RADI1127 Nuelar Medicine In Diagnosing Of Primary Hyperparathyroidism

Introduction:

Hyperparathyroidism is a disease caused in parathyroid glands due to excessive production of parathyroid hormone (PTH) by parathyroid tumors. This disease leads to slow destruction of tissues as well as multiple organs of the human body. Parathyroid adenoma is basically a tumor in parathyroid gland which is in benign stage and it is one of the most commonly found reason behind hyperparathyroidism. Overproduction of PTH causes disruption in calcium and phosphorus ion balance, which directly affects human tissues. Hyperparathyroidism is considered as the second most emerging disease throughout the world after diabetes. It has been estimated that approximately 1 to 4 out of every 1000 individuals are diagnosed with hyperparathyroidism (Michells & Kelly, 2013). Application of nuclear medicine in diagnosis has advanced the process of identification of serious diseases such as hyperparathyroidism. In this procedure of nuclear medicine in diagnosis, nuclear medicines termed as radioactive tracers are either injected in the bloodstream of the patient or consumed by the patient in order to get an image of the target organ. The radiotracers typically travels through the body of the patient and in presence of gamma ray at the targeted organ the image is then captured with help of complex detectors. Nowadays, the use of nuclear medicine in diagnosis of primary hyperparathyroidism is rapidly growing as it provides a unique functional detail that helps in detection of parathyroid benign tumors in the parathyroid gland compared to other image processing techniques (Balon et al., 2013). Here in this study, available literatures on the topic of application of nuclear medicine in diagnosis of primary hyperparathyroidism due to parathyroid adenoma will be discussed and reviewed.

Methodology (search strategy):

To search previously done research literatures regarding the use of nuclear medicine in diagnosis of hyperparathyroidism, the keywords that were used are ‘radiotracers’, ‘protocols of nuclear medicine imaging process’, ‘hyperparathyroidism’ and so on.

Protocols of parathyroid scintigraphy:

When a dual phase 99mTc-sestamibi is performed, paralle-lhole collimator, a pinhole collimator or a converging collimator with high resolution ability. Usually a pinhole collimator is used if SPECT/CT is not included in the imaging process. High number of images were taken of the neck and chest of the patient. The imaging process include an early imaging step that is performed after 10-30 minutes of injection of the radiotracer. The later step includes delayed type imaging after 1.5-2.5 hours of administration of 99mTc-sestamibi. This method does not require any special patient preparation methods which makes it easier to perform. Planar images of neck and inferior cardiac margin is taken using a gamma-camera associated with a high resolution collimator (Greenspan et al., 2012).

The radioactive tracer is taken up by the thyroid as the thyroid naturally requires iodine to produce thyroid hormone. Other tracers used like 99mTc- Sestamibi or Tetrofosmin act as an iodine analogue and that is why they allow for earlier imaging and reduced radiation burden on the patient there is rapid tracer washout, iodine-123 is organified and taken up by the thyroid.

There are several radiotracers are available for performing the nuclear medicine imaging technique. The most commonly utilized radiotracers or nuclear medicines are I-123, I-131, Tc-99m Sestamibi, Tc-99m Pertechnetate and F-18 fluordeoxyglucose (FDG) (Kanthan et al., 2016).

Multiple protocols are used to perform the scanning and imaging of parathyroid gland using nuclear medicine to detect parathyroid adenoma, such as:

• Dual tracer 99mTc-Sestamibi/Iodine-123:  In this method two types of radiopharmaceuticals are used, 99mTc-Sestamibi and Iodine-123. The dual tracer protocol requires the administration of 99mTc-Sestamibi intravenously. I-123 generally is administered orally as it is delivered in capsule form. The protocol also includes patient positioning reported in (Caveny et al., 2012).  A total of 37 patients participated in this study with supported evidence of parathyroid adenomas present. Each individual patient was given a 22.2 MBq I-123 capsule orally. Early images where acquired at 15 minutes and delayed acquisitions 3 hours post administration of 99mTc- Sestamibi. The protocol reports images taken where 5 minute pinhole acquisitions from neck to the base of the heart both anterior and oblique views (45⁰) (Caveny et al., 2012).
• Parathyroid scan sestamibi:The radiotracer Tc-99m Sestamibi is administered intravenously in body of the patient. It is also one of the most generically used radiotracers along with the protocol. Some hospital practices will adjust protocols to their own opinions. For imaging procedure collimators with low energy high resolution, are used. Initially, the planar images of neck and upper chest are captured within 10 minutes and 2 hours after administration of the nuclear medicine. Immediately after taking the planar images, SPECT-CT images from nose to the base of the heart is are acquisitioned (Im Hiyung-Jum et al., 2014).  Once SPECT-CT acquisition has been completed the CT data is fused with the SPECT data and 3 imaging views are created which are transverse, sagittal and axial slices.
• Parathyroid tetrofosmin:The radiopharmaceuticals used in this process is 99mTc- Tetrofosmin.  Another frequently used radiotracer used in practice as an alternative for other tracers. Using the radioactive tracer tetrofosmin has similarly practiced protocols as sestamibi as it comparable traits to sestamibi. 740 Mbq of 99mTc- Tetrofosmin was intravenously administered into the patient (Romanidis et al., 2014). Images where than acquired post-20 minutes and 2.5 hours after administration of tetrofosmin- 99mTc. Using low energy high resolution collimators images acquired where set to 100,000 counts (100k counts). The image acquisitions where acquired over a field of view from the neck down to the chest cavity (base of the heart). (Romanidis et al., 2014). 

