Unmasking the Disease
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Unmasking Thyroid Disease

With symptoms that masquerade as myriad medical and mental disorders, thyroid disease often eludes diagnosis.

By Alana Mikkelsen

Latasha Pettis had always been a good student, but during her sophomore year of high school her grades plummeted and her personality changed dramatically.

The normally mild-mannered 15-year-old cursed at her French teacher and stormed out of a classroom because of a minor misunderstanding. Routine reminders to do homework or chores sent her into screaming and crying fits. In the winter, when her family nudged up the thermostat in their East Palo Alto home, Pettis found the temperature so unbearable that she rigged a makeshift sleeping place in the back yard.

"I thought Latasha was losing her mind," says her grandmother, Minnie Pettis.

A visit to a psychiatrist, however, would not have solved her problem.

Eventually, a swelling in Pettis' neck betrayed the cause of her bizarre behavior. Her thyroid, a butterfly-shaped gland just below the Adam's apple, was five times larger than normal and pumping out unusually high quantities of hormones.

Thyroid disease, which afflicts nearly 20 million people in the United States, often masquerades as a variety of med-

ical problems. Consequently, underactive and overactive thyroid conditions may go undiagnosed for months or even years, specialists say. The symptoms can be so subtle they are missed. Or, like those of Pettis, they can be striking but confusingly similar to other mental or physical disorders.

But when physicians recognize that another face may be lurking behind the mask, they can help patients avoid extreme consequences of the disease -- ranging from digestive and nervous system complications to heart failure and death. A simple blood test can detect the disorder, and treatment is easy and effective, says I. Ross McDougall, MD, PhD, chief of Stanford University Hospital's thyroid clinic.

"Thyroid disease is very common," says McDougall, professor of radiology and medicine. "But suspected thyroid disease is even more common. Part of our job is to show patients with suspected thyroid disease that they are normal rather than abnormal, and if they are abnormal, prove that to the patients and determine the best treatment."

"A high index of suspicion" toward any symptoms suggestive of thyroid disease is very important, says McDougall, who runs the thyroid clinic within the division of nuclear medicine. The clinic offers diagnostic testing and several forms of treatment for overactive and underactive thyroid conditions and for thyroid cancer. McDougall works closely with adult and pediatric endocrinologists, as well as surgeons, radiation oncologists and ophthalmologists at the medical center.

Laura Bachrach, MD, a Stanford pediatric endocrinologist, referred Pettis to McDougall for treatment of her condition: Graves' disease, the most common cause of an overactive thyroid. Graves' disease, an autoimmune disorder, gained notoriety when physicians diagnosed former President George Bush and Mrs. Barbara Bush with the disease.

The condition arises when antibodies produced by immune cells attach to receptors on the surface of thyroid cells and mimic thyroid-stimulating hormone (TSH), the thyroid's primary activator. Thyroid hormones, which influence metabolic processes and trigger cells to consume energy and oxygen, aid the growth and development of nearly every tissue in the body.

In the hyperthyroid condition, excess thyroid hormone produces a metabolic overdrive. People with an overactive thyroid may appear nervous or anxious and have a racing heart, warm and sweaty skin or diarrhea. They commonly feel hot in cool temperatures, lose weight despite eating a lot and suffer from hair loss, muscle tremors and fatigue. Extreme hyperthyroidism can put patients at risk of heart failure and incapacitation due to dehydration.

A more common condition, an underactive thyroid gland or hypothyroidism, is comparatively silent. Cases of hypothyroidism are considerably more common than those of hyperthyroiditis, says Bachrach.

As in the overactive condition, the most common cause of an underactive thyroid is an autoimmune disorder-- called Hashimoto's disease. Also called chronic lymphocytic thyroiditis, Hashimoto's disease results when antibodies latch on to proteins in the thyroid tissue. The binding is a call to action to the rest of the immune system, and the thyroid is subsequently invaded by numerous immune cells, or lymphocytes, which progressively destroy the hormone-producing thyroid tissue in an errant attempt to rid the body of what it thinks is an invader.

The resulting hormone deficiency slows metabolism and causes people to lose their appetite, become lethargic, gain weight and suffer from constipation. Dry skin and hair, brittle nails, a puffy face and muscle cramps are common. Prolonged hypothyroidism can make adults forgetful and can lead to hypertension and organ damage.

Children, who may be oblivious to some of the disease's subtle symptoms, are more likely to progress to longstanding hypothyroidism than adults.

"Children don't focus on their weight as much [as adults]. They may not notice subtle changes in energy. Their mood may be attributed to a stage they're going through, and they don't get as frantic if they get constipated as older people do," says Bachrach. "I've seen children who have profound hypothyroidism that's gone on for six or seven years who've never complained."

