Radioisotopes in Medicine :: DIAGNOSIS Pinpointing Disease

DIAGNOSIS Pinpointing Disease

Mr. Peters, 35-year-old father of four and a resident of Chicago’s northwest side, went to a Chicago hospital one winter day after persistent headaches had made his life miserable. Routine examinations showed nothing amiss and his doctor ordered a “brain scan” in the hospital’s department of nuclear medicine.

Thirty minutes before “scan time”, Mr. Peters was given, by intravenous injection, a minute amount of radioactive technetium. This radiochemical had been structured so that, if there were a tumor in his cranium, the radioisotopes would be attracted to it. Then he was positioned so an instrument called a scanner could pass close to his head.

As the motor-driven scanner passed back and forth, it picked up the gamma rays being emitted by the radioactive technetium, much as a Geiger counter detects other radiation. These rays were recorded as black blocks on sensitized film inside the scanner. The result was a piece of exposed film that, when developed, bore an architectural likeness or image of Mr. Peters’ cranium.

The inset picture shows a brain scan made with a positron scintillation camera. A tumor is indicated by light area above ear. (Light area in facial region is caused by uptake in bone and extracellular space.) The photograph shows a patient, completely comfortable, receiving a brain scan on one of the three rectilinear scanning devices in the nuclear medicine laboratory of a hospital.

Mr. Peters, who admitted to no pain or other adverse reaction from the scanning, was photographed by the scanner from the front and both sides. The procedure took less than an hour. The developed film showed that the technetium had concentrated in one spot, indicating definitely that a tumor was present. Comparison of front and side views made it possible to pinpoint the location exactly.

Surgery followed to remove the tumor. Today, thanks to sound and early diagnosis, Mr. Peters is well and back on the job. His case is an example of how radioisotopes are used in hospitals and medical centers for diagnosis.

The first whole body scanner, which was developed at the Donner Laboratory in 1952 and is still being used. The lead collimator contains 10 scintillation counters and moves across the subject. The bed is moved and serial scans are made and then joined together to form a head-to-toe picture of the subject.

The diagram shows a scan and the parts of a scanner. (Also see page 21.)

In one representative hospital, 17 different kinds of radioisotope measurements are available to aid physicians in making their diagnoses. All the methods use tracer quantities of materials. Other hospitals may use only a few of them, some may use even more. In any case they are merely tools to augment the doctors’ skill. Examples of measurements that can be made include blood volume, blood circulation rate, red blood cell turnover, glandular activity, location of cancerous tissue, and rates of formation of bone tissue or blood cells.

Of the more than 100 different radioisotopes that have been used by doctors during the past 30 years, five have received by far the greatest attention. These are iodine-131, phosphorus-32, gold-198, chromium-51, and iron-59. Some others have important uses, too, but have been less widely employed than these five. The use of individual radioisotopes in making important diagnostic tests makes a fascinating story. Typical instances will be described in the following pages.

A differential multi-detector developed at Brookhaven National Laboratory locates brain tumors with positron-emitting isotopes. By using many pairs of detection crystals, the device shortens the scanning time and increases accuracy. (See cover for another type of positron scanner.)

Arsenic-74

Brain tumors tend to concentrate certain ions (charged atoms or molecules). When these ions are gamma-ray emitters, it is possible to take advantage of the penetrating power of their gamma rays to locate the tumor with a scanning device located outside the skull.

Arsenic-74 and copper-64 are isotopes emitting positrons,[8] which have one peculiar property. Immediately after a positron is emitted from a nucleus it decays, producing two gamma rays that travel in exactly opposite directions. The scanning device has two detectors called scintillation counters, one mounted on each side of the patient’s head.

The electrical circuitry in the scanner is such that only those gamma rays are counted that impinge simultaneously on both counters. This procedure eliminates most of the “noise”, or scattered and background radiation.

