Organ system- and disorder-based list
Elaborate overview of Nuclear Medicine
Differences with diagnostic radiology
Positron emission tomography (PET)
What about radiation exposure?
Apprehensions surrounding ionizing radiation
What are other sources of free radicals?
Calculation of risk from radiation exposure
Highly simplified explanation of radiation exposure from a single PET-CT scan
Are there natural sources of radiation?
Nuclear medicine (NM) is a branch of conventional medicine that involves use of unsealed sources[1] of ionizing radiation (henceforth referred to as simply 'radiation') for diagnosis and treatment of various illnesses. An unsealed source of radiation fit for human medical use is called a 'radiopharmaceutical' (RP). Every NM procedure involves introducing an RP into the patient's body — most commonly through injection into a vein (just like other medicines that are injected into the vein, e.g., when hospitalized). Some of the NM procedures involve taking the RP into the body through mouth or even by breathing it in!
The unsealed source of radiation mentioned above is called a 'radionuclide'. Every radionuclide undergoes radioactive decay, i.e., it disintegrates into products with differing physical and chemical properties; some of the products of radioactive decay could be electromagnetic radiation or particulate radiation (explained below). Thus, every radionuclide has a 'half-life', which is the fixed time-period in which exactly half of the radionuclide undergoes radioactive decay. So, if there is 20 units of radionuclide with a half-life of 1 hour kept in a glass vial, then at the end of 1 hour, only 10 units would be left, and at 2 hours, only 5 units would be left, and so forth.
Ionization is a process by which an (uncharged) atom or molecule becomes electrically charged by losing or gaining electron(s). Ionization requires transfer of energy.
A form of energy that can cause ionization can be loosely called 'ionizing radiation', which is of 2 types: electromagnetic (EM) waves and particles.
EM radiation travels in form of discrete packets of energy called 'photons' at very high speed ('speed of light', i.e., 3,00,000 km/s). EM radiation are classified based on energy carried in the individual photon. Low-energy and non-ionizing EM radiation are radio waves (used in FM 'radio' and 'Bluetooth'), microwaves (used in ovens and communication devices), infrared rays (well known for their heating ability), and visible light (which we sense through our eyes). Higher-energy EM radiation includes ultraviolet (UV) rays, X-rays and gamma rays, which have ionizing potential (with the exception of low-energy UV rays).
Owing to high energy and much smaller size of individual photons compared to the intervening atoms and molecules, X-rays and gamma rays can travel very long distances before transferring their energy to ionize surrounding matter. That's why they can penetrate human body and even thin layers of metal.
Ionizing particles are subatomic particles, which also travel at very high speeds but typically are appreciably slower than EM radiation. As these particles have much higher probability of encountering atoms and molecules, they are stopped in their path as they instantly transfer their energy to induce ionization. Hence, they have much shorter path (less than a millimetre), and in contrast to ionizing EM radiation, they cannot penetrate through the human body. Pertinent examples of particulate radiation include beta particle (electron travelling at high speed) and positron.
In summary, EM radiation is less likely to cause ionization, but can travel longer. Whereas, radiation particles are more likely to cause ionization, but travel for very short distances.
A diagnostic NM procedure involves scanning a patient with administered RP on a machine ('scanner') that can detect EM radiation coming out of their body. For diagnostic procedures, EM radiation-emitting RPs are preferred and particle-emitting ones are avoided.
The administered RP enters the bloodstream to further reach all the organs of the body. In healthy state, individual organs have differing tendency to accumulate a given RP, which is known as normal 'biodistribution'. E.g., RP 'a' would be accumulated more by the thyroid but not by heart muscles, whereas RP 'b' would be accumulated more by heart muscles but not by the thyroid. Abnormal (either less or more) accumulation of an RP by an organ suggests its altered (abnormal) functioning.
Detectors used for diagnostic NM procedures are very sensitive (i.e., they can detect very minute amount of radiation coming out of the body). That's why RPs are administered in trace amounts. These amounts are so less that they are not measured by their weight (as against milligrams used for quantifying the dose of conventional drugs). Instead the administered doses are quantified according to the number of radioactive decay events happening per second ('activity'). The actual number of radioactive molecules in the administered dose is so less that we call them 'nanomolar quantity'. Such minute quantities of administered RP ensure that there are no side effects because of interaction with cells and tissues of the body.
In summary, owing to minute dose, RPs administered as part of diagnostic NM procedures have absolutely no effect on functioning of any of the organs. Hence, they cannot produce any side effects like nausea, vomiting, headache, fever, skin rashes, etc. However, as part of some of the NM procedures, other non-radioactive drugs are also administered to improve the scan quality or to derive more detailed information, which could have minor and transient side effects.
Diagnostic imaging exploits ability of X-rays and gamma rays to penetrate the human body.
