The Last Supper

Want to know What meal ended the House of Habsburg and was said by Voltaire to have changed the destiny of Europe? The risks associated with foraging, and what milk thistle might be an antidote for? 

Listen to find out!

Transcript

This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patient survive this podcast? It’s up to you and the choices you make. 

Want to know What meal ended the House of Habsburg and was said by Voltaire to have changed the destiny of Europe? The risks associated with foraging, and what milk thistle might be an antidote for? Listen to find out!

Today's episode starts in the emergency department. The intern says, "I need to tell you about the patient in room six. She's yellow." He says it’s a 35-year-old woman complaining of nausea and vomiting since last night. She has right upper quadrant abdominal pain along with dark-colored urine. She denies constipation or diarrhea. No fever. He says her vital signs are as follows: Temperature 98.6°F (37°C), heart rate 115 beats per minute, blood pressure 90/60, respiratory rate 18, and pulse ox 100% on room air.

In the room, the patient is sitting on the stretcher, awake and alert, she does indeed have a yellow tint to her skin as well as the whites of her eyes. On exam, her lungs are clear, her heart is mildly fast but otherwise normal and she has some tenderness in the right upper quadrant. 

Quick side note: When we examine the abdomen, we divide it into four quadrants with imaginary vertical and horizontal lines drawn through the belly button. The right upper quadrant has the liver and gallbladder. The left upper quadrant the stomach and spleen. The right lower quadrant is where the appendix is located. Both lower quadrants contain intestines and pelvic organs. It helps us localize which disease processes may be more likely. So her pain is in the area of the liver and the gallbladder.

She confirms the resident's history, she has no medical problems, doesn't take any medicines, and has no allergies. She's not taking any supplements or over-the-counter medicines. She denies tobacco, alcohol, and drugs.

The obvious problem here is the yellow color of her skin and eyes. The medical term is jaundice and scleral icterus is the word for yellow eyes. Specifically, the whites of the eye. The eye color itself doesn't change.

Question 1. What does jaundice indicate? I bet you know. 

A, a stomach ulcer

B, radiation exposure

C, liver disease

Answer. C. Jaundice is a classic indication of liver disease. Let's get some things started, then come back to what might be happening with our patient. The intern orders some basic labs, including, liver function tests. You want a urinalysis to look for blood or bilirubin in the urine, which could be making it dark. He's ordered an IV, IV fluids, and medicine for pain and nausea. 

She needs imaging, I'd start with a right upper quadrant ultrasound, but if you want to do a CT scan of her abdomen, that would be fine too. The right upper quadrant ultrasound looks at the gallbladder, the biliary ducts, and gives an overview of the liver.

With the workup pending, let's talk about causes of jaundice. What it actually is, is an excessive amount of bilirubin. Bilirubin is found inside red blood cells and in bile. It happens to be yellow in color. So if you have extra bilirubin, for whatever the reason, your skin and eyes turn yellow.

 What causes excessive bilirubin? You can break it down into things outside and inside the liver. Outside, you can have too much bilirubin spilling out of red cells. If you have anemia, not iron deficiency, but types where red blood cells are broken down, like hemolytic anemia, then bilirubin is released. Patients with sickle cell or beta thalassemia can have elevated levels for this reason. 

I'm sure you've heard of neonatal jaundice where the babies might need light therapy. This is because in the first few days of life, babies have trouble breaking down and processing bilirubin normally. A gallstone which gets stuck in the common bile duct, the duct between the gallbladder and the liver, called choledocholithiasis can cause jaundice. Patients do have significant abdominal pain with this. Cholangitis is an infection in the bile ducts. This is a true emergency, but is associated with fever which she doesn’t have.

Within the liver, it can be caused by infections like hepatitis A, B, or C. You can get parasitic infections which can cause it, ascaris and liver flukes for example. Cancer. And of course, the very common, classic culprit: alcohol. 

