Chapter 27: Nuclear Techniques for Disease Diagnoisis

This chapter was published on “Inuitech – Intuitech Technologies for Sustainability” on May 26, 2012.

Medicine is field of applied science and art of healing.  It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness in human beings.  Contemporary medicine applies health science, biomedical research, and medical technology to diagnose and treat injury and disease, typically through medication or surgery, but also through therapies as diverse as psychotherapy, external splints & traction, prostheses, biologics, ionizing radiation and others. The word medicine is derived from the Latin ars medicina, meaning the art of healing.

Nuclear medicine is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease.   A specialty (or speciality) in medicine is a branch of medical science.  After completing medical school, physicians or surgeons usually further their medical education in a specific specialty of medicine by completing a multiple year residency to become a medical specialist.  At the same time radioactive is defined as the process of emitting energy waves due to decaying atomic nuclei.  Radioactive substances are used in medicine as tracers for diagnosis and in treatment to kill cancerous cells.

Here is a brief history of nuclear medicine:

  • The history of nuclear medicine is rich with contributions from gifted scientists across different disciplines in physics, chemistry, engineering, and medicine. The multidisciplinary nature of nuclear medicine makes it difficult for medical historians to determine the birthdate of nuclear medicine;
  • The origins of this medical idea date back as far as the mid-1920s in Freiburg, Germany, when George de Hevesy made experiments with radionuclides administered to rats, thus displaying metabolic pathways of these substances and establishing the tracer principle. Possibly, the genesis of this medical field took place in 1936, when John Lawrence, known as “the father of nuclear medicine”, took a leave of absence from his faculty position at Yale Medical School, to visit his brother Ernest Lawrence at his new radiation laboratory (now known as the Lawrence Berkeley National Laboratory) in Berkeley, California. Later on, John Lawrence made the first application in patients of an artificial radionuclide when he used phosphorus-32 to treat leukemia;
  • Nuclear medicine gained public recognition as a potential specialty on December 7, 1946 when an article was published in the Journal of the American Medical Association by Sam Seidlin.  The article described a successful treatment of a patient with thyroid cancer metastases using radioiodine.  This is considered by many historians as the most important article ever published in nuclear medicine.  Although, the earliest use of I-131 was devoted to therapy of thyroid cancer, its use was later expanded to include imaging of the thyroid gland, quantification of the thyroid function, and therapy for hyperthyroidism;
  • Widespread clinical use of nuclear medicine began in the early 1950s, as knowledge expanded about radionuclides, detection of radioactivity, and using certain radionuclides to trace biochemical processes. Pioneering works by Benedict Cassen in developing the first rectilinear scanner and Hal O. Anger‘s scintillation camera (Anger camera) broadened the young discipline of nuclear medicine into a full-fledged medical imaging specialty.  In these years of nuclear medicine, the growth was phenomenal. The Society of Nuclear Medicine was formed in 1954 in Spokane, Washington, USA. In 1960, the Society began publication of the Journal of Nuclear Medicine, the premier scientific journal for the discipline in America. There was a flurry of research and development of new radionuclides and radiopharmaceuticals for use with the imaging devices and for in-vitro studies5; and
  • In the 1980s, radiopharmaceuticals were designed for use in diagnosis of heart disease. The development of single photon emission computed tomography (SPECT), around the same time, led to three-dimensional reconstruction of the heart and establishment of the field of nuclear cardiology.  More recent developments in nuclear medicine include the invention of the first positron emission tomography scanner (PET). The concept of emission and transmission tomography, later developed into single photon emission computed tomography (SPECT), was introduced by David E. Kuhl and Roy Edwards in the late 1950s. Their work led to the design and construction of several tomographic instruments at the University of Pennsylvania. Tomographic imaging techniques were further developed at the Washington University School of Medicine. These innovations led to fusion imaging with SPECT and CT by Bruce Hasegawa from University of California San Francisco (UCSF), and the first PET/CT prototype by D. W. Townsend from University of Pittsburgh in 1998.

