The causes of a low white blood cell count range from trivial to life threatening. The two most common causes of a low count are drug side effects and infections. Many different medications can cause a low white blood cell count, either because they halt the production of these cells in the bone marrow or because they induce an immune-mediated destruction of them. But Linda wasn’t taking any medications at all. Infections can cause a low white count. Sometimes these infections are trivial, such as those caused by common viruses. Other, more ominous infections can also lower the white blood count, such as malaria, or life-threatening bacterial sepsis. Linda, however, had no signs of infection of any kind.
There was no evidence for a hereditary cause or a large spleen, which can sometimes sequester circulating white cells. Vitamin deficiencies can also cause low counts, but Linda’s diet was excellent. An autoimmune disease, such as lupus or rheumatoid arthritis, can lower the white count, but again, these diseases simply did not fit the picture of a healthy young college student with no symptoms whatsoever. The most serious possibility of all was a disease that infiltrated the bone marrow, the place in the body where blood cells are manufactured. The most serious diseases in this category are cancer and leukemia.
The other component of Linda’s white blood cell abnormality was an elevated level of a specific type of white cell—the lymphocytes. Of the more common causes of elevated lymphocytes, leukemia was also on the list, as were various infections like mononucleosis, syphilis, and tuberculosis.
With no apparent cause, and with leukemia on both lists, Corsetti’s father promptly made an appointment for his daughter with a hematologist in the family’s hometown of Providence, Rhode Island. By the time Corsetti walked into the doctor’s office in early January 1984, her classmates were going through orientation in Rome. The doctor took a history and learned that his new patient was in excellent health. To rule out the most serious diagnosis first, he decided to directly examine Corsetti’s bone marrow. After she was given a local anesthetic, a hollow needle was inserted into the pelvic bone, near the small of the back, and some bone marrow was aspirated into a syringe and examined under a microscope.
A couple of days later, the results were in: Corsetti’s bone marrow was normal and the hematologist had ruled out leukemia. But there was still a mystery. What was causing the low white cell count? Given the testing that the hematologist had done, the serious infections and malignancies had been excluded; most likely it was just some virus. The doctor thought it was safe for Corsetti to catch up with her schoolmates in Rome. “The doctor told me that with the low white blood count, I might be more susceptible to infections, and he was exactly right,” she recalls. “The first week I was in Rome, I came down with a really bad virus and had to stay in the infirmary at the dorm for several days. I was really sick; I even thought about coming home, but I didn’t want to alarm anybody. Also, by that point, I’d have missed out on Italy, missed my semester at Bowdoin, and would have had to graduate late.”
So she stuck it out. Corsetti recuperated in the infirmary and went on to enjoy a glorious semester abroad in the Eternal City.
She came home in June 1984, finished her senior year at Bowdoin, and graduated in the spring of 1985. Thinking back, she says that she may have been a bit irritable at times. She may have cried more easily than normal. And she had a voracious appetite. John Carnivale, then her boyfriend and now her husband, was a football player at Bowdoin, weighing in at 215 pounds. “Linda would go fork for fork with me, and I ate a lot,” he says. “And after the meal, she’d still be hungry.” But she didn’t gain any weight.
After graduation, Corsetti took a front-desk job at the Omni Parker House in Boston. “My hours were crazy,” she says. “Sometimes I’d work till 11 PM, and then have to be back at 7 AM. My appetite was still enormous, but I began losing weight. I had no patience at all; I must have been impossible to work with. And I couldn’t deal with the customers or the complaints. I threatened to quit every other day.”
One very cold night in January 1986, Corsetti, Carnivale, and her family went to a play. Despite freezing temperatures, she wore only a sweater. “I remember my father yelling at me, ‘You don’t take care of yourself. You don’t dress properly.’ But I felt perfectly comfortable,” recalls Corsetti.