The patient denies alcohol use. She doesn't have cancer or a fever. The intern ordered tests for Hepatitis A, B, and C. B and C, as you know, are transferred via bodily fluids. Hep A, however, comes from eating infected shellfish, often times oysters. Hepatitis tests take a few days to come back, but she doesn't have risk factors for sexually transmitted infection, She denies recently eating shellfish and she hasn't traveled to areas where liver parasites are endemic. The cause the cause of her jaundice is not entirely clear at this point.

An hour later, you get her lab results. Her blood counts are normal, including her red blood cell count, ruling out hemolytic anemia. Her chemistry panel and her creatinine are normal; no evidence of kidney failure. Not surprisingly, her liver function tests are elevated. Very elevated her ALT and AST are 5,000 units/L each. Normal is 50 or less. Her total bilirubin is 5 mg/dL, Normal is 1 mg/dL or less. So, this is moderately elevated, enough to give her jaundice, but not dramatically high.

Common things being common. Is this alcohol? She said no. Do you believe her? We're taught in medical school to always take what the patients say at face value, but unfortunately, in the emergency department, this practice doesn't always work. First, even if she does have an undisclosed alcohol use disorder or coma, she's still pretty young to have hepatitis, not impossible but not likely. 

There is a little trick you can do with the liver function tests to raise or lower your suspicion for alcohol. Far from Definitive, but useful to consider. It’s the ratio of the AST to the ALT. If AST is twice as high the ALT, this strongly suggests that the cause of hepatitis is alcohol. With most other causes of liver disease, the ALT and AST go up roughly the same amount. It's not always true, and if you don't see it, it doesn't mean it's not alcoholic hepatitis. But taken in combination with her history, it supports focusing on other etiologies.  

The intern tells you her ultrasound comes back normal, there's no sign of gallbladder disease, gallstones, and the liver looks normal on the ultrasound. The patient continues to have abdominal pain and she's still vomiting. It will take days to rule out medical causes, let's skip ahead and I'll tell you that work up is negative, because of course this isn't a hepatology or gastroenterology podcast. It's a toxicology podcast. Time to focus on toxins.

Before we do that, I should probably clarify the difference between acute and chronic liver failure, as well as some of the terms I've been using, like hepatitis and cirrhosis. Acute liver failure is something that happens over days, so for example, if you eat oysters, you contract hepatitis A, you develop acute liver failure. Hepatitis means inflammation or infection in the liver. Then there is chronic liver disease, this would be classically from something like alcohol, or Hep C which can cause cirrhosis when the liver is so damaged scarring, called fibrosis, replaces healthy tissue. The scarred fibrotic tissue is similar to a scar on your arm. It holds everything together, but it doesn't do much else.

How do we tell the difference? Well, mainly, of course, by history, based on how long the patient has had symptoms and what's the source of the liver disease. But as I said, patients may not always be forthcoming. And if a person has chronic liver disease and cirrhosis, there are many, many physical exam findings that tell you this has been long-standing in nature. They're called the stigmata of liver disease, we all learn about them in medical school, and we've all seen them on our patients. In addition to jaundice, you see abdominal swelling from ascites or fluid in the abdominal cavity. This is often in combination with skinny arms and legs due to muscle wasting. You see broken blood vessels, which are called spider angioma in medical terms. Caput Medusa is the name for enlarged veins descending out from the belly button. Medusa, like the snakes from her head. You can see gynecomastia or breast enlargement in men. Our patient doesn't have any of this. I’d call this hepatitis right now, her liver problem is clearly acute, based on both history and physical exam. 

Question number 2. When we think about liver disease and toxicology, what's the first and most important toxin we need to ask about?

 A. Ibuprofen ie Motrin

B. Acetaminophen or paracetamol, ie Tylenol

C. Diphenhydramine ie Benadryl

D. dextromethorphan, in cough syrup

Answer: A. acetaminophen, paracetamol, or Tylenol. It's over-the-counter, easy to get and of course famously causes liver failure. In a young healthy person with otherwise unexplained liver failure. This is numbers 1-10 at the top of your list until you rule it out. That said, she denies exposure. You can always send a level to check, but it's not likely the source here.