Here are some interesting facts about nuclear medicine according to a report which was updated in October 2011 by World Nuclear Association:

  • Five Nobel Laureates have been intimately involved with the use of radioactive tracers in medicine;
  • Over 10,000 hospitals worldwide use radioisotopes in medicine, and about 90 percent of the procedures are for diagnosis;
  • The most common radioisotope used in diagnosis is technetium-99, with some 30 million procedures per year, accounting for 80 percent of all nuclear medicine procedures worldwide;
  • In developed countries (26 percent of world population) the frequency of diagnostic nuclear medicine is 1.9 percent per year, and the frequency of therapy with radioisotopes is about one tenth of this;
  • In the USA there are some 18 million nuclear medicine procedures per year among 311 million people, and in Europe about 10 million among 500 million people; and
  • In Australia there are about 560,000 per year among 21 million people, 470,000 of these using reactor isotopes. The use of radiopharmaceuticals in diagnosis is growing at over 10 percent per year.

Nuclear medicine can identify abnormalities early in the progression of a disease – long before some medical problems are apparent with other diagnostic tests. This allows a disease to be treated early in its course when there may be a more successful prognosis.

Examples of Nuclear Medicine:

  • Bone scans examine tumors, metabolic disease and orthopedic injuries;
  • Heart scans evaluate blood flow to the heart muscle, measure cardiac function, and determine the extent of damage after a heart attack;
  • Liver and gallbladder scans evaluate organ function and detect disease;
  • Brain scans investigate blood circulation and cerebral structure;
  • Renal imaging gives sensitive diagnostic information about kidney function;
  • Ovarian, prostate, breast, colorectal, lung, and lymphoma are just some of the many cancers that are scanned. Imaging detects tumors and determines the severity (staging) of disease, thus assisting in planning treatment;
  • Positron Emission Tomography, or PET scanning, is a powerful new Nuclear Medicine technique which uses special tracers and cameras to give extraordinary three-dimensional diagnostic information about the entire body; and
  • Positron Emission Tomography (PET scanning) accurately detects infection in 96 percent of patients.

As far as the nuclear diagnostic practices are concerned, the use of nuclear techniques allows the detection and characterization of pathogens within 24 hours of their onset, helping to differentiate one particular virus strain from another.  An example of this differentiation is noted in the case of the Influenza A H1N1 virus, from Influenza A H5N1.  Nuclear techniques are also important in determining the nucleic acid sequence that describes the capacity of a particular virus strain to cause a disease.  Different strains of the same virus may affect birds and also humans, e.g. Influenza A H5N1 low pathogenicity versus Influenza A H5N1 high pathogenicity.  The latter causes deaths in more than 60 percent of infected humans.  The isotopic analysis of the genetic make-up of such a virus can be used by health authorities in making decisions ranging from public notification – as was the case of Influenza A H1N1 (low pathogen) — to immediate pandemic action in the case of Influenza A H1N1 (high pathogen).  This information not only aids disease control personnel and policy makers in their attempts to control and eliminate veterinary and public health pathogens, but also forms the basis for decision making that affects transboundary trade and travel.

Diagnostic techniques in nuclear medicine use radioactive tracers which emit gamma rays from within the body. These tracers are generally short-lived isotopes linked to chemical compounds which permit specific physiological processes to be scrutinized. They can be given by injection, inhalation or orally. The first type is where single photons are detected by a gamma camera which can view organs from many different angles. The camera builds up an image from the points from which radiation is emitted; this image is enhanced by a computer and viewed by a physician on a monitor for indications of abnormal conditions.

Positioning of the radiation source within the body makes the fundamental difference between nuclear medicine imaging and other imaging techniques such as x-rays. Gamma imaging by either method described provides a view of the position and concentration of the radioisotope within the body. Organ malfunction can be indicated if the isotope is either partially taken up in the organ (cold spot), or taken up in excess (hot spot). If a series of images is taken over a period of time, an unusual pattern or rate of isotope movement could indicate malfunction in the organ.  A distinct advantage of nuclear imaging over x-ray techniques is that both bone and soft tissue can be imaged very successfully. This has led to its common use in developed countries where the probability of anyone having such a test is about one in two and rising.