Chromium-51

Because chromium, in the molecule sodium chromate, attaches itself to red blood cells, it is useful in several kinds of tests. The procedures are slightly complicated, but yield useful information. In one, a sample of the patient’s blood is withdrawn, stabilized with heparin (to prevent clotting) and incubated with a tracer of radioactive sodium chromate. Excess chromate that is not taken up by the cells is reduced and washed away. Then the radioactivity of the cells is measured, just before injection into the patient. After a suitable time to permit thorough mixing of the added material throughout the blood stream, a new blood sample is taken and its radioactivity is measured. The total volume of red blood cells then can be calculated by dividing the total radioactivity of the injected sample by the activity per milliliter of the second sample.

Spleen scans made with red blood cells, which had been altered by heat treatment and tagged with chromium-51. Such damaged cells are selectively removed by the spleen. A is a normal spleen. B shows an abscess in the spleen. Note dark ring of radioactivity surrounding the lighter area of decreased activity at the central portion of spleen.

In certain types of anemia the patient’s red blood cells die before completing the usual red-cell lifetime of about 120 days. To diagnose this, red cells are tagged with chromium-51 (5¹Cr) in the manner just described. Then some of them are injected back into the patient and an identical sample is injected into a compatible normal individual. If the tracer shows that the cells’ survival time is too short in both recipients to the same degree, the conclusion is that the red cells themselves must be abnormal. On the other hand, if the cell-survival time is normal in the normal individual and too short in the patient, the diagnosis is that the patient’s blood contains some substance that destroys the red cells.

When chromium trichloride, CrCl3, is used as the tagging agent, the chromium is bound almost exclusively to plasma proteins, rather than the red cells. Chromium-51 may thus be used for estimating the volume of plasma circulating in the heart and blood vessels. The same type of computation is carried on for red cells (after correction for a small amount of chromium taken up by the red blood cells). This procedure is easy to carry out because the radioactive chromium chloride is injected directly into a vein.

An ingenious automatic device has been devised for computing a patient’s total blood volume using the 5¹Cr measurement of the red blood cell volume as its basis. This determination of total blood volume is of course necessary in deciding whether blood or plasma transfusions are needed in cases involving bleeding, burns, or surgical shock. This 5¹Cr procedure was used during the Korean War to determine how much blood had been lost by wounded patients, and helped to save many, many lives.

For several years, iodine-131 has been used as a tracer in determining cardiac output, which is the rate of blood flow from the heart. It has appeared recently that red blood cells tagged with 5¹Cr are more satisfactory for this measurement than iodine-labeled albumin in the blood serum. It is obvious that the blood-flow rate is an extremely important physiological quantity, and a doctor must know it to treat either heart ailments or circulatory disturbances.

In contrast to the iodine-131 procedure, which requires that an artery be punctured and blood samples be removed regularly for measurement, chromium labeling merely requires that a radiation counter be mounted on the outside of the chest over the aorta (main artery leaving the heart). A sample of labeled red blood cells is introduced into a vein, and the recording device counts the radioactivity appearing in the aorta as a function of time. Eventually, of course, the counting rate (the number of radioactive disintegrations per second) levels off when the indicator sample has become mixed uniformly in the blood stream. From the shape of the curve on which the data are recorded during the measurements taken before that time, the operator calculates the heart output per second.

In this cardiac output study a probe is positioned over the heart and the passage of iodine-131 labeled human serum albumin through this area is recorded.

Obstetricians caring for expectant mothers use red cells tagged with 5¹Cr to find the exact location of the placenta. For example, in the condition known as placenta previa, the placenta—the organ within the uterus by which nourishment is transferred from the mother’s blood to that of the unborn child—may be placed in such a position that fatal bleeding can occur. A radiation-counting instrument placed over the lower abdomen gives information about the exact location of the placenta. If an abnormal situation exists, the attending physician is then alert and ready to cope with it. The advantages of chromium over iodine-131, which has also been used, are that smaller doses are required, and that there is no transfer of radioactivity to the fetal circulation.