We have a lot of unanswered questions, but in the short term, she needs to stay in the hospital. You call your hospitalist colleagues, and they work on getting her upstairs. They do want a toxicology consult. You have a lot more work to do to figure out what's happening here.

You pull out your 50-pound Goldfrank's Toxicologic Emergencies, i.e., the toxicology bible, and open to the table with poisons causing liver disease. There are about 150 compounds listed, and the table notes it's only selected xenobiotics, meaning not all of them. If you'd rather look online, you could check the NIH's website LiverTox, another amazing resource, Summarizing the available medical literature on things causing hepatotoxicity or liver disease. Their list of toxins numbers in the thousands. 

Where should we start? Well, you can do it however you want, but I like to start with common things being common. There are a number of antibiotics on the list, she denies any recent use. Iron is something that many young women take. It does cause liver failure, but only an overdose. Steroids are a really classic cause of liver disease. We think about anabolic steroids and bodybuilders because they take very large doses. But also, oral contraceptives are possible, though this is pretty rare. She says she isn't on birth control. All right, well, if she's not on birth control, we might think about abortifacients in a woman of childbearing age.

Now, whatever your position on abortion, this is not a discussion about that. Women have been using herbs to end pregnancies since ancient times, and many of these cause liver failure. You may be aware that abortion laws have been changing recently in the United States, requiring increased awareness of this topic especially by ER doctors, toxicologists and OBGYNs, because if women don't have access via healthcare, they often choose alternative sources. Penny Royal Tea, I'm sure you've heard of, but also other herbs like Blue Cohosh and rue can cause liver failure. 

Other causes of liver disease include Anti-epileptics or seizure drugs which can be pretty toxic to the liver. Sometimes these are used as mood stabilizers.

Question 3. Heavy metals can be a culprit, including which two from the following list? 

A.    Copper 

B.     Gold. 

C.     Bismuth

Answer  A and B copper, gold. Both can cause liver problems. We talked about vitamin A toxicity causing liver failure, especially if you eat polar bear liver. Chemotherapeutic agents.

Okay, I said we were going to start with common things, but this list has definitely gotten into less common toxins and rare exposures. Let's stop before we get totally lost in the weeds. There is one really common thing we need to talk to her about, and that's related to her diet. 

Question 4.  We want to know if she has recently eaten which of the following? 

A.        Oranges 

B.        Carrots 

C.        Mushrooms 

D.        Canned food 

Answer: C. my burning question right now is has she eaten any mushrooms. Specifically foraged mushrooms, not regular grocery store varieties. Most of the ones we eat are cultivated, like regular white buttons or portobellos. These are totally safe. Foraged mushrooms are the issue here, because of the risk of misidentification. Many poisonings are someone looking for a delicious edible variety and mistakenly picking a toxic mushroom. Misidentification happens in a number of different ways, we'll talk about some of them as we go.

You go back in the room. She points to the man standing next to the bed, introducing him as her husband. Before you can say anything, he rushes over to the sink and starts vomiting. 

Hmm, what's happening here?

He finishes vomiting, wipes his face and sits back down. You give him an emesis basin in case he feels sick again.  You asked the patient what she ate yesterday. She says for breakfast, she had coffee and yoghurt, for lunch a turkey sandwich and dinner soup. 

What was in the soup, you ask? 

Beef, carrots, celery, and mushrooms, she says. Some spices. 

What kind of mushrooms, you ask?

She looks at her husband, and he says, "Matsutakis”

Uh-oh. 

You ask, who ate the soup. She says they had a family gathering to celebrate a milestone. Everyone ate the soup, including herself and her husband, as well as her parents and her sister. 

You ask who else is sick. A look of concern passes across her face. She looks at her phone and says everyone. 

Maybe the beef wasn't cooked enough? She asks. “Is this food poisoning?”

Could be, but not like she’s thinking. This isn’t a diarrheal illness from raw meat. 

Who cooked you ask? 

“I did,” she says. 

Where did the mushrooms come from? 

She nods at her husband. I picked them, he says. “I’m a mushroom forager.”