1.      DIAGNOSTIC TECHNIQUES IN NUCLEAR MEDICINE:

There are several techniques of diagnostic nuclear medicine:

1.1    Bone Scintigraphy:

A bone scan or bone scintigraphy is a nuclear scanning test to find certain abnormalities in bone that are triggering the bone’s attempts to heal. It is primarily used to help diagnose a number of conditions relating to bones, including: cancer of the bone or cancers that have spread (metastasized) to the bone, locating some sources of bone inflammation (e.g. bone pain such as lower back pain due to a fracture), the diagnosis of fractures that may not be visible in traditional x-ray images, and the detection of damage to bones due to certain infections and other problems. Slide1

In the nuclear medicine technique, the patient is injected (usually into a vein in the arm or hand, occasionally the foot) with a small amount of radioactive material such as 600 MBq of technetium-99m-MDP and then scanned with a gamma camera, a device sensitive to the radiation emitted by the injected material. Two-dimensional projections of scintigraphy may be enough, but in order to view small lesions (less than 1 cm) especially in the spine, single photon emission computed tomography (SPECT) imaging technique may be required. In the United States, most insurance companies require separate authorization for SPECT imaging. A disruption of bone turnover by a pathologic process on the order of 5 to 15 percent from normal can be detected by bone scintigraphy. Specificity of bone scintigraphy can be increased by performing an indium 111-labeled white blood cell test combined with a Technetium-99m-MDP injection.

About half of the radioactive material is localized by the bones. The more active the bone turnover, the more radioactive material will be seen. Some tumors, fractures and infections show up as areas of increased uptake. Others can cause decreased uptake of radioactive material. Not all tumors are easily seen on the bone scan. Some lesions, especially lytic (destructive) ones, require positron emission tomography (PET) for visualization.  About half of the radioactive material leaves the body through the kidneys and bladder in urine. Anyone having a study should empty their bladder immediately before images are taken.

In evaluating for tumors, the patient is injected with the radioisotope and returns in 2-3 hours for imaging. Image acquisition takes from 30 to 70 minutes, depending if SPECT images are required. If the physician wants to evaluate for osteomyelitis (bone infection) or fractures, then a Three Phase/Triphasic Bone Scan is performed where 20-30 minutes of images (1st and 2nd Phases) are taken during the initial injection. The patient then returns in 2-3 hours for additional images (3rd Phase). Sometimes late images are taken at 24 hours after injection.

The three phase bone scan detects different types of pathology in the bone. The first phase is also known as the nuclear angiogram or the flow phase. During this phase, serial scans are taken during the first 2 to 5 seconds after injection of the Technetium-99m-MDP. This phase typically shows perfusion to a lesion. Cellulitis shows up more in phase 1 and phase 2 scan, but not in phase 3. Pathology that is more moderate to severe will show more in the first two phases. Pathology that is chronic or partially treated will be more pronounced in the third phase of a triphasic scan.

The second phase image, also known as the blood pool image is obtained 5 minutes after injection. This shows the relative vascularity to the area. Areas with moderate to severe inflammation have dilated capillaries, which is where the blood flow is stagnant and the radioisotope can “pool”. This phase shows areas of intense or acute inflammation more definitively compared with the third phase.

The third phase is obtained 3 hours after the injection, when the majority of the radioisotope has been metabolized. This phase best shows the amount of bone turnover associated with a lesion.

1.2       Myocardial Perfusion Scan:

Myocardial perfusion scan is a nuclear medicine procedure that illustrates the function of the heart muscle (myocardium).  It evaluates many heart conditions from coronary artery disease (CAD) to hypertrophic cardiomyopathy and myocardial wall motion abnormalities. The function of the myocardium is also evaluated by calculating the left ventricular ejection fraction (LVEF) of the heart. This scan is done in conjunction with a cardiac stress test.

Planar techniques, such as conventional scintigraphy, are rarely used. Rather, SPECT is more common in the US. With multi-head SPECT systems, imaging can often be completed in less than 10 minutes. With SPECT, interior and posterior abnormalities and small areas of infarction can be identified, as well as the occluded blood vessels and the mass of infarcted and viable myocardium.