To search previously done research literatures regarding the use of nuclear medicine in diagnosis of hyperparathyroidism, the above mentioned related terms and topics were used such as the examples of radiotracers, protocols of nuclear medicine imaging process and so on.

Current practices performed to diagnose primary hyperparathyroidism using nuclear medicine:

A research study done on the topic of primary hyperparathyroidism caused by parathyroid adenomas involved the usage of two radiotracers in order to diagnose primary hyperparathyroidism. A 23-year old man with symptoms like swollen thyroid gland, pain at the right chest and probable case of clubbing fingers. The tracer Technetium 99m (^99mTc) pertechnate is used for the targeted imaging of thyroid scintigraphy, while ^99mTc-sestamibi radiotracers are used for parathyroid imaging due to the rapid wash out from normal thyroid tissue. The report also states that although Computed tomography (CT) of neck and Magnetic Resonance Imaging (MRI) are available for diagnosis of primary hyperparathyroidism, yet ^99mTc-sestamibi scintigraphy for parathyroid gland is the most reliable and best option available to ensure the detection of parathyroid adenoma (Vitetta et al., 2014). The high quality imaging process and use of radioactive nuclear medicines tracers made it easier to detect the tumors even in its benign stage. Another literature discussed a pilot study performed on the topic localization of over-functioning thyroid tissue of a primary hyperparathyroidism patients. Four major nuclear medicine imaging processes, 18F- Fluorocholine PET/CT, 99mTc-sestamibi SPECT/CT, 99mTc-sestamibi dual phase imaging and 99mTc-sestamibi/Pertechnetate, were followed. The literature also presents a comparative study between the current practices using nuclear medicine imaging for diagnosis of parathyroid adenoma. The result shows that the sensitivity and accuracy of 18F-Fluorocholine PET/CT was the highest with 92% and 100% efficiency (Lezaic et al., 2014). An important research presents the comparative study between the efficiency of ultrasound and radiopharmaceuticals for diagnosing primary hyperparathyroidism. The ^99mTc-sestamibi with additional pharmacokinetic qualities assists to develop two phased scintigraphy of parathyroid. 10-15 minutes and 1.5-2.5 hours after administration of radiopharmaceutical probes, the two scintigraphic imaging processes are performed. Increased level of radiotracer indicates the presence of parathyroid adenoma cells. It further elaborates accumulation of 99mTc-sestamibi and 99mTc-tetrofosmin occurs both in thyroid cells and parathyroid cells, whereas parathyroid tissue do not uptake I-123 and 99mTc-pertechneate. Another research investigates the role of radionuclide imaging in primary hyperparathyroidism detection. The report explains two major factors for not using ultrasound technique only for parathyroid adenoma detection purpose. The factors involve low sensitivity and variation of sensitivity in different experiments. This process of imaging was performed using a parallel collimator and images were captured at 15 minutes and 2-3 hours. However, the process still faces some obstacles and seldom generates false-positive result. The efficiency and accuracy increases multiple times by incorporating 99mTc-sestamibi and I-123 using the dual-isotope dual phase protocol. Application of SPECT/CT with a pinhole collimator helps in optimizing resolution of images. In addition to optimizing image resolution it also accounts for attenuation correction and anatomical localization. This improvement helps in producing images with better image quality that helps in identification of the parathyroid tumor (Nieciecki, Cacko & Krolicki, 2015).