Growth in hypothyroid children typically stops "right in its tracks," says Bachrach. For instance, a hypothyroid child whose height is in the 50th percentile for his age one year may measure as tall or taller than only 20 percent of his peers the next year. Taken at face value, the child's height for both years would be plotted within average ranges of stature. But Bachrach warns against the misconception that as long as children's absolute heights are normal, their underlying health is fine.

"That kind of change in growth percentiles is very abnormal," she notes.

From the age of two until puberty, a child should remain at roughly the same place on a growth curve, Bachrach says. Any significant change in growth rate -- the crucial indicator of normal development -- should be taken seriously. Bachrach notes that physicians should make sure their young patients' heights are plotted on growth curves and compared with measurements from previous years. And parents should be suspicious if their child rarely changes shoe or clothing size.

Spotting hypothyroidism in adults can require an even more critical eye. Like all autoimmune disorders (including Graves'), hypothyroidism preferentially attacks females. And, because it most commonly occurs after mid-life, it is often mistaken for menopause.

In addition, about one in 20 women will be afflicted by a short-term change in thyroid function immediately following pregnancy. The disorder -- in which the thyroid usually becomes overactive then underactive with consequent changes in mood -- can easily be mistaken for postpartum depression. Women with insulin-independent diabetes have a higher risk for this transient disorder, which usually returns to normal after several months.

In both Graves' and Hashimoto's diseases, lymphocyte infiltration -- in which immune cells home to and penetrate a site of immune attack -- can lead to a goiter, or swelling, of the thyroid gland. Few goiters are as large as Pettis' plum-sized swelling, but they are often a cause of concern.

"A lot of parents notice the swelling, and they get anxious because they think it is a tumor," says Bachrach. Thyroid cancer is rare, however, and most enlarged thyroids are benign, she notes.

In 90 percent of Hashimoto's cases, for example, the thyroid gland is not damaged enough to produce a hormonal imbalance. This condition, called euthyroidism, does not require treatment. Some of these goiters disappear without therapy, but physicians should monitor patients with Hashimoto's thyroiditis because they are at greater risk of developing hypothyroidism later in life, McDougall says.

When a goiter or other symptoms lead physicians to suspect a thyroid condition, they typically use blood tests to measure thyroxine and TSH levels in the blood. Thyroxine comes in two forms: free and bound to protein. Only the free form of the hormone is metabolically active, and McDougall cautions that total thyroxine measures can give an inaccurate result and may lead physicians to prescribe unnecessary treatment.

McDougall also warns physicians to be alert to coincidental conditions that can throw the tests off -- for example, acute psychiatric conditions and some medications for heart arrhythmias, as well as narcotics like cocaine. In the early 1980s, McDougall and the late Joseph P. Kriss, MD, (McDougall's predecessor in the thyroid clinic), found in patients they studied that up to half of patients with psychiatric and severe physical illnesses had abnormal thyroid tests. When these illnesses subsided, the tests returned to normal.

After making the thyroid disease diagnosis, physicians can usually cure the patient. The simplest form of thyroid disease to treat is hypothyroidism. Synthetic hormone replaces the natural insufficiency, and patients usually take substitute pills daily at a cost of between $60 and $80 a year.

An overactive thyroid gland is more challenging to treat. Drug therapy, which consists of pills that must be taken up to three times a day, is inconvenient and may have undesirable side effects such as a rash. For that reason, many patients -- including Pettis -- opt for radioactive iodine therapy, which destroys the overactive gland. Surgical removal of the thyroid is an alternative means to permanently "cure" hyperthyroidism.

"Most patients who hear about treatment with radioactive iodine get a little anxious," McDougall says, "but it's the safest, simplest, cheapest and best approach to treating hyperthyroidism."

Patients take the treatment in the form of a tasteless, odorless drink, and one treatment is usually all it takes. The thyroid gland needs iodine to make its hormones and is one of the few places in the body where iodine is metabolized, so most of the radioactive iodine homes to the gland. Because patients are mildly radioactive for a few days following treatment, they are usually required to sleep alone, wash their personal clothes and bed sheets separately from family members and use disposable plates and eating utensils.

McDougall says the risk of damage to others from exposure to radioactivity is extremely small. "If you sat three feet from a patient for one hour, you would be exposed to about the amount of radiation that you would get from two days of background [from the sun and earth]," McDougall says. "If you slept beside someone for eight hours, you would get about eight times that. That's still a very small amount of radiation."

After a few days, the radiation given off from the patient is virtually imperceptible, he adds.

Because radioactive iodine eventually destroys the thyroid gland, most patients who take the treatment become hypothyroid after several months. Like those with naturally underactive thyroid glands, they require hormone replacement for the rest of their lives. McDougall says most patients find trading hyperthyroidism for hypothyroidism definitely worthwhile.

"It's quite dramatic," he says. "In about six weeks, patients can be made normal. About three months later they go on a replacement pill and can pretty much get away from doctors once the dose of thyroxine is adjusted, although a blood test every year or two is recommended."