Major indications for a Myocardial Perfusion Scan test include:

  • Diagnosis of CAD and various cardiac abnormalities;
  • Identifying location, criticality of existing coronary stenosis and degree of coronary artery disease (CAD) in patients with a history of CAD;
  • Prognostication (risk stratification) and evaluation of patients that are at risk of having a myocardial or coronary incident. (ex: myocardial infarction, myocardial ischemia, coronary aneurysm, wall motion abnormalities);
  • Assessment of viable myocardium in particular coronary artery territory following heart attacks to justify revascularization; and
  • Post intervention revascularization (coronary artery bypass graft, angioplasty) evaluation of heart.

Critics have written that myocardial perfusion imaging is associated with an increased risk of cancer due to high radiation doses that are not justified by randomized, controlled studies demonstrating benefit.  However, radiation doses received during CT angiography and conventional coronary angiography are higher than those received during myocardial perfusion imaging done with 99m-Technetium labeled agents. The psychological block associated with radioactive materials may be responsible for these fears.Slide21.3        Parathyroid Scan:

A parathyroid scan is sometimes called a parathyroid localization scan or parathyroid scintigraphy. This scan uses radioactive pharmaceuticals that are readily taken up by cells in the parathyroid glands to obtain an image of the glands and any abnormally active areas within them.  The parathyroid glands, embedded in the thyroid gland in the neck, but separate from the thyroid in function, control calcium metabolism in the body. The parathyroid glands produce parathyroid hormone (PTH). PTH regulates the level of calcium in the blood.Slide3A parathyroid scan is a non-invasive procedure that uses two radiopharmaceuticals (drugs with a radioactive marker) to obtain an image of highly active areas of the parathyroid glands. The test can be done in two ways.

If the test is to be performed immediately, the patient lies down on an imaging table with his head and neck extended and immobilized. The patient is injected with the first radiopharmaceutical. After waiting 20 minutes, the patient is positioned under the camera for imaging. Each image takes five minutes. It is essential that the patient remain still during imaging.  After the first image, the patient is injected with a second radiopharmaceutical, and imaging continues for another 25 minutes. Total time for the test is about one hour: injection 10 minutes, waiting period 20 minutes, and imaging 30 minutes.  Another way to do this test is as follows. After the first images are acquired, the patient returns two hours later for additional images. Time for this procedure totals about three hours: injection 10 minutes, waiting period two hours and 20 minutes, and imaging 30 minutes.

In a delayed parathyroid scan, the patient is asked to swallow capsules containing the first radiopharmaceutical. The patient returns after a four hour waiting period, and the initial image is made. Then the patient is injected with the second radiopharmaceutical. Imaging continues for another 25 minutes. The total time is about four hours and 40 minutes: waiting period four hours, injection 10 minutes, and imaging 30 minutes.

1.4       Normal Hepatobiliary Scan:

Hepatobiliary scan or HIDA scan is conducted to examine the functioning of the liver. It checks if bile is being made and excreted, if the bile ducts or drainage system are functioning appropriately, and if there is any malfunction in the gallbladder. Typically, a hepatobiliary scan is coupled with an ultrasound of the gallbladder for a comprehensive evaluation. HIDA scan is also referred to as a hepatobiliary iminodiacetic acid scan or an NM hepatobiliary scan. This scan is an imaging process through which your doctor can track bile movements, its production and its flow into the small intestines from your liver. Basically, this scan generates pictures of your biliary tract, liver, gallbladder, and small intestine. It falls under the imaging study called nuclear medicine scans (NM scans).  Nuclear medicine scans use a tracer, which are radioactive chemicals to highlight particular organs in the imaging scans.Slide4The liver is one of the most complicated organs of the human body. This organ is responsible for many different functions including some functions on which the life of the individual depends. No person can live without a liver that is partially functional. One of the many different functions of the liver is the production of bile. Bile is a fluid that is used to break down fatty foods in the digestive system. This fluid is produced in the liver and passed into the gall bladder where it is stored until the individual needs to digest food. When digestion takes place, bile flows directly from the liver into the small intestine. At the same time, bile from the gall bladder will also enter the area. This increases the amount of bile available, thus ensuring that even large quantities of food get broken down effectively.

