The researchers examined the wheat and calculated that about three hundred milligrams of Heliotropium seeds had made their way into every kilogram of wheat. Analysis of the Heliotropium plant showed substances called pyrrolizidine alkaloids, which cause inflammation of the small hepatic veins, one cause of the Budd-Chiari syndrome. Hundreds of plant species contain these toxic alkaloids, but most come from those known as Senecio, Crotalaria, and Heliotropium.
The first reported case of veno-occlusive disease of the liver, in South Africa in 1920, was caused by eating bread contaminated with Senecio plants; veterinarians have diagnosed the same problem in livestock since the 1950s. In the mid-1970s in India, a moderately large outbreak of Budd-Chiari syndrome was nearly a carbon copy of the Afghan epidemic. This one occurred in the drought-prone Sarguja district in north-central India, where 486 people lived in four villages. The dietary staple is a cereal called gondli. The cereal in the district became contaminated with a wild plant of the Crotalaria group, and an investigation was begun after some villagers developed ascites and swollen livers. Of the sixty-seven affected villagers, twenty-eight died (a mortality rate of 42 percent). The specimens from liver biopsies as well as examination by autopsy of the fatal cases were all consistent with veno-occlusive disease of the liver.
More recently, in Iraq in 1993, a family of Bedouins living near the city of Mosul placed some of their grain under their dwellings, a traditional practice for storing grain to be consumed later, during the winter. As in the Afghanistan epidemic, the Bedouins had unwittingly mixed some Senecio weeds in with the wheat. During the winter of 1994, fourteen of them were admitted to the hospital with massive ascites and enlarged livers; two of them died.
Budd-Chiari syndrome from veno-occlusive disease brought on by these toxic alkaloids is not only a third-world phenomenon, and it is not only related to inadvertent consumption of tainted grains. In 1976, a twenty-six-year-old transplant to Britain from the Caribbean islands developed ascites and liver disease. She was found to be “addicted” to maté, a Paraguayan tea that she had been taking for years made from the leaves of various species of Ilex plants. After two liver biopsies and finally a portal shunt procedure, she ultimately died from her disease. Samples of this maté tea, both bought at stores as well as some that was owned by the woman, tested positive for pyrrolizidine alkaloids.
Not long thereafter, reports were published of two Arizona infants who died from liver disease after they were given herbal teas for a cough. The first case was that of a six-month-old Latino girl who was admitted to a Tucson hospital because of vomiting and irritability. Two weeks earlier the child had visited the pediatrician for a probable upper respiratory viral infection. On admission to the hospital, the child had an enlarged liver and massive ascites. A liver biopsy and other test results were consistent with veno-occlusive disease of the liver. On questioning, the child’s parents admitted to feeding her large quantities of a tea prepared from a local herb called gordolobo yerba. When the tea was analyzed in the laboratory, it was found that the tea was in fact made from a Senecio plant.
The second case was that of a two-month-old infant admitted to a Phoenix hospital for a one-day history of lethargy and vomiting. The doctors found massive ascites and liver damage. Despite intensive therapy, the child died. The parents had been giving the child an herbal preparation for a cough. The tea was sold at a local pharmacy; on analysis, it was found to contain the same Senecio plant as in the other Arizona case.
The common denominator among these deadly plants and herbs was that they all contained a toxin from the group called pyrrolizidine alkaloids. These substances cause inflammation of the hepatic veins that drain blood away from the liver and back to the heart. They can lead to potentially deadly scarring and obstruction of venous flow. Despite these cases, the concept of a Budd-Chiari syndrome from a toxic plant was still off the radar screen of most physicians in 1982. In a lengthy review of the syndrome published in a major journal in that year, only a few sentences were devoted to the subject of the plants.
Aware of the Jamaican bush tea episode and now focused on their patient’s penchant for herbal teas and natural remedies, the Harvard doctors and their student were intrigued that this might be the potential link to her condition. As a medical student, Ridker had the most time on his hands. Young recalls that he “asked me to bring everything that I used.”
