A life-or-death situation: Family poisoned by mushrooms first to receive experimental treatment
By Jondi Gumz
Santa Cruz Sentinel staff writer
January 14, 2007
When a family of six showed up at Dominican Hospital complaining of nausea, vomiting and diarrhea, it was more than a routine case for doctors Todd Mitchell and Wendy Knapp.
Once they heard all six had eaten tacos made with wild mushrooms, they knew what to suspect. Most likely the family had eaten "death cap" mushrooms, a fungus that could destroy their liver and kidneys and eventually cause death.
The hard part was telling the family. "Oh my God," said one family member, a 29-year-old man. "I just ate a ton of this stuff. Am I going to need a liver transplant? Am I going to die?"
The family, ranging in age from 17 to 83, lives in Aptos. They had picked several varieties of mushrooms in Wilder Ranch State Park on New Year's Day. Now they faced the fight of their lives. In the United States, there is no known antidote for mushroom poisoning. Unless doctors could find one, the meal they had eaten could be their last.
Even experts can mistake Amanita phalloides, known as the "death cap," for similar-looking nontoxic mushrooms. Ten years ago, one person in Santa Cruz County and another in Sonoma County died after eating death cap mushrooms. Five years ago, a couple from Jordan visiting Watsonville fell gravely ill and spent weeks in the hospital before recovering. Typically, wild mushrooms appear in wooded areas in Northern California late in December or early January. Often people who pick them are immigrant families familiar with mushrooms in their native country. Of the 5,000 known mushroom species, about 100 are poisonous, with the death cap accounting for most fatalities. Mushroom poisoning sent nearly 400 people to the hospital in California last year. For Mitchell, who had worked at Dominican Hospital for 10 years, this case was his first. Mitchell, 49, is married with three children, ages 14, 12 and 9. He's slender with short brownish hair. If he has to work late, he likes to eat at Cafe La Vie for its vegetarian entrees. He knows medical miracles are possible. The staff at Dominican Hospital, he said after finishing a salad late one Friday night, saved the life of his wife last year.
The way doctors confirm mushroom poisoning is with a blood test. When the Aptos family came into the hospital January 2, the levels of liver enzymes were in a normal range, from 25-50. Six hours later, the numbers jumped into the 100s, and doubled every six hours after that. Those counts were like fingerprints, confirming the presence of "amatoxin" poison. Even when the uneaten mushrooms were brought in for the doctors to examine, and none was a death cap, Mitchell and Knapp felt it was prudent to "prepare for the worst and hope for the best". Like an overdose of the painkiller Tylenol, amatoxin shuts down the liver over a period of days. Mitchell knew of no "ironclad" antidote. He could not give the family any guarantees. "We're going to do everything humanly possible," the two physicians told the family. "We're pulling out all the stops."
The morning after being admitted to the hospital, the patients were feeling better, but they actually were getting more sick. The toxin was binding to the RNA in their cells, shutting down the liver's normal operations, and refusing to let go. The liver turns food into chemical components for use in other parts of the body, stores sugar and vitamins and filters waste and poisons out of the bloodstream. Without a liver, the body can't function.
Mitchell is not only a physician, he's also a volunteer at Mount Madonna School, run by a spiritual community. Asked if he's the kind of doctor who turns to prayer, he demurred. "If it's God's will for them to recover, they will," he said. "If it's not, they won't. It's not kosher for me to determine what's God's will. My time is better spent figuring out what they need to heal."
Into the night that Tuesday and early Wednesday morning, Mitchell looked for information. Using Google Scholar, a search engine of scholarly literature, he found a promising avenue of treatment: Extract from milk thistle, a nuisance weed for farmers and used as a liver tonic in European folk medicine. Milk thistle extract, or silymarin, has been used in Europe to treat cirrhosis of the liver, scarring that often proves fatal. In a 1970s experiment, beagles that received milk thistle intravenously were protected from mushroom poisoning. That treatment, intravenous milk thistle extract, is not available in the United States and is not approved by the Food and Drug Administration. Mitchell found a pharmaceutical company, Madaus Pharma, in Brussels, Belgium, that produced Legalon-Sil, milk thistle extract in an intravenous form. But it was too late to call because of the time difference.