The hepatobiliary scan is a scan used to determine the effectiveness of the liver’s functioning, particularly relating to its production and release of bile. A person may even have to go through a hepatobiliary scan with gallbladder ejection fraction in certain cases. The hepatobiliary scan is a nuclear medicine scan. This means that a radioactive tracer substance needs to be injected into the body. Tracer substances are used to mark out various organs and tissues in the body. This makes it possible for them to be seen clearly on any subsequent scan. The liver is used to filter out waste products from the blood. Thus, the tracer material will make the parts of the liver very clear in any scan.

The hepatobiliary scan is done in order to check if there is any obstruction in the bile ducts of the liver. This scan is also done to check if there is any obstruction or inflammation of the gall bladder. There may even be a situation where bile leaks into the intestines when it is not needed for digestion. This sort of test will be able to determine if that is the case.

1.5       Normal Pulmonary Ventilation and Perfusion Scan:

The ventilation scan is used to see how well air and blood flow moves through the lungs. The perfusion scan measures the blood supply through the lungs.Slide5A ventilation and perfusion scan is most often done to detect a pulmonary embolus (blood clot in the lungs). It is also used to:

  • Detect abnormal circulation (shunts) in the blood vessels of the lungs (pulmonary vessels)
  • Test lung function in people with advanced pulmonary disease, such as COPD.

A pulmonary ventilation/perfusion scan involves two nuclear scan tests. These tests use inhaled and injected radioactive material (radioisotopes) to measure breathing (ventilation) and circulation (perfusion) in all areas of the lungs.

A pulmonary ventilation/perfusion scan is actually two tests. These tests may be performed separately or together.

During the perfusion scan, a health care provider injects radioactive albumin into your vein. You are placed on a movable table that is under the arm of a scanner. The machine scans your lungs as blood flows through them to find the location of the radioactive particles.

During the ventilation scan, you breathe in radioactive gas through a mask while you are sitting or lying on a table under the scanner arm.

The table may feel hard or cold. You may feel a sharp prick while the material is injected into the vein for the perfusion part of the scan.  The mask used during the ventilation scan may make you feel nervous about being in a small space (claustrophobia). You must lie still during the scan.  The radioisotope injection usually does not cause discomfort.

Risks are about the same as for x-rays (radiation) and needle pricks.  No radiation is released from the scanner. Instead, it detects radiation and converts it into an image.  There is a small exposure to radiation from the radioisotope. The radioisotopes used during scans are short-lived. All of the radiation leaves the body in a few days. However, as with any radiation exposure, caution is advised for pregnant or breast-feeding women.

There is a slight risk for infection or bleeding at the site where the needle is inserted. The risk with perfusion scan is the same as with inserting an intravenous needle for any other purpose.  In rare cases, a person may develop an allergy to the radioisotope. This may include a serious anaphylactic reaction.

1.6       Thyroid Scan with Iodine-123:

An Iodine-131 (131I) was the first radioactive isotope of iodine available for medical use. Thus, there is more data applicable to it than to any other iodine isotope. It is still the choice for therapeutic administration, but has been largely replaced for diagnostic scans by 123I which delivers a much smaller dose to the thyroid and to the whole body than its predecessor, largely because of its shorter physical half-life (13 hours for 123I versus eight days for 131I). Thus it is eliminated from the body much more rapidly. Radiation dose to the patient varies strongly with thyroid activity, or the ability of the thyroid to concentrate the administered iodine.

For example, the radiation dose to the thyroid from a standard scan (400 microcuries) using 123I varies from about 1 milligram (for 0% uptake to the thyroid) to 100 (for 55 percent uptake) milligray. For the same administered dose of 131I, thyroid dose may be as much as 100 times greater. Whole-body effective dose for 131I is also about 100 times greater than that for 123I.

A thyroid scan is a type of nuclear medicine imaging. The radioactive iodine uptake test (RAIU) is also known as a thyroid uptake. It is a measurement of thyroid function, but does not involve imaging.  The thyroid scan and thyroid uptake provide information about the structure and function of the thyroid. The thyroid is a gland in the neck that controls metabolism, a chemical process that regulates the rate at which the body converts food to energy.