Still another common measurement using 5¹Cr-labeled red blood cells is the determination of the amount and location of bleeding from the gastrointestinal tract (the stomach and bowels). The amount is found by simple measurement of chromium in the blood that appears in the stools. To find the location is slightly more complicated. The intestinal contents are sampled at different levels through an inserted tube, and the radiation of the samples determined separately.

Finally, gastrointestinal loss of protein can be measured with the aid of 5¹Cr-labeled blood serum. The serum is treated with CrCl3 and then injected into a vein. In several very serious ailments there is serious loss of blood protein through the intestines. In these conditions the 5¹Cr level in the intestinal excretions is high, and this alerts the doctor to apply remedial measures.

Cobalt-60

Vitamin B12 is a cobalt compound. Normally the few milligrams of B12 in the body are stored in the liver and released to the blood stream as needed. In pernicious anemia, a potentially fatal but curable disease, the B12 content of the blood falls from the usual level of 300-900 micromicrograms per milliliter (ml) to 0 to 100 micromicrograms per ml. The administration of massive doses of B12 is the only known remedy for this condition.

If the B12 is labeled with radioactive cobalt, its passage into the blood stream may be observed by several different methods. The simplest is to give the B12 by mouth, and after about 8 hours study the level of cobalt radioactivity in the blood. Cobalt-60 has been used for several years, but recently cobalt-58 has been found more satisfactory. It has a half-life of 72 days while 6Co has a 5.3-year half-life. This reduces greatly the amount of radiation to the patient’s liver by the retained radioactivity.

Iodine-131

Like chromium-51, iodine is a versatile tracer element. It is used to determine blood volume, cardiac output, plasma volume, liver activity, fat metabolism, thyroid cancer metastases, brain tumors, and the size, shape, and activity of the thyroid gland.

A linear photoscanner produced these pictures of (A) a normal thyroid, (B) an enlarged thyroid, and (C) a cancerous thyroid.

Because of its unique connection with the thyroid gland, iodine-131 is most valuable in measurements connected with that organ. Thyroxin, an iodine compound, is manufactured in the thyroid gland, and transferred by the blood stream to the body tissues. The thyroxin helps to govern the oxygen consumption of the body and therefore helps control its metabolism. Proper production of thyroxin is essential to the proper utilization of nutrients. Lowered metabolism means increased body weight. Lowered thyroid activity may mean expansion of the gland, causing one form of goiter.

Iodine-131 behaves in the body just as the natural non-radioactive isotope, iodine-127, does, but the radioactivity permits observation from outside the body with some form of radiation counter. Iodine can exist in the body in many different chemical compounds, and the counter can tell where it is but not in what form. Hence chemical manipulation is necessary in applying this technique to different diagnostic procedures.

The thyroid gland, which is located at the base of the neck, is very efficient in trapping inorganic iodide from the blood stream, concentrating and storing the iodine-containing material and gradually releasing it to the blood stream in the form of protein-bound iodine (PBI).

One of the common diagnostic procedures for determining thyroid function, therefore, is to measure the percentage of an administered dose of ¹³¹I that is taken up by the gland. Usually the patient is given a very small dose of radioactive sodium iodide solution to drink, and two hours later the amount of iodine in the gland is determined by measuring the radiation coming from the neck area. In hyperthyroidism, or high thyroid gland activity, the gland removes iodide ions from the blood stream more rapidly than normal.

Screening test for Hyperthyroidism

It is especially important in isotope studies on infants and small children that the radiation exposure be low. By carrying out studies in the whole body counter room, the administered dose can be greatly reduced. The photographs illustrate a technique of measuring radioiodine uptake in the thyroid gland with extremely small amounts of a mixture of iodine-131 and iodine-125. A shows a small television set that is mounted above the crystal in such a way that good viewing requires that the head be kept in the desired position. This helps solve the problem of keeping small children still during a 15-minute counting period. B shows a child in position for a thyroid uptake study.