In NM, the detected photon originates from within the body, and there is no way to control its origin, direction or timing of emission. Typically, gamma ray photons are emitted by the organ in all directions and at random times. As the number of photons emitted by an organ is dependent on its functional state, and not its structural characteristics, the information we get is 'functional' in nature. In simpler words, it is the organ that 'decides' how much radiation to emit. We also get some idea of its structure, but other imaging modalities perform much better in that regard.
In contrast, most of the radiology modalities like X-ray, computed tomography (CT) and ultrasonography (USG) allow for controlling the origin (usually outside the patient's body), direction and timing of photons (or ultrasound waves) directed towards the patient. Hence, direction and timing of photon coming out of the body are almost completely determined by us (i.e., the scanning machine). The structural characteristics (e.g., size, density, uniformity, etc.) of an organ almost completely determine the fate of the interacting photon (transmission, absorption, scatter, reflection, etc.). In simpler words, it is we (as against the functional state of the organ) who largely decide the quantity and timing of radiation coming out of that organ. Radiology modalities also provide some information on functional state of an organ (especially blood flow).
Gamma camera (GC) is one of the oldest nuclear medicine imaging devices. RPs used for GC scans emit gamma rays that are detected by a salt-based crystal to be converted into electrical signals. Regions of the detector that capture more number of gamma photons produce a stronger electrical current.
The RP molecules in the target organ emit EM rays in all the directions. When the detector captures a photon, it has no way to 'know' the direction from which the photon had originated. Hence, detectors are covered by thick sheets of metals with cylindrical holes in them (called 'collimators'), which allow gamma photons travelling only in a specific direction to reach up to the detector. Collimation helps in formation of a somewhat sharp image, but because of rejection of many photons, scan times have to be greatly prolonged to get a somewhat acceptable image.
If the GC detector is made to rotate around the patient, we can get 3-dimensional images instead of planar (2-dimensional) ones. This technique is known as single-photon emission computed tomography (SPECT). SPECT is essential for cardiac imaging. It can be also used to complement some of the planar GC scans. As SPECT scan acquisitions are very time-consuming, they are not performed, if avoidable.
Most of the drugs used for gamma camera scans are themselves not radioactive, but are chemically combined with a radioactive element called technetium-99m, which has a half-life of ~6 hours. The form of technetium that combines with these drugs is called 'pertechnetate' (TcO4-). Most NM facilities derive ('elute') technetium-99m from a generator, and its pertechnetate store keeps on depleting with time because of elution as well as radioactive decay.
The RP molecules used in PET scans emit a 'positron' (which in turn is like a positively charged electron). This positron travels for a very short distance (~1 mm or less) when it encounters an electron to undergo 'annihilation', with complete conversion of their combined masses into energy (in accordance with Einstein's famous equation of E = mc2). This energy is released in form of 2 photons (called 'annihilation photons') of equal energy travelling in opposite directions.
Annihilation photons are captured by the detector (just like in a GC). However, unlike a GC, collimator is not needed because the direction of origin of the photons would be 'known' as they would be detected simultaneously. This feature reduces the scan times and also results in sharper images.
Fluorodeoxyglucose (FDG) is the most commonly used RP for PET-CT imaging. The fluorine-18 (F-18) part of the compound is radioactive with a half-life of ~110 min. Just like pertechnetate mentioned above, F-18 is chemically combined with other types of non-radioactive drugs like PSMA ligand and DOTATATE.
When a SPECT or PET scan is performed on the same scanner along with a CT or MRI scan, it is known as 'hybrid' imaging.
PET-CT scanners as the name suggests combine PET and (X-rays-based) computed tomography (CT) scans into a single procedure. This process produces much more reliable results compared to performing PET and CT acquisitions on separate scanners and later combining them through software. Also, such hybrid imaging is much more convenient for the patient. PET-CT scans are the most common type of hybrid imaging in NM.
For treatment applications, particle-emitting radiation sources are chosen. Other desirable properties include a somewhat longer half-life (few days to weeks) and ability to stay for prolonged periods in the target organ. Emission of EM photons that can be imaged is an added advantage.
Cells of certain organs or tumours express proteins on their surface that are unique to them, and are not expressed by other cell types of the body. If a particle-emitting RP molecule binds tightly to these surface proteins, it is engulfed by the cell (through a process called endocytosis). Within the cell, it causes ionization of oxygen- and nitrogen-based molecules resulting in formation of 'free radicals'. These free radicals are unstable, and have their own ionization potential; they migrate to the cell nucleus to cause breaks in the strands of genetic material called 'DNA'. Cells with damaged DNA are not able to divide and die.
The term 'radiotherapy' when used unqualified usually refers to use of radiation directed to specific bodily sites. The radiation affects all the cells at the targeted site irrespective of whether they are cancerous or normal. Tissues closer to the target site sustain greater damage.