Indeed, Pettis has bounced back after her radioactive iodine treatment. Her grade point average has jumped from last year's 1.8 up to 3.0, and in June she was inducted into the National Honor Society. This summer she'll become hypothyroid and begin taking replacement hormone.

She says the lifelong treatment is a small trade-off for the possible dire consequences of staying hyperthyroid.

"I feel great," Pettis says. "I feel better, I act better and my attitude is positive."

Pettis' turnaround is satisfying to McDougall, as well.

"There are very few areas in medicine where you can actually cure patients," he says. "... but with thyroid disease you frequently can."




Graves' consequences


Itchy, watery, sandy-feeling eyes. Swollen eyelids. Allergy medication won't cure these irritating symptoms if the underlying problem is a mysterious eye disease called Graves' ophthalmopathy, which can spontaneously appear or insidiously progress toward Eyelid swelling, double vision and varying degrees of sight loss.

Although it usually accompanies Graves' disease (see main story), Graves' ophthalmopathy may appear immediately before or decades after a patient has been treated for hyperthyroidism. The eye condition may also be associated with an underactive thyroid or no thyroid condition at all.

Some researchers suspect the disease is caused when antibodies already present against the thyroid gland migrate toward the eye and attack the connective tissue and muscles of the orbit -- the bony socket in the skull that houses the eyeball and eye muscles. Inflamed by the immune attack, the muscles can become stiff. Often the eye muscles swell so much that they push the eyeballs out toward the front of the face. The resulting bulginess can dry out and damage the cornea -- the eye's protective surface -- and can severely affect a person's appearance as well as self-image. Sometimes patients have difficulty closing the eyelids, which causes a characteristic stare.

"The eye socket is surrounded by bone, so there's no place for the swollen tissues to go but forward," explains Peter Levin, MD, chief of ophthalmic and orbital surgery in Stanford's department of ophthalmology.

In severe cases, the swollen muscles press on the optic nerve and endanger a person's sight. Such serious cases are uncommon and can be treated with an operation called surgical decompression. During the procedure, the surgeon removes one or more of the bones that separate the orbital cavity from the sinuses. The swollen membranes can then expand inward and the eyes sink back to their proper place in the face.

Other symptoms of Graves' ophthalmopathy, including double vision or cross-eye, can be surgically corrected by cutting the muscles on either side of the eye and reconnecting them at a position that pulls the eyeballs back to center. The operation is difficult, Levin says, because the muscles must be precisely aligned and the patients are asleep at surgery. However, an "adjustable suture" used by Stanford eye surgeon Deborah Alcorn, MD, gives doctors a second chance. The stitch -- effectively a slipknot -- allows the doctor to reposition the muscle's connection to the eye in the office on the day following surgery, Levin says.

At Stanford, physicians most commonly treat progressive Graves' ophthalmopathy by aiming a fine X-ray beam at the eye muscles. The technique, which was developed at Stanford for treating cancer, uses a medical linear accelerator -- a compact version of the huge "atom-smashers" physicists use to study atomic particles. The medical version of the machine uses pulses of microwave energy to excite electrons to near-light speed, then aims them against a gold-plated target. The resulting collision produces highly penetrative X-rays, which are emitted from the machine and targeted to the patient's orbital muscles.

The lymphocytes that create the inflammation are particularly sensitive to radiation and are preferentially killed by the low dose of X-rays. Once the culprit cells have been killed, the swelling in the connective tissues usually regresses.

"There are several good places in the country that can do the same [eye] treatment, but we remain ... the one with the longest history and the largest number of treated patients," says Sarah Donaldson, MD, Stanford professor of radiation oncology and past president of the American Society for Therapeutic Radiology and Oncology.

Donaldson conducted the first study to follow the effectiveness of radiation treatment for Graves' ophthalmopathy, which began in the late 1950s under the direction of Malcolm Bagshaw, MD, former director of Stanford's radiation oncology department, and the late Joseph P. Kriss, MD, professor of nuclear medicine and a specialist in thyroid disease.

The interdepartmental cooperation continues today. Donaldson, Levin and thyroid specialist I. Ross McDougall, MD, PhD, collaborate on the diagnosis and treatment of each Graves' disease patient who comes under their care. The teamwork has contributed to the success of more than 400 patients who have undergone radiation therapy for Graves' ophthalmopathy at Stanford, Donaldson says.

"Our opinion has always been that we should treat ophthalmopathy if it's progressive -- not if it's stable, but if it continues to get worse and there are signs and symptoms that ... a functional impairment may affect the patients' ability to perform a job, take care of themselves or live independently," Donaldson says.

"By using the treatment selectively," she says, "80 to 90 percent of our patients have their worrisome, troublesome problems go away."

-- Alana Mikkelsen