Very early Wednesday morning, Mitchell called the company and got the number of its office in Germany, where the drug is approved for use. He reached Peter Odenthal of Madaus in Cologne, Germany, and explained the situation. It was already afternoon in Germany. Odenthal agreed to donate enough Legalon to treat all six family members. Shortly thereafter, Mitchell got a call from Joe Veilleux, U.S. president of Madaus whose office is in Pittsburgh. It was bad news. The medication could be stopped at the border unless the FDA approved its use. "You can't ship over anything you want even if it's a dire emergency," said Veilleux. "Unfortunately it's not registered for us here. It's awfully expensive to do."
He referred Mitchell to a researcher at the National Institutes of Health. NIH, a federal agency and one of the world's foremost research centers, takes the position that there is not enough evidence that milk thistle has medical benefits. The agency says studies of oral milk thistle conducted outside the United States are flawed. A multi-year study of using milk thistle orally to treat hepatitis, a liver disease, is in the beginning stages in the United States. It has the support of the National Advisory Council for Complementary and Alternative Medicine. If the FDA granted an emergency IND number, identifying Legalon as an investigative new drug, the medication could be shipped to California. Mitchell also had read up on oral milk thistle in capsules. The FDA hasn't approved that either, but a lot of companies sell milk thistle extract in that form as a supplement. One of them was right in Santa Cruz: Aloha Medicinals. Once the clock ticked past 8 a.m., when the company opens for business, Mitchell called and spoke to company president Megan Powers. Research director John Holliday responded almost immediately, delivering a case of Aloha's Bio-Silymarin to Dominican Hospital. Usually it costs $12.95 for a bottle of 60 capsules. In this case, there was no charge.
The patients began taking the capsules that day, but Mitchell wasn't sure it would be enough. The patients were already nauseous and vomiting. Candace Walker, the medical librarian at Dominican Hospital, faxed information to the FDA about the patients, their conditions and the lab data to bolster Mitchell's request for an emergency IND number.
But the FDA wasn't the only roadblock. Mitchell would have to get approval from the Institutional Review Board at Dominican Hospital to administer an investigational drug. The board consists of a dozen people, including community members, who consider safety and ethics of using something experimental. Members heard the results with Legalon in Germany were promising. They heard that the patients had signed a form consenting to its use. They too gave their consent. It seemed worth a try. That same day, the FDA granted the permission needed. Under FDA regulations, the agency doesn't discuss investigative new drugs but Madaus Pharma confirmed that the approval came swiftly. "Surprisingly he was able to get this within a matter of hours," said Veilleux. "People were asking me, 'What are the chances he'll get permission?' I said, one in 1,000."
Increasing the odds
While Mitchell was pursuing the German medication, Knapp was doing her best to advocate for her patients. Like Mitchell, she is a "hospitalist" specializing in the case of hospital inpatients. At 42, she has been a doctor for 10 years. She also is a mom with one child. She called the Poison Control Center, which located a one-day supply of injectable milk thistle at a compounding pharmacy in New Jersey. Unlike Madaus, the company was not willing to donate its product. Carl Washburn, the pharmacist at Dominican Hospital, put the order on his personal credit card with the blessing of the new president, Dr. Nanette Mickiewicz. Everyone hoped it would arrive in time.
By Wednesday evening, some of the patients were much more sick. If any of them suffered liver failure, a liver transplant would be their only chance to survive. Those operations are done only at institutions with transplant specialists, not at general hospitals like Dominican. Knapp got on the phone, calling to find a medical center where a doctor would accept the patients — not an easy task. Often when multiple patients require treatment, they are divided among hospitals so as not to overwhelm a single institution. She found Dr. Robert Gish at the Transplantation Center at California Pacific Medical Center. When Gish agreed to take all six patients and to use Legalon, even though it was experimental, the two doctors at Dominican felt a sense of relief. If any hospital could increase the odds for the family in Santa Cruz, it was Pacific Medical. It was a place with liver experts and facilities for liver transplants.