The play was presented by the second-year class at Harvard Medical School, where her brother John was a student. That same month, he was studying endocrinology with Dr. Ron Arky, the Charles Davidson Professor of Medicine at the medical school and chief of medicine at the Mount Auburn Hospital in Cambridge. As John Corsetti listened to Arky explain various endocrine conditions, he thought that some of them sounded all too familiar; his sister’s symptoms matched those of the teaching case. He recalled: “It first struck me when she was cutting my hair one day. I was taking endocrine as a second-year medical student. My apartment was very cool but Linda felt very hot. She took off her sweatshirt and was still complaining that the apartment was too hot. The next day, I spoke to Dr. Arky.”
Remembers Arky: “After a lecture one day, John came up to me and asked me to see his sister as a patient. I saw her late one February afternoon, and there was no question that she had classic hyperthyroidism.”
The thyroid gland straddles the windpipe just below the Adam’s apple in the neck. It is a ductless gland that manufactures the hormone thyroxine, which it secretes directly into the bloodstream. The word “thyroid” comes from the Greek threos, for shield-shaped. Leonardo da Vinci was one of the first to identify the gland in sketches he made in 1511. The material came from anatomical studies done at the Santa Maria Nuova, a hospital that still stands not far from the Duomo in Florence.
Thyroxine controls the body’s metabolic rate. Normally, the amount of the hormone circulating in the body ranges from roughly five to eleven micrograms per one hundred cubic centimeters of blood. That narrow range is maintained by intricate feedback loops controlled by the hypothalamus and the pituitary gland, the body’s master regulators, deep in the brain. It is a delicate balance. Too much thyroxine, a condition known as thyrotoxicosis or hyperthyroidism, speeds up the metabolism, and too little slows it down. There are several different conditions that can lead to thyrotoxicosis. Benign and malignant tumors of the gland, if they secrete the hormone (and many do not), can result in hyperthyroidism. Sometimes a nodule or inflammation of the gland will do the same. And then there is the condition that we now call Graves’ disease.
In 1835, Robert J. Graves, an Irish physician, described four patients with the disease that now bears his name. Robert James Graves was born in Dublin in 1796. He studied the classics and science as an undergraduate student, and received his medical degree at age twenty-three from Trinity College in Dublin. On graduating first in his class in 1818, he was awarded Trinity’s gold medal. Like many physicians in his time, Graves served a peripatetic apprenticeship, traveling across continental Europe to study with the masters in France, Germany, and Austria. He was greatly influenced by the clinical teaching methods in Germany. Even beyond medicine, he led a fascinating life.
So well did he learn German that he was once arrested as a German spy in Austria, after having forgotten his passport. He was detained for a fortnight, as the authorities refused to believe that any Irishman could speak their language so fluently. He traveled and painted for a while in Rome and Florence with an older man he befriended. Only months later did he learn that his painting companion was J. M. W. Turner.
He returned to Dublin in 1821 and began a very successful private practice as well as taking a teaching post at the university, where he would begin his teaching rounds early in the morning, illuminated by candlelight. He brought some of the bedside teaching techniques that he had seen in Germany back to Ireland. As many as one hundred students would pack into his afternoon lectures, which were delivered with quite a bit of theatrics. He also was one of the first physicians to deliver his lectures not in Latin but in English. Of educating doctors, Graves said: “The phys
icians’ profession is acquaintance with disease and its remedies. It is not chemistry, it is not anatomy, it is not physic, it is not physiology, it is disease.” Once again taking the lead of the great teachers of medicine from the continent, Graves insisted that his students attend autopsies of their patients in order to better understand the symptoms and signs that had preceded their deaths.
Although Robert Graves is best known for his description of hyperthyroidism, his collected lectures covered the entire corpus of medicine—cardiology, chest diseases, neurology, syphilis, typhoid fever, and other common infectious diseases of his time. The description of hyperthyroidism was made by others before him. A twelfth-century Persian physician named Sayyid Ismail Al-Jurjani reported an association of goiter (a swelling of the thyroid gland) and exophthalmos (bulging eyes). The word “goiter” derives from the Latin guttur, meaning throat. The first known record of a goiter (but not the association with the eye findings) was by the Chinese physician Tshui Chih-Thi in 85 AD. When a goiter secretes thyroxine into the bloodstream, hyperthyroidism occurs, and exophthalmos is one symptom of hyperthyroidism.