This simple procedure has been used widely. One difficulty in using it is that its success is dependent upon the time interval between injection and measurement. An overactive gland both concentrates iodine rapidly and also discharges it back to the blood stream as PBI more rapidly than normal. Modifications of the test have been made to compare the amount of iodine-131 that was administered with the amount circulating in the blood as PBI. The system acquires chemical separation of the two forms of iodine from a sample of blood removed from a vein, followed by separate counting. This computation of the “conversion ratio” of radioactive plasma PBI to plasma-total ¹³¹I gives results that are less subject to misinterpretation.

To determine local activity in small portions of the thyroid, an automatic scanner is used. A collimator[9] shields the detector (a Geiger-MÜller tube or scintillating crystal) so that only those impulses originating within a very small area are accepted by the instrument. The detector is then moved back and forth slowly over the entire area and the radiation is automatically recorded at definite intervals, creating a “map” of the active area. In cases where lumps, or nodules, have been discovered in the thyroid, the map is quite helpful in distinguishing between cancerous and benign nodules. The former are almost always less radioactive than surrounding tissues.

Seven serial scans made with the whole body scanner were put together to provide a whole body scan of this patient with thyroid cancer that had spread to the lung. One millicurie of iodine-131 was administered and the scan made 72 hours later. Note the uptake in the lung. This patient was successfully treated with large doses of iodine-131.

Fragments of cancerous thyroid tissue may migrate to other parts of the body and grow there. These new cancers are known as metastatic cancers and are a signal of an advanced state of disease. In such a situation even complete surgical removal of the original cancer may not save the patient. If these metastases are capable of concentrating iodine (less than 10% of them are), they can be located by scanning the whole body in the manner that was just described. When a thyroid cancer is discovered, therefore, a doctor may look for metastases before deciding to operate.

Human blood serum albumin labeled with ¹³¹I is used for measurement of the volume of circulating plasma. The procedure is quite similar to that used with radioactive chromium. Iodinated human serum albumin labeled with ¹³¹I is injected into a vein. Then, after allowing time for complete mixing of the sample with the blood, a second sample is counted using a scintillation counter.

Time-lapse motion pictures of the liver of a 3-year-old girl were made with the scintillation camera 1 hour after injection of 50 microcuries of iodine-131-labeled rose bengal dye. This child was born without a bile-duct system and an artificial bile duct had been created surgically. She developed symptoms that caused concern that the duct had closed. These scans show the mass of material containing the radioactive material (small light area) moving downward and to the right, indicating that the duct was still open.

For many years, a dye known as rose bengal has been used in testing liver function. About 10 years ago this procedure was improved by labeling the dye with ¹³¹I. When this dye is injected into a vein it goes to the liver, which removes it from the blood stream and transfers it to the intestines to be excreted. The rate of disappearance of the dye from the blood stream is therefore a measure of the liver activity. Immediately after administration of the radioactive dye, counts are recorded, preferably continuously from several sites with shielded, collimated detectors. One counter is placed over the side of the head or the thigh to record the clearance of the dye from the blood stream. A second is placed over the liver, and a third over the abdomen to record the passage of the dye into the small intestine.

Human serum albumin labeled with ¹³¹I is sometimes used for location of brain tumors. It appears that tumors alter a normal “barrier” between the brain and blood in such a manner that the labeled albumin can penetrate tumorous tissues although it would be excluded from healthy brain tissue.

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The brain behaves almost uniquely among body tissues in that a “blood-brain barrier” exists, so that substances injected into the blood stream will not pass into brain cells although they will pass readily into muscular tissue. This blood-brain barrier does not exist in brain tumors. A systematic scanning of the skull then permits location of these cancerous “hot spots”.

Iron-59

Iron is a necessary constituent of red blood cells, so its radioactive form, 5?Fe, has been used frequently in measurement of the rate of formation of red cells, the lifetime of red cells, and red cell volumes. The labeling is more difficult than labeling with chromium for the same purposes, so this procedure no longer has the importance it once had.