Most thyroid scan and thyroid uptake procedures are painless. However, during the thyroid scan, patients may feel uncomfortable when lying completely still with your head extended backward while the gamma camera is taking images.  When the radiotracer is given intravenously, you will feel a slight pin prick when the needle is inserted into your vein for the intravenous line. When the radioactive material is injected into your arm, you may feel a cold sensation moving up your arm, but there are generally no other side effects.  When swallowed, the radiotracer has little or no taste. When inhaled, you should feel no differently than when breathing room air or holding your breath.

It is important that you remain still while the images are being recorded. Though nuclear imaging itself causes no pain, there may be some discomfort from having to remain still or to stay in one particular position during imaging.

Unless your physician tells you otherwise, you may resume your normal activities after your nuclear medicine scan. If any special instructions are necessary, you will be informed by a technologist, nurse or physician before you leave the nuclear medicine department.Slide5Through the natural process of radioactive decay, the small amount of radiotracer in the body will lose its radioactivity over time. It may also pass out of the body through the urine or stool during the first few hours or days following the test. Patients should also drink plenty of water to help flush the radioactive material out of their bodies as instructed by the nuclear medicine personnel.

2.     CONCLUSION:

Radioisotope labeled assays that use isotope levels that are below the limit of disposal are under development. Isotope based nucleic acid hybridization approaches are used to detect genetic material in host tissues that will allow direct identification of infected animals as well as provide information of epidemiological importance in relation to the strain type or variant of the agent.  These tests depend on the preparation of suitable DNA probes labelled with sulphur-35 or phosphor-32 and their amplification in vitro by a nucleic acid amplification technique (PCR) to increase the amount of the specific target.

Nucleic acid thermal amplification technologies shorten the time for a test result to less than a day and in many cases a result can be obtained within an hour. Recent successes using this technology include the development of tests to diagnose diseases such as the Peste des Petit Ruminants disease and capripox virus disease (the collective word for goat pox, sheep pox and cattle pox viruses) and in the sequencing of the different genomes. To set up an appropriate control against the outbreak of one of the three pox viruses in a livestock herd, the outbreak virus needs to be identified. Currently, the capripox virus family, although closely related, requires three different vaccines for protection, i.e. there is no cross-protection between the different capripox virus strains. Sheep pox virus, goat pox virus and cattle pox or lumpy skin disease virus, the third member of the capripox virus genus can be differentiated using the nuclear related thermal amplification real-time PCR approach, thereby selecting the correct vaccine to protect against the homologous pathogen.

Nuclear technologies are also vital to animal disease diagnosis where rapid decision making would be an advantage and especially in situations where the suspected disease occurs in difficult to reach or remote areas that are far from the laboratory. The time saved by determining whether a disease is present or not, could be the difference between containing a disease at its point of origin and protecting human lives or preventing the spread of a disease to an animal market place or further afield. Conventional molecular techniques including thermal amplification or PCR require sophisticated, expensive equipment. A robust test at the molecular level, i.e. the loop mediated isothermal amplification (LAMP) PCR, has been developed using nuclear techniques, which is a more cost effective alternative to thermal DNA amplification. The LAMP PCR can be carried out within 30–60 minutes in a simple water bath at constant temperature and the presence or absence of the isothermally amplified DNA product can be detected visually, i.e. a change in colour (Fig. II–4). Another advantage of the LAMP PCR platform is that it can be developed for use on-site or on-farm as a penside (point of care) rapid diagnostic test.

Resources:

  1. Wikipedia – Applied Science;
  2. Wikipedia – Nuclear Medicine;
  3. Wikipedia – Oak Ridge Laboratory;
  4. Ask Jeeves – Nuclear Medicine;
  5. World Nuclear Association;
  6. Michener/University of Toronto;
  7. IAEA – Nuclear Technology Review 2010;
  8. Wikipedia – Bone Scintigraphy;
  9. Wikipedia – Myocardial Perfusion Imaging;
  10. The Free Dictionary – Parathyroid Scan;
  11. Medical Health Test;
  12. Health Guide;
  13. Health Physics Society; and
  14. Thyroid Scan and Uptake.

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