Oh no. I think we've gotten to the bottom of what is causing her jaundice, but this is just the beginning of her problems. And, I’m beginning to think, the families’ problem. 

There are at least hundreds, probably more like thousands, of different types of toxic mushrooms. In toxicology, we loosely group them together based on the symptoms they cause. There are mushrooms that cause seizures, these are the false morels. Mushrooms containing Psilocybin causing hallucinations. Some interact with alcohol causing nausea and vomiting. Others cause renal failure or muscle breakdown and rhabdomyolysis. Just to name a few.

The mushroom that causes liver failure, the classic mushroom toxicity is Amanita phalloides, also known as the death cap or the death angel. I would be very, very suspicious that the foraged mushrooms were not Matsutake mushrooms but rather Amanita phylloides or similar mistakenly identified by her husband. Matsutakes, as you may know, are extremely delicious. They're very expensive, and if you buy cultivated ones, safe. But they are often mistaken by foragers for Amanitas due to their similar appearance. 

Amanita phylloides is a small white mushroom found all over the world. It has a cap that can be white or yellow or greenish, a white stem and gills. It can be mistaken for several delicious mushrooms, including matsutaki and puff balls. 

Mushrooms are my most favorite food in the whole world. For my birthday every year, my husband would find a restaurant with forged mushrooms, and take me for an amazing meal to celebrate. But once I became a toxicology fellow, sadly, I had to tell him no more forged mushrooms. Just this December, the California Department of public health issued a warning about eating forage mushrooms after 35 people were poisoned, three died and three had liver transplants. Not remotely worth the risk in my opinion. 

Death caps cause about 50 to 100 deaths per year in Europe. There are fewer in the US and other places. This mainly reflects a tradition of foraging for mushrooms, particularly Eastern Europe. In the US, toxicologists and ER doctors will often tell you many patients with mushroom toxicity are immigrants of Eastern European or South Asian descent.

Why? Well, it can and does happen to anyone. But there’s a tradition of foraging in these cultures and mushrooms that might be safe to eat in Europe or in South Asia can look like Amanitas found here. 

So, how do we know if it’s Amanita toxicity? From a clinical standpoint, this is pretty consistent, including the timeline, which we'll come back to in a few minutes.

I've been asked by colleagues as well as patients to identify mushrooms. Let me clear up this misconception immediately. I am not a mycologist. I'm much better at figuring out what mushroom it is based on the patient's clinical presentation then the mushroom's appearance. 

Many health departments have arrangements with mycologists if they need to identify a mushroom. But from a toxicology standpoint, the mushroom is often missing. It's already been eaten. It's common for parents to bring in a mushroom that their child took a bite out of, asking for it to be identified. Its not happening in most ERs. We do have clinical protocols to determine who is or isn’t at risk. And just for the record, it's pretty rare for kids to accidentally take a bite of an Amanita. Usually, it's a totally benign little brown mushroom from the backyard, and the kid is fine.

It's a common call to poison centers and to emergency departments for patients to present with concern for a toxic mushroom. A classic scenario is the one above, a kid who eats something in the yard. Typically, the protocol is for observation. This can certainly be done at home if the person is fine or in the emergency department if they're symptomatic. Many mushrooms cause nausea and vomiting. It's the less toxic mushrooms that cause nausea and vomiting immediately. The patients that we're worried about with Amanita toxicity typically don't have onset of symptoms until more than six hours after ingestion. Now there is one mushroom which causes us toxicologists difficulty. It grows in the Pacific Northwest and it does have earlier onset of nausea and vomiting. It's called Amanita smithiana. But this is the one exception that I'm aware of to the six-hour cut off with toxicity onset before usually being benign and after at least raising concern for an Amanita exposure. 

Practitioners love to check the liver function tests as soon as the patient shows up to the emergency department, but this isn't usually helpful because with Amanita exposure, the liver function abnormalities don't begin until six hours after exposure, potentially even longer. If a patient has symptoms before six hours and improves with supportive care, it's perfectly reasonable to let them go home with strict return precautions. If the person is at home and has no symptoms, they can stay home but with instructions to go to the emergency department if they develop symptoms after 6 hours. 