Impact of radiopharmaceuticals on patient outcome:

A research study performed to examine the effective dose of 338 radiopharmaceuticals in adult patient which were previously published and identified by International Commission on Radiological Protection (ICRP), shows that 79% of the radiopharmaceutical showed efficiency at a low level of the nuclear medicines (Andersson et al., 2014). The dose that was effective for these patients from adult age range was estimated by ICRP or ICRU reference of voxel phantoms and decay data. For recalculation the effective dose for the adult patients ICRP human tract model has also been used. The calculations and dose level estimated in this research were more reliable than previous studies as it estimated the dose levels with help of different references (Russ et al., 2013). Another research was done to investigate the importance of 99mTc-sestamibi SPECT-CT imaging technique for the patients with primary hyperparathyroidism who will undergo surgery. The study showed that application of dual phase parathyroid scan using single isotope was extremely beneficial for presurgical diagnosis of the patients with primary hyperparathyroidism. The study result showed 90.6% accuracy in identifying and localizing the site with the parathyroid adenoma in patients which ensures the high efficiency of this procedure in preoperative stage (Andersson et al., 2014).

Literature gap:

The literature papers that were reviewed in this study showed some gaps in their research that may indicate the future scopes for innovation in imaging technique using nuclear medicines or radiotracers. The above mentioned studies did not present any information regarding the detection of the efficiency of new drugs used to treat primary hyperparathyroidism. In these studies it is nowhere mentioned that how the radiotracer techniques can be modified to make the techniques more cost effective and more personalized to individual patients. Another major lack can be noticed that the studies have not presented any information regarding increasing the sensitivity and accuracy of the nuclear medicine. Although the nuclear medicine imaging technique is highly efficient in diagnosis of primary hyperparathyroidism caused by parathyroid adenoma, sometimes it provides false positive test which is a major drawback of the method. Further development and research is required to find the solution of this problem.

Future scopes for research and development:

In past few years, application of nuclear medicine in diagnosis of primary hyperparathyroidism has been advanced rapidly. In order to simplify and facilitate the use of radiopharmaceuticals, more innovations and developments are required in this field. There is a major scope for further research in development of nuclear medicine imaging technique which will help to grow personalized medicines for the patients diagnosed with hyperparathyroidism. Further research can also include in finding new radionucleotide therapeutic imaging process that will be targeted for individual patients (Lan et al., 2014). Development of more advanced radiotracers can be advantageous for detecting the biochemical changes at the parthyroid adenoma site. Development of more techniques using radiotracers is required for evaluating the efficiency of new drugs developed for hyperparathyroidism. This method can also help to detect the changes in a patient at the parathyroid gland post treatment and therapy (Yeong et al., 2014). Further advancement is required to accelerate the use of these radionucleotides for diagnosis of the hyperparathyroidism and to reduce the cost for performing the diagnosis technique. More sensitive nuclear medicine imaging techniques are required with high resolution in order to increase the accuracy level. Patients often do not show the symptoms for hyperparathyroidism at primary stage. Collaboration of these nuclear medicine imaging technique with technologies like PET and MRI will be advantageous for diagnosis of hyperparathyroidism at primary level.

Summaryr:

Hyperparathyroidism is an emerging disease and considered as the second most rapidly growing disease after diabetes. The rate of individuals diagnosed with hyperparathyroidism is very high. Another important fact is often people with primary hyperparathyroidism are not properly diagnosed due to lack of clinical symptoms. Application of nuclear medicine to diagnose the hyperparathyroidism disease at a primary stage is now gaining high popularity for its accuracy and sensitivity. This study was performed to review some previously published literatures to understand the impact of nuclear medicines in diagnosis of primary hyperparathyroidism caused due to parathyroid adenoma. Multiple studies have been done that explains the importance and use of radiotracers or radionucleotide therapeutics in detecting hyperparathyroidism at a primary stage. Individual studies followed different protocols that involved use of different radiotracers. The literatures also show the comparative analysis between the techniques that involves application of nuclear medicine and the conventional methods that were already available for diagnosis of primary hyperparathyroidism. This study also shows sometimes these techniques can provide false positive tests, and further development is required to rectify this problem. To conclude, it can be said that application of nuclear medicine in diagnosis of primary hyperthyroidism is highly advantageous as it can detect the biochemical changes of the parathyroid gland at an early age which helps to initiate the treatment.

Reference:

Andersson, M., Johansson, L., Minarik, D., Leide-Svegborn, S., & Mattsson, S. (2014). Effective dose to adult patients from 338 radiopharmaceuticals estimated using ICRP biokinetic data, ICRP/ICRU computational reference phantoms and ICRP 2007 tissue weighting factors. EJNMMI physics, 1(1), 9.