The next person to describe hyperthyroidism was an esteemed British physician named Caleb Hillier Parry. In 1786, he described five cases of exophthalmic goiter, palpitation, and anxiety. He wrote of these patients, “the eyes were protruded from their sockets, faces exhibited an appearance of agitation and distress, the heart beat was so violent that each systole of the heart shook the whole thorax.” His report, however, was not published until years after his death. In 1800, an Italian doctor, Giuseppe Flajani, also reported some cases of the same disease. In fairness, these three men had priority over Graves.
Graves, though, composed a graphic report, initially of three patients, and this is what led to his name becoming associated with the disorder. He wrote,
I have lately seen three cases of violent and long-continued palpitations in females, in each of which the same peculiarity presented itself: enlargement of the thyroid gland; the size of this gland, at all times considerably greater than natural, was subject to remarkable variations in every one of these patients. When the palpitations were violent, the gland used notably to swell and become distended, having all the appearance of being increased in size . . . [that] had attracted forcibly the attention, both of the patients and of their friends.
The enlargement of the thyroid of which I am now speaking, seems to be essentially different from goiter, in not attaining a size at all equal to that observed in the latter disease. . . . The well-known connection which exists between the uterine functions of the female and the development of the thyroid observed at puberty renders this affection worth of attention, particularly when we find it so closely related by sympathy to those palpitations of the heart which are of so frequent occurrence in hysterical and nervous females.
Graves’ first three patients (and a fourth he added shortly thereafter) all had prominent bulging eyes, a rapid metabolism, and a curious swelling in the front of the neck. Goiter is a generic term used to simply describe swelling of the thyroid. In some areas of the world, where dietary iodine is lacking, endemic goiter exists. These people do not get sufficient iodine (required for making thyroxine), so their glands enlarge, sometimes to massive proportions, in an attempt to make up for the deficiency. This is called endemic goiter. These patients are not thyrotoxic, however. They have symptoms in the neck from pressure of the goiter on the windpipe, but they do not have all of the hyperthyroid symptoms that Graves described. In Graves’ disease, the degree of thyroid enlargement was much less than in endemic goiter. And Graves’ patients were all female. In spite of his anachronistic and incorrect association of the uterus and the thyroid, Graves did correctly make the observation that the disease is far more common in women than in men.
Graves didn’t know the cause of his patients’ malady; in fact, he thought it was a cardiac problem. Today we know that Graves’ disease is an autoimmune problem in which the thyroid is whipped into a frenzy by antibodies that stimulate the gland. As in the famous I Love Lucy episode making candy on the assembly line, the thyroid cranks out more and more thyroxine—so much that the body can’t handle it.
Patients with Graves’ disease can have a wide range of symptoms: heat intolerance and sweating, palpitations, nervousness, insomnia, irritability, tremors, muscle weakness, weight loss despite a good appetite, diarrhea, goiter, and the characteristic exophthalmos. In addition to the high level of thyroxine in the blood, some patients have a low white blood cell count with a high percentage of lymphocytes. This is unusual as the initial finding in Graves’ disease, but it did explain Linda Corsetti’s blood abnormality.
“Linda had many of these symptoms,” recalls Arky, “and she had been aware of a goiter since the beginning of college. I sent off the blood work, but I was pretty sure she had Graves’ disease.” Corsetti’s initial appointment with Dr. Arky was Wednesday, February 19, 1986. Two days later, her blood work returned. Her white blood cell count was still low, with many lymphocytes, and her thyroxine level was markedly elevated at eighteen micrograms. Arky started Corsetti on a drug called propylthiouracil, or PTU, as it’s commonly known. PTU decreases the thyroid’s ability to produce its hormone, but it is also one of those medications that can cause a decrease in the white blood count, so Arky had to monitor Linda’s blood measurements very carefully.