The patient's husband continues to vomit. You tell him he better go out to triage and sign in to be seen. If we think this is Amanita toxicity, does it change our treatment? Is there an antidote?

That’s Question 6. 

A.    Yes

B.     No

Answer: no. There is no antidote, unfortunately, for Amanita toxicity. We do have some options, but let's talk about what happens with toxicity, then come back to treatment.

Amanita phyllodes mushrooms contain a number of toxic compounds, referred to as amatoxins. If you eat a mushroom, amatoxins are absorbed and taken up into liver cells. Once inside, they inhibit RNA polymerase, which interferes with DNA transcription and protein synthesis, resulting in cell death.

Oh, and it's important to note the toxins are heat stable meaning specifically cooking the mushrooms doesn't make them any less poisonous. One mushroom is enough to kill a human being. I've seen patients develop liver failure after even a bite.

Ok, so you have amatoxin exposure. The amatoxins are getting into your liver and killing off the cells. What does this look like clinically? Toxicity is divided into three phases. Phase I is Vomiting and diarrhea (looks at pretty much just like a stomach virus). As I mentioned, the key with Amanitas (with the exception of Amanita smithiana) is that it starts anywhere from 5 to 24 hours after exposure. 

In phase 2, The patient often seems to improve, vomiting and diarrhea get better, but this is when the liver function tests start to rise and the hepatic injury becomes apparent. 

Phase three is fulminant hepatic toxicity. It typically starts 2-6 days after ingestion. It can progress to complete hepatic failure, coma, coagulopathy, and bleeding as the liver is where your clotting proteins are made, and ultimately death.

Back to the treatment. This topic is always a matter of debate in toxicology. At every conference, there are studies and reviews about what maybe works or maybe doesn't work. Once again, we toxicologists are limited by the fact that we can't give death cap mushrooms to half the patients in the study to see how they respond to treatment options. When patients present with toxicity, we don't know if they took a tiny bite or ate several. We don't know exactly what species of Amanita they may have been exposed to, etc.

All toxicologists and hepatologists agree on good supportive care, but some of the other interventions generate more debate. The first thing I would use is N-acetylcysteine (NAC), which you may remember is the antidote for acetaminophen (Tylenol) overdoses. This has been studied in all sorts of types of liver failure. The data is pretty variable, with the exception of acetaminophen, for which it is a really and truly amazing antidote. Does it work for Amanita toxicity? Well, the data quite frankly is not great. But the thing about NAC is that it has very few side effects. You can have some anaphylactoid-type reactions, usually avoidable if given at a slow rate. So as long as the patient it tolerates it, I would give it. 

Another option that's debated at just about every toxicology meeting is milk thistle. There is some evidence, although again controversial, the active ingredient Silybin may be useful. There is an IV form brand name Legalon approved for use in Europe and is I think still undergoing clinical trials in the US. 

Not in a clinical trial? It's easily available in the oral form over the counter at any health food store. Does it work? Silybin studies in animals’ have shown a benefit, but benefit in humans has been difficult to prove. If your patient can tolerate oral medicine and you want to give it, I think there's very little harm as, like NAC, it has very few side effects. Other treatments that have been tried include high-dose antibiotics like penicillin, dialysis and hemofiltration, but none have proven effective and are not currently recommended.

What about a liver transplant? That's a difficult question without a good answer. If the person survives the mushroom toxicity, then their liver will regenerate and return to normal, just like after a Tylenol overdose. The data suggest about 40-60% of patients survive with standard medical care.

This means, given the limited number of organs available for transplant, no surgeon wants to rush to put a new liver in somebody who isn't seriously ill. The problem with all liver transplants is that once you're sick enough to be at the top of the list, you are often too sick to undergo or to survive the surgery. It's a tricky issue to decide if the patient is reasonably past the point where they can be expected to survive, but before the point at which they're too sick to have surgery.

