Radioactive Iodine: A Slice of History

Case History and Course of One of the First Patients Treated with RAI

On September 8, 1941, a 9-year-old girl was admitted to the MGH with a chief complaint of hyperthyroidism. There was a 6-week history of weight loss (11 pounds, or 4.99 kg) with preserved appetite, accelerated growth, increased nervousness, heat intolerance, increased perspiration, and easy fatigability. Her mother had undergone a subtotal thyroidectomy for hyperthyroidism at the MGH 14 years earlier, in 1927. The patient was unable to cooperate with a basal metabolic rate (BMR) test and her mother therefore brought her to the MGH.

Her height was 55¾ inches (141.6 cm) and her weight was 34.5 kg. Her pulse was 120–130 beats/min. There were no abnormal eye signs or eye complaints. The thyroid gland was described as palpable, firm, and twice normal in size with bilateral bruits. A marked tremor was present. The BMR was elevated at +70 (Normal: −5±1 SE). The serum calcium was elevated at 11.1 mg/dL with a phosphorus of 6.0 mg/dL.

Six days later, on September 14, 1941, the patient had gained almost 2 kg. The medical record contained the following note: “Dr. Hertz would like to treat the child with radioactive iodine. Permission will be obtained from the mother before this is done.”

Dr. James Howard Means also saw the patient at the mother's request, and he wrote in her record that “the thyrotoxicosis is clinically mild. There are no eye signs. The goiter is small and is very firm…I would be strongly in favor of non-surgical treatment until such time as it has been proved inadequate. She might be controlled by iodine alone, but since we have radio[active] iodine available would prefer to use this.”

Eleven days after admission, on September 19, 1941, the patient's BMR had declined from +70 to +37. On September 19, 1941, at 11:30 p.m. her chart records the following: “given 9 cc of radioactive iodine solution containing 0.18 mg I=2.7 mg of radiation.” A penciled note records 14.5 mCi ¹³⁰I. On September 22, 1941, 14 days after admission, the patient was described as very comfortable and not as restless as on admission. On September 24, 1941, she was “given 20 cc RaI sol. containing 0.4 mg I.” A penciled note says 3.5 mCi ¹³⁰I.

On October 1, 1941, her weight was 30.5 kg. On October 3, 1941, the notes mention that although “she has lost weight she seems much quieter and less toxic. Will now give Lugols 8–10 drops every other day.” A surgeon was consulted because it seemed likely that she would need surgery in the future. On October 10, 1941, her heart rate was 90–100. On October 11, 1941 her BMR was +30, her weight was 30.3 kg, and she was discharged from the hospital ward to the metabolic ward. On November 5, 1941, her BMR was +26 and her weight was 37.2, up 1.7 kg from admission. Her thyroid gland was thought to be virtually impalpable. On January 16, 1942, her iodine drops (Lugols) were stopped.

On September 2, 1947, 6 years after receiving RAI therapy, her BMR was low at −21, but since she felt fine no thyroid hormone was prescribed. Her thyroid was described as 1.5 times normal and soft. On September 12, 1950, her thyroid gland was described as gradually increasing in size. Her protein-bound iodine (PBI; 6.0) and BMR (+3) were within normal limits. Her 48-hour RAI uptake was within normal limits at 34%.

In August 1958, 17 years after receiving RAI, her hyperthyroidism recurred with a PBI of 13.5 (normal 4–8). Her RAI uptake was elevated at 71%. Her thyroid gland was described as diffusely enlarged, twice normal in size. Propylthiouracil was started at 300 mg per day, and potassium iodide was added in preparation for surgery.