On the other hand, direct measurement of absorption of iron by the digestive tract can be accomplished only by using 5?Fe. In achlorhydria the gastric juice in the stomach is deficient in hydrochloric acid, and this condition has been shown to lower the iron absorption. A normal diet contains much more iron than the body needs, but in special cases, sometimes called “tired blood” in advertising for medicines, iron compounds are prescribed for the patient. If 5?Fe is included, its appearance in the blood stream can be monitored and the effectiveness of the medication noted.

This multiple-port scintillation counter is used for iron-kinetic studies. The tracer dose of iron-59 is administered into the arm vein and then the activities in the bone marrow, liver, and spleen are recorded simultaneously with counters positioned over these areas, and show distribution of iron-59 as a function of time. When the data are analyzed in conjunction with iron-59 content in blood, information can be obtained about sites of red blood cell production and destruction.

Phosphorus-32

The phosphate ion is a normal constituent of the blood. In many kinds of tumors, phosphates seem to be present in the cancerous tissue in a concentration several times that of the surrounding healthy tissue. This offers a way of using phosphorus-32 to distinguish between cancer cells and their neighbors. Due to the fact that ³²P gives off beta rays but no gammas, the counter must be placed very close to the suspected tissue, since beta particles have very little penetrating power. This fact limits the use of the test to skin cancers or to cancers exposed by surgery.

Some kinds of brain tumors, for instance, are difficult to distinguish visually from the healthy brain tissue. In such cases, the patient may be given ³²P labeled phosphate intravenously some hours before surgery. A tiny beta-sensitive probe counter then can be moved about within the operative site to indicate to the surgeon the limits of the cancerous area.

Sodium-24

Normal blood is about 1% sodium chloride or ordinary salt. This fact makes possible the use of ²4Na in some measurements of the blood and other fluids. The figure illustrates this technique. A sample of ²4NaCl solution is injected into a vein in an arm or leg. The time the radioisotope arrives at another part of the body is detected with a shielded radiation counter. The elapsed time is a good indication of the presence or absence of constrictions or obstructions in the circulatory system.

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The passage of blood through the heart may also be measured with the aid of sodium-24. Since this isotope emits gamma rays, measurement is done using counters on the outside of the body, placed at appropriate locations above the different sections of the heart.

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Technetium-99^m

Because of its short half-life of six hours, technetium-99^m[10] is coming into use for diagnosis using scanning devices, particularly for brain tumors. It lasts such a short time it obviously cannot be kept in stock, so it is prepared by the beta decay of molybdenum-99.[11] A stock of molybdenum is kept in a shielded container in which it undergoes radioactive decay yielding technetium. Every morning, as the technetium is needed, it is extracted from its parent by a brine solution. This general procedure of extracting a short-lived isotope from its parent is also used in other cases. We shall see later that radon gas is obtained by an analogous method from its parent, radium.

Using a “nuclear cow” to get technetium from its parent isotope. The “cow” is being fed saltwater through a tube. The saltwater drains through a high-radiation (hot) isotope. The resultant drip-off is a daughter such as technetium-99^m. This new, mild isotope can be mixed with other elements and these become the day’s supply of radioisotopes for other scans. Technetium-99^m decays in 6 hours. Thus greater amounts, with less possibility of injury, can be administered and a better picture results.

Thulium-170 and Gamma Radiography

For years it has been recognized that there would be many uses for a truly portable device for taking X-ray pictures—one that could be carried by the doctor to the bedside or to the scene of an accident. Conventional X-ray equipment has been in use by doctors for many years, and highly efficient apparatus has become indispensable, especially in treating bone conditions. There is, however, a need for a means of examining patients who cannot be moved to a hospital X-ray room, and are located where electric current sources are not available.