Her symptoms gradually faded, but although the PTU did not affect her white blood cell count, she did become aware of other issues. Over the weeks to months after starting the PTU, she felt much better, and many of her original problems resolved. “But I started having other symptoms,” she recalls. “My hair was falling out in clumps. I went sailing one day and the whole boat was covered with my hair. And on top of all that, my eyes were asymmetric and I was concerned that would be permanent.”
Although her bulging eyes were clearly improving, they weren’t improving at the same rate: the left eye was noticeably worse than the right one. In retrospect, the eye findings had been present for a while, but because the problem had developed slowly, she hadn’t noticed it. Over the spring, summer, and fall of 1986, her symptoms of hyperthyroidism resolved, her weight normalized, and her blood work showed normal thyroid function. Although the exophthalmos was slow to resolve, she felt well. On Christmas Day, John proposed to her, and they became engaged to be married.
As is customary, a year after Arky started Corsetti on PTU, he took her off it. In 30 percent of patients with Graves’ disease, the disorder goes into complete remission even after the medication is withdrawn. But not Linda Corsetti. By May, a month before her wedding, she was clearly hyperthyroid again, and in June, Arky took another blood sample to recheck her thyroxine, and this time it was twenty-four micrograms. He wrote another prescription for PTU.
Linda had other concerns. First there were the usual stresses and then some: planning a wedding and a honeymoon, looking for a house, buying a new car, and traveling back and forth between Boston and Providence. Second, she didn’t want to be a bride with asymmetrical eyes.
But the major issue was the dress.
“I had gained back the fifteen pounds I had lost,” she remembers, “and probably twenty more. After the engagement, I began dieting. From Christmas to May, I lost forty-five pounds. I bought a really fitted dress, and they had to keep taking it in every few weeks. I knew that if I went back on the PTU, I’d gain the weight back and never fit into the gown.”
Although her untreated hyperthyroidism provided what she considered a sartorial benefit, it did create other problems. Her husband recalls, “The time around the wedding was crazy; it was hell. After one fight we nearly canceled it. Then we went to Bermuda on our honeymoon. It was hot, and Linda couldn’t stand the heat. Our hotel, Grotto Bay, offered cave swimming every day between noon and 1 PM. The water was about forty-five degrees, and nobody went in—except Linda. She was there every day. Once I jumped in and I thought I’d have a heart attack.”
Corsetti remember
s, “Needless to say, my engagement and honeymoon were tense. I had no patience at all. Bermuda was really hot, in the nineties, and I felt like I couldn’t breathe. I felt hot all the time. The only refreshing thing was this ice-cold natural pool. I’d swim in it once or twice per day. Everybody else would be saying, ‘Oh my God, there’s a girl swimming in the freezing water! Can you believe it?’”
Hyperthyroidism can produce all sorts of mental symptoms, from mild irritability to frank psychosis. And patients with hyperthyroidism can do odd things. Says Arky, “I’ve seen couples split up over hyperthyroidism. The patient will want to open all the windows in the house and the spouse will be freezing.
“The most bizarre one I’d ever had was a former secretary of mine with classical Graves’ disease; she had both a goiter and the exophthalmos. She was a Jehovah’s Witness and refused to have any blood drawn. We could follow very easily when her condition was exacerbated and when she had remissions merely by the heat setting in the office. Also, when she was toxic, she’d consume eight thousand calories a day without gaining weight. And she was the fastest typist that existed. She peddled the Watchtower on weekends. She would start on the corner of Longwood Avenue and Huntington Street and literally walk out Route 9 to Route 128, about ten miles and back. And she wasn’t fazed by it.
“There was never any question as to when she was thyrotoxic. Her energy was unbounding and she was impossible to get along with. She worked for me for three years; finally she allowed us to draw her blood; her thyroxine was twenty-four, but she would never accept any therapy. She went elsewhere to work and I lost track of her, but she was a character of the first class—but only when she was toxic.”
The Deadly Dinner Party: and Other Medical Detective Stories Page 18