In contrast, radionuclide therapy affects mainly the cells of a specific kind that can attract the administered RP. These could include cancerous as well as normal cells of that particular type. It also targets cancer cells that would have metastasized (spread through blood) to distant organs.
While radionuclide therapy is more specific in terms of cells it affects, it is available for very few types of cancers. Radionuclide therapies for some of the commonest cancers like head and neck cancers, breast cancer, lung cancer, etc. do not exist or are at best only experimental. Additionally, as more advanced a cancer gets, the cancer cells could stop producing the protein to which the RP binds making radionuclide therapy less effective. Hence, a diagnostic scan is almost always performed to ascertain expression of target proteins before administering radionuclide therapy.
With advances in medical field, RPs for more and more cancer types are being discovered and are entering mainstream medical practice.
To understand differences between external beam radiotherapy (EBRT) and radionuclide therapy (RNT), let us see an example of patient with pancreatic cancer that has spread to many sites in the liver.
| Tumour / site | EBRT | RNT |
|---|---|---|
| Treatment possible? | Yes | Only if scan is positive |
| Pancreatic tumour | Destroyed | Destroyed |
| Pancreas around the tumour | Destroyed | Minimal damage |
| Pancreas away from the tumour | Irreversible damage likely | No / minimal damage |
| Adjoining blood vessels | Damage likely | No damage |
| Adjoining intestines | Damage likely | No damage |
| Tumours in liver | Not affected | Cured / reduced |
As explained above, ionizing radiation makes atoms and molecules in the cells unstable (converting them to 'free radicals'), which in turn can cause damage to the genetic material called DNA[3]. These free radicals can enter varying biochemical pathways. These pathways (roughly in order of decreasing probability, but increasing hazard) are as follows:
At very high doses of radiation exposure, the heat energy from radiation itself could cause direct damage to the cells and tissues independent of DNA damage. However, such doses are much higher (at least thousands of times) than that encountered in practice of nuclear medicine and diagnostic radiology, and are not relevant to the present discussion.
All the undesirable effects of ionizing radiation are because of free radical production. But, they are not the only cause of free radical production in the cells; other important causes include the following.
Models for predicting harms (carcinogenesis and teratogenesis) of radiation exposure have been derived from incidents like Hiroshima and Nagasaki bombings of 1945. These models are based on assumption of 'linear, no-threshold (LNT)' effect of radiation. In simple words, these models assume that ionizing radiation is harmful at any dose greater than zero, and that harms are directly proportional to radiation dose one is exposed to accumulated over ones lifetime. However, the radiation dose received as part of a diagnostic NM or diagnostic radiology procedure is one-thousandth or even less (compared to atomic bombings). To give a crude analogy, it is like assessing safety of a single tablet of paracetamol by noting effects of a 1,000 pills taken by a person in a one go! Hence, radiation safety bodies tend to recommend the LNT model for formulating radiation safety guidelines (erring on side of caution), but not for actual prediction of effects of low-dose radiation.
Effect of radiation exposure from a diagnostic NM or radiology procedure cannot be reliably predicted. However, LNT is the only accepted model to do so.
According to currently accepted models, exposure to 1,000 mSv of radiation leads to an increased risk of cancer-related death by 5.5%. What does this statement mean?
Let us say in a population of 1,00,000 people not exposed to any radiation, 10 cancer-related deaths happen every year. Now let us assume that if the entire population is exposed to 1,000 mSv of radiation. In that case, every year, 10.55 cancer related deaths would occur (instead of 10).
Radiation exposure from a PET-CT scan is estimated to be ~25 mSv. So, if everyone from the population of 1,00,000 people were to undergo a PET-CT scan, then 10.014 cancer-related deaths would occur every year (instead of 10).
Yes, very much so! Following are some of the examples.
Following are some of the relevant facts / considerations.
So, in summary, avoiding a radiation based medical procedure is lot more likely to cause harm than actually carrying it out.
In absence of a physical barrier, there is exposure to radiation of the nearby people that includes radiation professionals (involved in production, storage, transport and use of radiation sources), and also the patients undergoing NM procedures and their carers. Strategies to minimize radiation exposure include the following.
Each time a cell divides, both strands of each chromosome separate and duplicate. The 2 'daughter cells' each receive their own copy of 46 chromosomes. This process is called 'DNA replication'
Organ system- and disorder-based list
Elaborate overview of Nuclear Medicine
Differences with diagnostic radiology
Positron emission tomography (PET)
What about radiation exposure?
Apprehensions surrounding ionizing radiation
What are other sources of free radicals?
Calculation of risk from radiation exposure
Highly simplified explanation of radiation exposure from a single PET-CT scan
Are there natural sources of radiation?