After the patient complied, Ridker reviewed exactly what herbal preparations Joanne was taking. “There was a long list,” he recalls. “I went around to the various health food stores where she shopped and bought the different preparations that she used. Then I spent days at Harvard Medical School’s botany library trying to identify the substances.”
There were, as it turned out, two suspicious preparations: a tea called MU-16 and comfrey-pepsin capsules. Because she enjoyed the taste so much, Joanne had been drinking three cups of tea per day for about six months before first seeing her doctor in April 1981. She had also been taking two of the capsules with each meal, to help digestion. The doctors sent samples of these preparations to Dr. Ryan Huxtable, a pharmacologist in Arizona with special expertise in pyrrolizidine alkaloid toxicity. The MU-16 tea, which was supposed to be ginseng, contained large amounts of pyrrolizidine alkaloids. Samples from different lots purchased at different times contained varying amounts of the toxic alkaloids, suggesting poor quality control by the manufacturer. The comfrey-pepsin capsules contained even larger amounts of the toxic alkaloids.
Unwittingly, Joanne Young had been poisoning herself over the four months before she got ill. She had been drinking as much as a quart of the MU-16 per day, in addition to taking six capsules of the comfreypepsin.
She is not the only patient to suffer serious side effects from comfrey. In 1986, a thirteen-year-old boy with inflammatory bowel disease decided to go off the medications prescribed by his physicians and started using acupuncture and ingesting large quantities of tea prepared from comfrey root. In June of that year, he developed profound fatigue, weight loss, and abdominal pain. His liver swelled and he developed massive ascites.
In 1978, a New York social worker consulted a homeopathic doctor because of allergies and feelings of fatigue. The doctor recommended comfrey tea. Four years later, blood tests showed mild abnormalities in her liver. Four years after that, in 1986, she developed ascites. Paracentesis was nondiagnostic, and the ascites persisted. Like Joanne Young, the social worker also required a surgical shunt to treat her intractable ascites. Her liver specialist saw her drinking herbal tea while she was being admitted for the shunt treatment. When he witnessed this, according to the patient, “It was like a light bulb went off in his head. He almost yelled at me, ‘Don’t take that stuff; it could ruin your liver.’ I was taking quite a bit of it.” Like Young, once the diagnosis was established, she stopped taking the comfrey and recovered.
Comfrey, Symphytum officinale, is a perennial bush native to Europe and Asia. The plant grows to between two and five feet tall, with oblong leaves and dull purple or white flowers that bloom in tight clusters. The root is fleshy and filled with a white liquid. Its roots and leaves contain a substance called allantoin, which has been used to maintain healthy skin and to treat pulled muscles and ligaments as well as sprains and fractures. People use it both as a topical ointment and as an oral preparation. There is no scientific data to support any of these uses. At the time that Joanne Young was taking her comfrey, the herb was completely unregulated. Because comfrey was on the market prior to 1958, when legislation governing food additives was passed, it was exempt from FDA regulations.
It is also difficult to know exactly what one is consuming in comfrey and other herbal preparations. For one thing, many of these potions are not standardized like typical pharmaceuticals. Batches of teas made from leaves of plants can be contaminated with other plants, and leaves harvested in one season may differ considerably in their active ingredients from those harvested at another time of year.
There is also th
e risk of simple misidentification. One elderly couple from Washington state went to a health spa, where it was recommended that they drink comfrey tea for their arthritis. So they went hunting for natural comfrey in the forest. On May 7, 1977, the wife picked some plants that she believed were comfrey and brewed a tea, which they both drank. Within an hour, they were both seized by nausea, vomiting, dizziness, and sweating.
The husband, who knew more about plants than his wife, went to the refrigerator a few hours later and realized that the leaves were not comfrey at all, but foxglove. This plant, which superficially resembles comfrey, is the source of the powerful cardiac drug digitalis. He immediately called an ambulance, but by the time it arrived, his wife was dead. The husband made it to the hospital, but despite intensive treatment, he too died less than a day later.