What about pregnant women exposed to Amanita's? This is pretty interesting because Amatoxins don’t cross the placenta. There are a couple of case reports where the mother was significantly poisoned, but the fetus was fine. Any illness in the mother is of course an issue for the fetus, but they don't get specifically liver failure.

The intern interrupts your thoughts with a new case he wants to present. It’s your patient’s husband. Several days ago, he went foraging for wild matutake mushrooms, finding about seven, which he gave to his wife to cook in the soup. He has the same symptoms, and you guessed it - his liver function tests are very abnormal. He gets admitted. You find out several other family members are sick and have been admitted to outside hospitals. The liver function tests on both patients continue to rise precipitously. Your patient develops coagulopathy or bleeding issues due to the liver failure. She's listed for transplant. The ICU is doing everything they can to treat her, buts its really a matter of waiting to see what happens at this point. Will she improve? Get a transplant? Or not make it? 

While we wait, let’s talk about some historical cases of possible Amanita poisoning. It's been suggested that Roman emperor Claudius was poisoned this way. 

Charles VI, the Holy Roman Emperor ate a dish of sautéed mushrooms and died 10 days later of symptoms consistent with Amanita toxicity, ending the House of Habsburg and leading to the War of Austrian Succession. Voltaire said "this mushroom dish has changed the destiny of Europe”. 

I really need to do a toxicology true crime series. I came across a fascinating case 1918. A man committed several homicides for the victim’s life insurance policies, killing them with amatoxins mixed with bacteria.  

And it's not just in the past. I know some of you have been following this case in Australia because you emailed or texted me about it. The more details I read, the more interesting it gets. Initially, the news reported that several family members became ill after eating a dish of beef wellington at lunch. The woman who hosted and cooked the food is named Erin Patterson. Patterson invited her Estranged husband, his parents, and her mother's-in-laws sister and husband to lunch. At the last minute, the estranged husband backed out. The following day, everyone went to the hospital with vomiting and diarrhea, and all except Patterson herself were admitted. She refused admission. Five days later, the two older women were dead, and the father-in-law died one day later, despite a liver transplant. 

Initially, reading the reports, it seemed like this could go either way. I have taken care of whole families that were sick after someone foraged for mushrooms and unwittingly put poisonous mushrooms into shared food, killing several family members. This is what Patterson alleged happened. But the more details that came out, the more suspect it seemed. She said she purchased the mushrooms at an Asian market about a hundred miles from her house. Her food dehydrator was found in a trash bin after she was accused of poisoning the family. It showed traces of Amania phyllodes. She said she called the family together to announce a recent diagnosis of ovarian cancer, but in fact she was never diagnosed with cancer. She took several trips to areas where it was known death's caps grew. In addition, her husband accused her of trying to kill him with poison several times in the past. This was suppressed as evidence in the trial but came out afterwards. Patterson was convicted of three counts of murder and one count of attempted murder.

 Back to our patients. After two weeks, critically ill in the ICU, the patient's liver begins to show signs of improvement. Against the odds, she survives without a transplant. Her husband also survives and has no significant sequelae. But they do tell you that your patient's mother-in-law, being cared for at a different hospital, died from the poisoning. 

This is a fictional case, as are all our cases, but it is based on real patients.

I wish you could see the shirt I'm wearing in honor of this episode. It has a favorite toxicology saying, "There are old mushroom hunters and there are bold mushroom hunters, but there are no old, bold mushroom hunters."

Ok, this has been a long episode, but I hope an interesting one. Last question in today's podcast. There's a condition mimicking jaundice, causing your skin to turn yellow. Is it due to excessive amounts of? 

A.      Oranges

B.      Lemons

C.      Silver

D.      Carrots

Follow the Twitter and Instagram feeds both @pickpoison1 for the answer. Remember, never try anything on this podcast at home or anywhere else. 

Thanks for listening. It helps if you subscribe, leave reviews and/or tell your friends. Transcripts are available at pickpoison.com. 

 While I’m a real doctor this podcast is fictional, meant for entertainment and educational purposes, not medical advice. If you have a medical problem, please see your primary care practitioner. Until next time, take care and stay safe.