The patient, now 26 years old, was admitted to the MGH on December 25, 1958, and 2 days later Dr. Oliver Cope performed a right total and left near-total thyroidectomy. The thyroid gland was described by the surgeon as a multinodular goiter with three separate adenomas in the right lobe. All four parathyroid glands were identified and found to be enlarged. The left superior parathyroid gland was biopsied. The final pathology diagnosis was a multinodular goiter with adenomas. Marked thyroid hyperplasia and hypertrophy, radiation changes and parathyroid hyperplasia were also present. The MGH thyroid pathologist Dr. Austin Vickery reported: “many large atypical hyperchromatic nuclei are seen amongst the follicular cells particularly in fibrous zones, as typically observed in other thyroids following radiation therapy. The hyperplasia pattern of nodules and adenomas, intermixed with areas of fibrous replacement and atrophic parenchymal elements, is distinctly unusual. Although foci of atypical follicular architecture are present, no definite signs of malignancy can be recognized, such as vascular invasion. The parathyroid shows no evidence of radiation damage.” Her postoperative calcium was 7.0 mg/dL. She was discharged from the hospital on January 2, 1959.

In May of 1982, she was hospitalized with diabetic ketoacidosis and has been on insulin ever since.

In 1996, she had surgery for hyperparathyroidism at Johns Hopkins University Hospital. Her preoperative calcium was elevated at 11.2 mg/dL with an elevated parathyroid hormone level of 168 pg/mL. A 440 mg enlarged parathyroid gland was removed. Her ionized calcium was low at the time of discharge. Her hyperparathyroidism has not recurred.

The patient is currently 80 years of age and in reasonable health 71 years after receiving RAI. Until 2001, she worked as an occupational therapist “as a direct result of my 5 week stay at MGH in 1941.” She currently resides in a continuous care facility. She has never been pregnant.

Patient Commentary

At the age of 15 or 16, the patient wrote a paper for her school in which she described her experience of being hyperthyroid and being treated for it.

In 2001, after years of reflection, she wrote:

Discussion

In the 1930s, the diagnosis and treatment of Graves' hyperthyroidism was still relatively primitive. A careful history and physical examination was the primary basis for making the diagnosis of hyperthyroidism and a persistently elevated BMR was the primary laboratory test used to confirm it. Unfortunately, there were significant problems with the sensitivity and specificity of the BMR test (1). A low serum cholesterol concentration was often used as additional evidence of hyperthyroidism. The experimental measurement of thyroidal RAI uptake in hyperthyroidism was pioneered in the late 1930s and early 1940s, but it was not yet generally available (2,3). The PBI test (related to the serum thyroxine) was not introduced until 1946 (4).

Therapy for Graves' hyperthyroidism during the 1930s and early 1940s was primarily surgical and had a checkered history. In 1912, the surgical mortality at London hospitals for Graves' hyperthyroidism was 30%. When the Australian surgeon Dr. Dunhill reported a surgical mortality for Graves' hyperthyroidism of less than 3% to the British Royal Society of Medicine, his results were met with disbelief (5). When Dr. Henry Plummer of the Mayo Clinic introduced the preoperative use of iodide for Graves' hyperthyroidism in the 1920s, the surgical mortality decreased from 3–4% to 1%. Equally important, the number of multistaged operations was reduced from 50% to 2%. It is unclear exactly how many patients died in the hospital while waiting for or being prepared for surgery, but the preoperative use of iodine for hyperthyroid patients waiting for surgery apparently decreased the mortality by two thirds (6).

External radiation to the thyroid was used during the 1920s and 1930s to treat some patient with Graves' hyperthyroidism who either refused surgery or were unable to undergo surgery. It was thought to be effective in about one third of the cases (7). Antithyroid drug therapy was introduced in 1943 by Dr. Astwood (8).

In 1936, members of the MGH Thyroid Unit attended a lecture on radioisotopes at the Harvard Medical School concerning radioisotopes entitled “What physics can do for biology and medicine.” The lecture was given by Dr. Karl Compton, then president of MIT (9). At the end of his talk, Dr. Saul Hertz asked Dr. Compton whether he could make a radioactive isotope of iodine (9). Dr. Compton replied that he would look into it. Most likely after conferring with the MIT physicist Dr. Robley Evans, he agreed in a letter to Dr. Hertz on Dec 15, 1936, that “iodine can be made artificially radioactive.” A week later, Dr. Hertz wrote back, that he hoped to do “animal experiments” and devise “a useful…therapy in cases of overactivity of the thyroid gland” (9).