Herbal remedies are a $1.8 billion industry in the United States alone. There is a general notion that if a substance is natural, or herbal, then it must be safe; this is clearly a misconception. Many different herbal preparations have serious health risks. Some lead to problems with blood coagulation. Others lead to acute hepatitis and gastroenteritis. Still others cause lethal cardiac conditions, and others lead to neurological symptoms. Many of them can be fatal. There are numerous case reports of herbs that have led to serious health consequences. One involved a life-threatening allergic reaction to chamomile. Another was the case of a newborn that died from veno-occlusive disease of the liver related to herbal tea her mother consumed during pregnancy.
Not long after the incident with Joanne, Dr. Ridker, now a professor at Harvard himself, said, “Nobody should drink comfrey. Even small amounts can have disastrous effects. There is just no risk to benefit ratio.” In July 2001, more than a decade after Joanne Young nearly died from using it, the FDA banned all oral comfrey preparations. Its advisory reads: “[The] FDA believes that the available scientific information is sufficient to firmly establish that dietary supplements that contain comfrey or any other source of pyrrolizidine alkaloids are adulterated. . . . The agency strongly recommends that firms marketing a product containing comfrey or another source of pyrrolizidine alkaloids remove the product from the market and alert its customers to immediately stop using the product. The agency advises that it is prepared to use its authority and resources to remove products from the market.” Many other countries have taken the same step.
As soon as the doctors learned the cause of Joanne’s liver ailment, they strongly recommended that she stop consuming comfrey, the substance that she had been taking to improve her health. She complied, of course, and she is now in good health—and shows no trace whatsoever of ascites. As for her penchant for herbal teas, she will enjoy a cup of chamomile tea from time to time. During the summer, she may have a glass of Red Zinger. Otherwise, she’s off herbs.
14 Little Luisa’s Blinding Headache
It all started as a perfectly routine case. Luisa Alvarez-Ruiz (as I’ll call her) was a five-year-old girl whose family brought her to the emergency department because of a headache. Among the long list of symptoms that bring patients to a doctor’s attention, headache is one of the most common. So the doctors began asking their usual questions and taking their normal measurements. However, they did not find anything particularly worrisome in the responses and metrics, and her physical examination seemed to be normal. But for some reason, in part because Luisa’s headaches had been present for a few months, the first pediatric emergency physicians who were taking care of Luisa were anxious; that sixth sense that all good doctors have was registering concern.
Head pain is nearly ubiquitous in human beings, and it is a rare individual who has never experienced a headache at some point. The vast majority of headaches are not severe in the sense that, if untreated, they will not cause death or loss of neurological or visual function. Most of these patients have tension-related or migraine headaches. These two “primary” headache disorders are incredibly common; the annual incidence of migraine alone in the general population is approximately 12 percent, and even higher in women. The lifetime incidence of migraine ranges from about 18 percent in men to 45 percent in women. Of course most of these patients never end up in an emergency room for these headaches.
But some do. One would expect that patients whose headaches are severe enough to bring them to an emergency department would have more serious causes, but even in this group, only about 5 percent of them are diagnosed with a life- or brain-threatening problem. When a patient with a headache does come to the hospital, the physician first goes through a series of questions designed to establish a particular diagnosis. Did the pain start abruptly or gradually? How severe is the pain? Is it the worst that the patient has ever had? Is the quality of the pain similar to prior episodes? Is there associated fever, or vomiting or any new neurological symptoms? After factoring in the answers to these and other questions, the physician will then perform a physical examination, again hoping to pinpoint the cause. The vast majority of migraine and tension headache sufferers have normal physical exams. By the end of the history and the physical, patients usually fall into one of three groups.