A few years ago, a unit was devised that weighed only a few pounds, and could take “X-ray pictures” (actually gamma radiographs) using the gamma rays from the radioisotope thulium-170. The thulium source is kept inside a lead shield, but a photographic shutter-release cable can be pressed to move it momentarily over an open port in the shielding. The picture is taken with an exposure of a few seconds. A somewhat similar device uses strontium-90 as the source of beta radiation that in turn stimulates the emission of gamma rays from a target within the instrument.

A technician holds an inexpensive portable X-ray unit that was developed by the Argonne National Laboratory. Compare its size with the standard X-ray machine shown at left and above.

Still more recently, ¹²5I has been used very successfully in a portable device as a low-energy gamma source for radiography. The gamma rays from this source are sufficiently penetrating for photographing the arms and legs, and the necessary shielding is easily supplied to protect the operator. By contrast with larger devices, the gamma-ray source can be as small as one-tenth millimeter in diameter, virtually a point source; this makes possible maximum sharpness of image. The latest device, using up to one curie[12] of ¹²5I, weighs 2 pounds, yet has adequate shielding for the operator. It is truly portable.

If this X-ray source is combined with a rapid developing photographic film, a physician can be completely freed from dependence upon the hospital laboratory for emergency X rays. A finished print can be ready for inspection in 10 seconds. The doctor thus can decide quickly whether it is safe to move an accident victim, for instance. In military operations, similarly, it becomes a simple matter to examine wounded soldiers in the field where conventional equipment is not available.

Tritium

More than 30 years ago, when deuterium (heavy hydrogen) was first discovered, heavy water (D2O) was used for the determination of total body water. A small sample of heavy water was given either intravenously or orally, and time was allowed for it to mix uniformly with all the water in the body (about 4 to 6 hours). A sample was then obtained of the mixed water and analyzed for its heavy water content. This procedure was useful but it was hard to make an accurate analysis of low concentrations of heavy water.

More recently, however, tritium (³H) (radioactive hydrogen) has been produced in abundance. Its oxide, tritiated water (³H2O), is chemically almost the same as ordinary water, but physically it may be distinguished by the beta rays given off by the tritium. This very soft (low-energy) beta ray requires the use of special counting equipment, either a windowless flow-gas counter or a liquid scintillator, but with the proper techniques accurate measurement is possible. The total body water can then be computed by the general isotope dilution formula used for measuring blood plasma volume.

The total body water is determined by the dilution method using tritiated water. This technician is purifying a urine sample so that the tritium content can be determined and the total body water calculated.

Activation Analysis

Another booklet in this series, Neutron Activation Analysis, discusses a new process by which microscopic quantities of many different materials may be analyzed accurately. Neutron irradiation of these samples changes some of their atoms to radioactive isotopes. A multichannel analyzer instrument gives a record of the concentration of any of about 50 of the known elements.

One use of this technique involved the analysis of a hair from Napoleon’s head. More than 100 years after his death it was shown that the French Emperor had been given arsenic in large quantities and that this possibly caused his death.

The ways in which activation analysis can be applied to medical diagnosis are at present largely limited to toxicology, the study of poisons, but the future may bring new possibilities.

Knowledge is still being sought, for example, about the physiological role played by minute quantities of some of the elements found in the body. The ability to determine accurately a few parts per million of “trace elements” in the various tissues and body fluids is expected to provide much useful information as to the functions of these materials.

Summary

A large number of different radioisotopes have been used for measurement of disease conditions in the human body. They may measure liquid volumes, rates of flow or rates of transfer through organs or membranes; they may show the behavior of internal organs; they may differentiate between normal and malignant tissues. Hundreds of hospitals are now making thousands of these tests annually.

This does not mean that all the diagnostic problems have been solved. Much of the work is on an experimental rather than a routine basis. Improvements in techniques are still being made. As quantities of radioisotopes available for these purposes grow, and as the cost continues to drop, it is expected there will be still more applications. Finally, this does not mean we no longer need the doctor’s diagnostic skill. All radioisotope procedures are merely tools to aid the skilled physician. As the practice of medicine has changed from an art to a science, radioisotopes have played a useful part.

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