Harmer, CL., Sharma, HL., and Smith, AG., (1990). Thyroid imaging using positron emission tomography—a comparison with ultrasound imaging and conventional scintigraphy in thyrotoxicosis. Br. J. Radiol.; 63: 325 - 330. Gedik, GK., Bozkurt, FM., Ugur, O., Grassetto, G., and Rubello, D., (2008). The additional diagnostic value of a single-session combined scintigraphic and ultrasonographic examination in patients with thyroid and parathyroid diseases. Panminerva Med.;50(3):199-205. Intenzo, CM., dePapp, AE., Jabbour, S., Miller, JL., Kim, SM., and Capuzzi, DM., (2003). Scintigraphic Manifestations of Thyrotoxicosis. RadioGraphics; 23: 857 - 869. Lass, P., Slawek, J., Derejko, M., and Rubello, D., (2008). Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging. Minerva Endocrinol; 33(2): 75-84. Meier, DA. and Kaplan, MM., (2001). Radioiodine uptake and thyroid scintiscanning. Endocrinol Metab Clin North Am.;30(2):291-313 Meller, J. and Becker, W., (1999). Scintigraphy with 99mTc-pertechnetate in the evaluation of functional thyroidal autonomy. Q J Nucl Med.;43(3):179-87. Meller, J. and Becker, W., (2002). The continuing importance of thyroid scintigraphy in the era of high-resolution ultrasound. Eur J Nucl Med Mol Imaging;29 Suppl 2:S425-38. Prvulovich, EM. and Bomanji, JB., (1998). Fortnightly review: The role of nuclear medicine in clinical investigation. BMJ; 316: 1140 - 1146. Sarkar, SD., (2006). Benign thyroid disease: what is the role of nuclear medicine? Semin Nucl Med; 36(3): 185-93. Schoen, EJ., Clapp, W., To, TT., Fireman, BH., (2004). The key role of newborn thyroid scintigraphy with isotopic iodide (123I) in defining and managing congenital hypothyroidism. Pediatrics;114(6):e683-8. Schreckenberger, MF., Egle, UT., Drecker, S., Buchholz, HG., Weber, MM., Bartenstein, P., and Kahaly, GJ., (2006). Positron Emission Tomography Reveals Correlations between Brain Metabolism and Mood Changes in Hyperthyroidism. J. Clin. Endocrinol. Metab.; 91: 4786 - 4791 Wu, SY. and Weiss, RE., (2006). Radioiodine imaging in the primary care of thyroid disease. Postgrad Med.;119(2):70-7. Questions What is hyperthyroidism? What different imaging modalities may be used in diagnosing hyperthyroidism? Can imaging modalities differentiate between aetiologies of hyperthyroidism? In relation to hyperthyroidism, what best can be diagnosed by radionuclide imaging? Can radionuclide scintigraphy be used in combination with other imaging modalities? What are the roles of PET and MRI scanning in relation to hyperthyroidism? What radionuclides are used for scintigraphy of the thyroid gland? What are the hormones that are released from the thyroid gland? Provide an example where ultrasonography may be better that nuclear imaging? What would be guidelines for using nuclear imaging in diagnosis of hyperthyroidism? Read More