At one extreme is the group that has no worrisome features. The headache sounds familiar to prior episodes or the characteristics are classic for migraine or tension syndromes; the physical examination is normal. These patients need treatment for their pain and follow-up with their primary care doctor. On the other extreme is a group with obvious, clear-cut worrisome findings. They have a new onset of a worstever unusual headache, or perhaps a new abnormality in their neurological examination, a high fever, or some other symptom or sign that strongly suggests a serious problem. The decision-making in this group is easy; these patients need further testing and treatment until the source of the finding is explained. And then there are patients who fall into a third, intermediate group. When the doctor factors in all the information available, the patients simply do not fall neatly into the first or the second group. The need to do further testing is ambiguous.
Most of the patients in this last group turn out to have simple problems that do not threaten their vision, brain, or life. A few, however, will have serious neurological dangers that need to be addressed, and which, if not diagnosed and treated properly, can end catastrophically.
Sometimes, in ambiguous cases, a doctor will decide to do further testing, just to be safe. Other times, he or she may simply arrange a follow-up appointment with the person’s primary care physician in the next few days and use time as a diagnostic tool. One other “test” that is sometimes available is a consultation with a specialist, such as a neurologist. This is what the emergency physicians decided to do in Luisa’s case.
“That was the point where I became involved,” recalls Dr. David Urion, a pediatric neurologist at Boston’s prestigious Children’s Hospital. “She came to the ED [emergency department] complaining of this headache that lasted for several months. The ED staff had already evaluated her but did not come up with a diagnosis. What they found was that the pain itself was fairly nondescript. The headache was ‘all over’ but more in the front and behind the eyes. It seemed to be a ‘pressure’ and it began very insidiously a few months ago. She was Latina and was accompanied by a hoard of family members—both of the parents, her grandmother, and a few cousins. The relatives did not seem to know exactly what we meant when we used the word ‘headache.’
“The pain was constant over time but seemed to wax and wane over the course of the day. She had some sensitivity to light, but there were no clear things that made the headache better or worse. She also had some nausea but no vomiting. They also had determined that there was no history of head trauma and no recent illnesses that seemed relevant. Also there was no family history of headaches in general, and specifically, no family history of migraine.
“Developmentally she was normal. One other thing that the family noticed was that she seemed clumsy and that she was bumping into things lately. When the doctors in the ED did their physical examination, it was
normal. Specifically her neurological examination was normal. The ED staff was properly concerned so they asked for a neurology consult,” recalls Dr. Urion, sitting in his neatly kept office on a top floor of a stately marble and granite building on the quadrangle of Harvard Medical School. Although Luisa’s case had occurred several years before the interview, it stood out in Urion’s memory such that he remembered the minute details with remarkable clarity.
Urion continues, “One question that all the doctors asked was, ‘did she take any medications?’ She did not. The only other piece of history that the neurology fellow obtained that the ED staff had not was an unusual social circumstance. The child lived with the parents in Boston every other month, and on the alternate months, she lived with her grandmother in New York, the Bronx I think.
“The ED fellow got a negative exam and the ED attending got a negative exam. The neurology resident also got a normal exam, and I found no venous pulsations (all had looked), but no frank papilledema.”
Papilledema is an ominous finding indeed. Checking the eyes is an important part of the neurological examination, especially in headache patients. Doctors look at the lids to see if they droop, and check the pupils to see if their reaction to bright light is normal. They ask the patients to look to the right and then to the left, up and down, to check the nerves that control the muscles that move the eyes. And they look at the retina using an ophthalmoscope. This instrument was invented in 1851 and both literally and figuratively opened up an entire new diagnostic world for physicians. The ophthalmoscope is the small cylindrical handheld instrument that the doctor holds close to the patient’s eye—within a half an inch or so—and then shines a light into the retina. The scope is designed so that the path of light and the aperture through which the physician looks are perfectly aligned, allowing a view of the retina.
The Deadly Dinner Party: and Other Medical Detective Stories Page 22