By the late 1930s, radioactive isotopes of iodine (¹²⁸I, ¹³⁰I, and ¹³¹I) were being manufactured at MIT and at the University of California, Berkeley, and these isotopes were being studied at the MGH Thyroid Unit and the University of California, Berkeley. The short-lived isotope ¹²⁸I (half life 25 minutes) was the first iodine isotope to be manufactured and this new isotope was used to demonstrate that iodine was concentrated in the rabbit thyroid gland. Subsequent isotopes of RAI were used to study and treat hyperthyroidism (9).

During the late 1930s and early 1940s, patients were treated with either ¹³¹I (half life=8 days; 90% of energy beta emission), ¹³⁰I (half life 12.5 hours 100% beta emission), or a combination of the two. Initially, most were treated with ¹³⁰I. On November 4, 1940, RAI was given to a hyperthyroid patient scheduled for surgery. The first therapeutic dose intended to treat hyperthyroidism was administered to Mrs. ED on March 31, 1941, and contained a mixture of ¹³¹I (10%) and ¹³⁰I (90%). Of the eight patients treated with RAI between 1940 and 1941, five received divided doses estimated at 1.5–6.2 mCi (average 3.9 mCi) (9).

As part of the protocol of RAI therapy at the MGH, stable nonradioactive iodine was administered to the patients several days after they received RAI. Stable iodine (which had been shown to improve the outcome when administered before surgery) was first given at the MGH after RAI at the insistence of Dr. Means who believed that it would “protect the patients against the mischief from thyrotoxicosis [when a] treatment of unknown efficacy was being tried out. I insisted on it” (10).

Dr. Saul Hertz headed the RAI research team at the MGH in the late 1930s and early 1940s. Dr. Hertz defined a success or a cure as a hyperthyroid patient who: (i) received RAI followed by stable iodine; (ii) improved clinically and by BMR; and (iii) had a normal BMR at least 3 or 4 months after the stable iodine was stopped. According to Sawin and Becker (9), Dr. Hertz reported the following results at the annual Society for Clinical Investigation meeting in 1942: five of his first eight patients were considered cured, two were classified as improved, but still taking stable iodine, and one had surgery within 2 weeks. It is worth noting that our 9-year-old patient would have been considered cured by Dr. Hertz.

In October 1941, a group in Berkeley also began to use RAI to treat Graves' hyperthyroidism (11). Of the initial three patients, two went into complete remission and a third improved with repeat RAI ¹³¹I. Whereas Dr. Hertz at the MGH was very enthusiastic about the treatment, Dr. Hamilton at UC Berkeley was concerned that RAI was a “potentially lethal agent” (9).

The initial MGH experience of treating hyperthyroidism with RAI during the early 1940s was described in two separate articles in the same 1946 issue of the Journal of the American Medical Association. Each article was written by a separate group in the MGH Thyroid Unit (12,13). Dr. Hertz initiated the studies, and Dr. Chapman continued them, while Dr. Hertz served in the Navy during World War II. The same issue of JAMA also included an anonymous editorial (14), written by James H. Means, MD, previously Chief of the MGH Thyroid Unit, and then Chief of Medicine at the MGH, as well as a commentary by Dr. Karl Compton on the contributions of sister sciences to medicine (15). Of the 29 patients described by Hertz and Roberts, 20 were considered successful. An additional 22 patients were treated by Chapman and Evans with higher doses of RAI without supplemental iodine. Fourteen of these patients responded well to a single dose of RAI, three were given two doses, and five were given three doses. Two patients remained hyperthyroid, and four patients developed myxedema.

Our patient (patient number 7 in Ref. 13), was one of two 9-year-old girls treated by the Hertz group. Although the hospital chart notes that she received doses of 14 and 3.5 mCi ¹³⁰I (subsequently confirmed by Dr. Chapman), the Table in reference 13 records two doses of ¹³⁰I, one of 1.4 mCi and one of 1.5 mCi for a total dose of 2.9 mCi. I have been unable to resolve this disparity.