Balon, H. R., Silberstein, E. B., Charkes, M. D., Royal, H. D., Sarkar, S. D., & Donohoe, K. J. (2013). Society of Nuclear Medicine procedure guideline for thyroid uptake measurement. Thyroid, 12, 0-11.

Brito, J. P., Morris, J. C., & Montori, V. M. (2013). Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumours. BMJ: British Medical Journal (Online), 347.

Caveny, S., Klingensmith, W., Martin, W., Sage-El, A., McIntyre, R., Raeburn, C., & Wolfe, P. (2012). Parathyroid Imaging: The Importance of Dual-Radiopharmaceutical Simultaneous Acquisition with 99mTc-Sestamibi and 123I. Journal Of Nuclear Medicine Technology, 40(2), 104-110. doi: 10.2967/jnmt.111.098400

Greenspan, B. S., Dillehay, G., Intenzo, C., Lavely, W. C., O'Doherty, M., Palestro, C. J., ... & Tulchinsky, M. (2012). SNM practice guideline for parathyroid scintigraphy 4.0. Journal of nuclear medicine technology, 40(2), 111-118.

Im, H. J., Lee, I. K., Paeng, J. C., Lee, K. E., Cheon, G. J., Kang, K. W., ... & Lee, D. S. (2014). Functional evaluation of parathyroid adenoma using 99mTc-MIBI parathyroid SPECT/CT: correlation with functional markers and disease severity. Nuclear medicine communications, 35(6), 649-654.

Johnson, K. A., Minoshima, S., Bohnen, N. I., Donohoe, K. J., Foster, N. L., Herscovitch, P., ... & Hedrick, S. (2013). Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimer's & Dementia, 9(1), E1-E16.

Kanthan, G. L., Drummond, J., Schembri, G. P., Izard, M. A., & Hsiao, E. (2016). Follicular Thyroid Adenoma Showing Avid Uptake on 68Ga PSMA-HBED-CC PET/CT. Clinical nuclear medicine, 41(4), 331-332.

Lan, M., Zhang, J., Zhu, X., Wang, P., Chen, X., Lee, C. S., & Zhang, W. (2015). Highly stable organic fluorescent nanorods for living-cell imaging. Nano Research, 8(7), 2380-2389.

Lezaic, L., Rep, S., Sever, M. J., Kocjan, T., Hocevar, M., & Fettich, J. (2014). 18 F-Fluorocholine PET/CT for localization of hyperfunctioning parathyroid tissue in primary hyperparathyroidism: a pilot study. European journal of nuclear medicine and molecular imaging, 41(11), 2083-2089.

Michels, T. C., & Kelly, K. M. (2013). Parathyroid disorders. Am Fam Physician, 88(4), 249-257.

Nieciecki, M., Cacko, M., & Królicki, L. (2015). The role of ultrasound and nuclear medicine methods in the preoperative diagnostics of primary hyperparathyroidism. Journal of ultrasonography, 15(63), 398.

Pellegriti, G., Frasca, F., Regalbuto, C., Squatrito, S., & Vigneri, R. (2013). Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. Journal of cancer epidemiology, 2013.

Romanidis, K., Karathanos, E., Nagorni, E., Giatromanolaki, A., Sibridis, E., & Zissimopoulos, A. et al. (2014). Parathyroid adenoma detected with 99mTc-tetrofosmin dual-phase scintigraphy: a case report. BMC Research Notes, 7(1), 335. doi: 10.1186/1756-0500-7-335

Russ, G., Royer, B., Bigorgne, C., Rouxel, A., Bienvenu-Perrard, M., & Leenhardt, L. (2013). Prospective evaluation of thyroid imaging reporting and data system on 4550 nodules with and without elastography. European journal of endocrinology, 168(5), 649-655.

Sunderland, J. J., & Christian, P. E. (2015). Quantitative PET/CT scanner performance characterization based upon the society of nuclear medicine and molecular imaging clinical trials network oncology clinical simulator phantom. J Nucl med, 56(1), 145-52.

Vitetta, G. M., Neri, P., Chiecchio, A., Carriero, A., Cirillo, S., Mussetto, A. B., & Codegone, A. (2014). Role of ultrasonography in the management of patients with primary hyperparathyroidism: retrospective comparison with technetium-99m sestamibi scintigraphy. Journal of ultrasound, 17(1), 1-12.

Yeong, C. H., Cheng, M. H., & Ng, K. H. (2014). Therapeutic radionuclides in nuclear medicine: current and future prospects. Journal of Zhejiang University SCIENCE B, 15(10), 845-863.