Another doctor, Maurizio Bonacini, had treated 17 mushroom poisoning cases in four years. In eight of those cases, people who were severely ill recovered without needing a liver transplant. The quicker the treatment, the better the outcome, Bonacini found. He had co-authored a paper on the subject for the American Gastroenterological Association. But there weren't enough beds for all six. Five patients were taken to San Francisco, and one stayed behind in Santa Cruz. Mitchell got on the phone to Veilleux at Madaus asking him to reroute the medication to San Francisco.
By the time the FDA had given its OK to administer Legalon, it was too late in Germany for Madaus to ship the medication by FedEx. So Veilleux arranged for a personal courier to pick up the product and board a plane early Thursday morning to San Francisco. The antidote fit into a box about the size of four shoe boxes. The plane ticket cost 3,600 Euros — about $5,000. Veilleux didn't want to wait until the next morning for the FedEx office to open. "Every hour could mean something," he said. Mitchell is astonished by how much cooperation he got. "Everyone grasped the gravity of the situation and worked to cut red tape," he said. He didn't realize there was still red tape ahead.
On Thursday morning, Mitchell called for an ambulance to take the last patient to San Francisco. None was available. Shortly after 2 p.m., Mitchell got more bad news: Highway 17 was closed. An armored truck had crashed, closing the northbound lanes. The backup was immense. Mitchell looked into helicopter transport. Too windy. That left one option: Highway 1. An ambulance departed at 5 p.m. Thursday, carrying the patient and the one-day supply of injectable milk thistle to San Francisco. Its lights were flashing and sirens sounding.
In San Francisco, the treatment included the Legalon milk thistle delivered by courier and three other medications: the antidote for an overdose of Tylenol, penicillin and activated charcoal. Some of the patients didn't receive any penicillin because of allergies. Two of the six patients got well very quickly. Bonacini, who took over their care a week ago Friday, said he felt they could have recovered just as well at Dominican. But it appeared one patient, the 29-year-old man, would need a liver transplant. Doctors looked for donor organs and even got offers.
Bonacini reserved the Legalon for the two sickest patients, the 29-year-old and the eldest. The eldest was not a good candidate for a liver transplant because of her age. She was 83, and 70 is "about the limit," according to Bonacini. Two more patients were released Wednesday. By Thursday, the 29-year-old had improved enough to go home. The matriarch of the family, the eldest patient, died that same day. The poison moved from her liver to her kidney, the organ that makes urine and discharges waste from the body. Ironically, her liver appeared to recover at the same time her kidneys failed. The hospitals have not released the names of the family members because of the federal laws on patient privacy. "I'm humbled by a poison as powerful as amatoxin," Mitchell said.
Mitchell learned Friday that these patients from Aptos were the first in America to be treated with intravenous milk thistle extract for mushroom poisoning. "We took a path not previously blazed," he said. He and his physician colleague, Wendy Knapp, are sad that one patient died, but elated to have five survive — and be spared a liver transplant. The experience may pave the way for broader changes. "We're going to work closely with the Poison Control Center, Madaus and the FDA to allow us to maintain a supply of this medicine in Northern California so it's available to be used within 12-24 hours," Mitchell said. If intravenous milk thistle is more readily accessible, doctors can gather more data on its effectiveness. "At the end of the day, we can't say whether it was the silymarin or dumb luck," Mitchell said. "But we can say folks at Dominican Hospital know how to pull together in a crisis, and when that happens, extraordinary things can happen."
Contact Jondi Gumz at firstname.lastname@example.org.
What science says
Some studies have looked at the effect of milk thistle on liver disease in humans, but these have been small. Some promising data have been reported, but results are mixed. Some studies conducted outside the United States support claims of oral milk thistle to improve liver function, but there have been flaws in study design and reporting. The National Center for Complementary and Alternative Medicine is supporting a research study to better understand the use of milk thistle for chronic hepatitis C. With the National Institute of Diabetes and Digestive and Kidney Diseases, the center is planning further studies of milk thistle for chronic hepatitis C and nonalcoholic liver disease. The National Cancer Institute and the National Institute of Nursing Research are studying milk thistle for cancer prevention and to treat complications in HIV patients. Side effects In clinical trials, milk thistle generally has few side effects. Occasionally, people report a laxative effect, upset stomach, diarrhea and bloating. Milk thistle can produce allergic reactions, which tend to be more common among people who are allergic to plants in the same family such as ragweed, chrysanthemum and daisies.
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