How might one have compared the risks and benefits of surgery and RAI in 1941? We do not know what the surgical mortality and the complication rate would have been for a 9-year-old thyrotoxic patient back in 1941 in the hands of a highly skilled surgeon. Here is what we do know. One of the studies published that year from a large municipal hospital in NY reported a 1.6% mortality in 245 patients (presumably adults) undergoing surgery for hyperthyroidism, where preoperative iodine was used in the 175 patients with exophthalmic goiter (Graves' disease) (16). Three of the 175 exophthalmic goiter patients died, and 1 of the 70 patients with toxic adenomas died at surgery. Surgery for Graves' disease was generally performed in two stages requiring two separate anesthesias: 1.7% of these patients had a postoperative hemorrhage, including one patient who required a tracheostomy; and 2.8% had a recurrent largyngeal nerve injury. In 1942, Sherwin wrote: “The mortality in operations for toxic goiter has been greatly reduced in recent years in the hands of most surgeons, but it is still higher than it ought to be throughout the country as a whole” (17). The mortality for surgery for Graves' hyperthyroidism at that time was still 1–2% in skilled hands and 8–10% in less skilled hands (9).

Testing a novel and potentially dangerous therapy such as RAI on minors would likely not pass modern IRB scrutiny, but such committees did not yet exist in 1941, nor were there published standards for informed consent. In 1946, Dr. Means shared his concerns about the efficacy and safety of RAI, writing that RAI was a “new and effective method of causing permanent remission in hyperthyroidism…Whether or not it will prove superior to all other forms of therapy for the malady in question cannot be foretold now. Much more data must be accumulated before it can be asserted that radioactive iodine gives the patient a better chance of permanent cure and freedom from untoward side effects than does subtotal thyroidectomy or prolonged treatment with an antithyroid drug. The possibility, however, that treatment with radioactive iodine may possess such superiority makes extended study desirable…However, the use of any form of radiation may be accompanied by late untoward side effects. The late development of cancer as a result of irradiation, although perhaps unlikely, is certainly within the realm of possibility” (14). Therefore it is still surprising that two of the first patients treated with this experimental therapy were only 9 years old. These concerns were shared by our patient. However, she seemed at least somewhat mollified when I told her about the potential risks and dangers of thyroid surgery in children and explained how traumatic the idea of surgery might have been for her mother, given her mother's own thyroidectomy.

Back in 1941, the investigators involved with the early use of RAI to treat Graves' hyperthyroidism probably posed certain key questions in the course of their experimental work: Does it work? Is stable iodine necessary after RAI? Are the effects permanent? What are the benefits and risks of RAI, particularly in children? What is the thyroid pathology after RAI? Seventy years later, many of these questions have been answered, while others remain unresolved.

In 1941, preliminary data suggested that RAI was effective in treating Graves' hyperthyroidism. By 1946, it was clear that the majority of patients treated with RAI had a successful outcome (12,13). In 2012, after more than one million Graves' patients have been treated with RAI, it is now clear that the success rate is almost 100% (18) and the response is generally a permanent one. With the exception of early thyroid stunning post-RAI (19), it is unusual for patients who develop overt hypothyroidism to have recurrent hyperthyroidism. RAI therapy generally relieves hyperthyroidism permanently, at the price of hypothyroidism (20).

Our patient's response to RAI was therefore unusual. Despite a low BMR 6 years after RAI, she was considered clinically euthyroid. Seventeen years after RAI she developed recurrent hyperthyroidism.

For many decades after the initial studies of RAI, the MGH Thyroid Unit routinely prescribed stable iodine after RAI therapy for Graves' disease (21). Although it is no longer considered necessary, it has been noted that patients receiving stable iodine after RAI, become euthyroid more quickly than those who do not (21,22). Randomized controlled trials are still lacking to verify this clinical observation.

In 1941, surgery was the standard therapy for Graves' hyperthyroidism and RAI was a new and little tested experimental therapy. With the information available to physicians and investigators in 1941, it was impossible to make a knowledgeable assessment of the advantages and disadvantages of RAI versus surgery in adults and particularly in children. After the introduction of antithyroid drugs in the early 1940s, the relative merits of RAI, surgery, and antithyroid drugs were still uncertain. In 2012, the relative merits of initial antithyroid drugs versus RAI are still being debated, but surgery has been relegated to a distant third choice for most patients. The choice of which of these three therapies to use is generally left to the patient, after careful discussion with the physician.

By the early 1960s, external radiation during childhood was a known cause of thyroid cancer (23). The Chernobyl meltdown re-emphasized concerns about the risk of neoplasia in the infant or juvenile thyroid exposed to radiation (24, 25). The precise risk of RAI causing thyroid neoplasia in children has not yet been definitely established (18). Cases of thyroid nodules and thyroid cancer have been reported in children after RAI therapy for Graves' disease (26). The risk of thyroid cancer seems to be greater with lower doses of RAI than with the currently employed higher doses of RAI, because the higher doses are more likely to kill all thyroid tissue (18). While some clinicians consider RAI the therapy of choice for childhood Graves' disease (27), RAI is still not recommended for children younger than 5 years of age. When very high doses of RAI are necessary (e.g., for thyroid size greater than 80 g), surgery is thought to be preferable (18).

The potential risk of thyroid or other malignancy after RAI was a genuine concern in 1941, and was mentioned by Dr. Means in his 1946 editorial (14). Although our patient recalls that she and her mother were told that the treatment might cause cancer, no mention is made of such a conversation in her medical record. However, the standard of care in 1941 for recording such conversations is unknown. We do know that the patient had surgery to remove a nodular goiter 17 years after RAI therapy and it is possible that these thyroid nodules were caused by her RAI therapy in 1941. Pathological changes of radiation damage were seen at the time of her subsequent surgery. It is clear that radiation changes in fine-needle aspiration specimens after RAI for Graves' disease need to be interpreted with caution and that they can be easily misinterpreted as thyroid cancer (28). There is some uncertainty about whether our patient received two low doses of RAI (as noted by Hertz and Roberts) or one higher and one lower dose of RAI (as noted in the medical record). The radiation dose to the thyroid (for an equivalent thyroidal uptake) is ∼8.7 times higher for ¹³¹I compared to ¹³⁰I (calculations kindly provided by Rex Woodleigh). Without knowledge of the 24-hour RAI uptake, we cannot calculate the specific radiation dose to the thyroid gland in our patient. Concerns about decreased fertility and increased birth defects were not raised in 1941 and fortunately were not borne out in future studies (18). Our patient did not try to conceive.

Hyperparathyroidism after external radiation was first reported in 1975 (29), and many additional cases were subsequently reported (30). Hyperparathyroidism has also been reported after RAI exposure. Colaço et al. (31) cared for 11 patients with hyperparathyroidism after RAI therapy and he also found an additional 36 cases in the medical literature. Of 37 cases where the pathology was known, only 4 had parathyroid hyperplasia (as was reported from our patient's initial surgery), 2 had double adenomas, and the remainder had a single adenoma. The mean latency between RAI and the diagnosis of hyperparathyroidism was 13.5±9.1 years. The latency was inversely correlated with the age at radioactive exposure. The youngest patient treated with RAI who later developed hyperparathyroidism was treated at age 8 and developed hyperparathyroidism at age 36.

In 1941, our patient's hypercalcemia without hypophosphatemia was likely due to hyperthyroidism. She was subsequently found to have enlarged hyperplastic parathyroid glands in 1958, 17 years after RAI therapy. No preoperative serum calcium was reported, and the patient developed tetany postoperatively. In 1996, the patient subsequently developed hyperparathyroidism requiring surgery to remove a enlarged parathyroid gland. The precise onset of her hyperparathyroidism is unknown. It is possible that her hyperparathyroidism was a consequence of her RAI therapy.

This case opens a window into the early history of RAI. The patient's experience of receiving RAI therapy at age 9 became an indelible part of her life and memory. She ultimately required surgery for recurrent hyperthyroidism and later for hyperparathyroidism. Nodular thyroid disease as well as hyperparathyroidism were possible consequences of her RAI therapy. We have learned a great deal about the benefits and risks of RAI in treating Graves' disease in the last 71 years, but there are still some questions about the safety of RAI in childhood that have yet to be answered.