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A Pill to Take or Not to Take

By Robert Roose, MD MPH | 3.05.07

For all the advances in medicine, doctoring is still a risky business. Dealing with complex problems in the most nuanced of systems, the human body, few things follow a pre-determined algorithm. While scientific evidence and clinical judgment certainly help steer the odds, diagnostic and treatment decisions often involve taking chances. And at times, like these, the stakes are high.


From across the dim hospital room, Nicola Marshall’s eyes were clearly glowing -- and as the senior resident on that night, it was my job to try to figure out why.

So as the intern asked questions, I took notes. She said she hadn’t noticed them turning yellow. Generally she had been feeling pretty well, but was more tired than usual. She had been working two jobs and stayed home a few times the previous week. But otherwise she was doing fine, without any concerns. She merely went to her doctor for a routine check, to refill her medications, and was surprised to have him send her to the hospital.

It was clear from her eyes’ yellow shine that the bilirubin level in her blood was extremely high. Bilirubin is a pigment formed when a protein in red blood cells breaks down. It’s the same pigment that causes jaundice in babies and bruises to turn yellowish before they disappear. When it’s circulating in abundance in the blood, it deposits in various places and the whites of the eyes quickly and predictably turn yellow. There was no doubt that Nicola had extra bilirubin in her blood; why she did was not so clear.

One of the more common reasons for excess bilirubin is liver damage. The liver helps manage the elimination of bilirubin in the body by conjugating it - making it soluble in water. Conjugated bilirubin is stored in the gallbladder as bile, and eventually sent out through the intestines. If liver function is compromised or if the normal route of bile flow is blocked, bilirubin backs up and leaks uncontrollably into the blood.

However, when we questioned Nicola about symptoms of liver injury, she denied having any fevers or chills, abdominal pain, vomiting or diarrhea. We wondered about liver-damaging viral hepatitis, but she said that she hadn’t eaten any different or raw foods lately (Hepatitis A), was sexually abstinent (Hepatitis B), and had never injected drugs or received a blood transfusion (Hepatitis C). What about binging on other common substances that might cause liver damage? It turned out that Nicola hadn’t had a drink in over two months and she couldn’t remember the last time she took Tylenol. And no one in her family ever had liver problems. She acknowledged after we brought it up that her urine was darker than normal and her stools seemed light, but that was no surprise to us; excessive amounts of bilirubin can result in “tea-colored” urine and “clay-colored” stools.

Other than her eyes, her physical examination was relatively unrevealing. Her breathing was untroubled and her heart rate was regular. Her abdomen was soft and non-tender, without distention or the presence of fluid. (Intra-abdominal fluid can be a result of liver failure, or leakage caused by abdominal tumors or infection.) Her liver was of normal size, and she had no peripheral edema (swelling in her arms or legs), tremors, or asterixis (an abnormal flapping of the wrists as a result of elevated ammonia levels in the blood), all of which made chronic liver failure unlikely. She was alert, oriented and wanted to make sure we knew that she wasn’t staying in the hospital past Friday, which is probably the surest sign of a working neurological system.

It wasn’t until we started looking into her recent medical history that we found some clues. Two months ago, Nicola had a heart attack – a big one. One day before her 57th birthday, and for the first time in her life, she felt a strong pain in her chest that woke her up from sleep. She popped an aspirin, felt nauseated, and called 911. By the time she got to the ER, her ST segments had shot up on her electrocardiogram and her cardiac enzymes were leaking into her blood, signifying serious damage to cardiac muscle cells. Her heart was dying, and if not for the 24-hour cardiac catheterization lab in the hospital, she might have died as well. Instead, she left the hospital pain-free with her right coronary artery propped open by three medication-coated stents (pastic tubes) and a stern warning never to stop taking her Plavix.

I wager that once you have a piece of plastic placed in an artery wrapped around your heart, all bets are off. Yes, the new stents are great at restoring blood flow, and in the setting of an ongoing heart attack, they undoubtedly save many people’s lives, like Nicola’s. But unless drastic lifestyle changes are made, the same underlying processes that led to the first heart attack remain – and now there is the ever-present risk of sudden re-occlusion.

If the stents were in me: once bitten, twice shy. At any moment after it’s placed, a stent can clog right up again. Just like that. With nary a warning sign, clumps of cells and protein can work themselves into a bundle right inside the stent itself. One minute the artery is open and the next minute it’s not, shutting out all the oxygen with it. Although it’s pretty uncommon, this complication of coronary artery intervention doesn’t often give second chances, usually leading to death or massive heart attack. It is this frighteningly serious event that has stent-carriers everywhere clutching their Plavix tight. Patients who take aspirin alone have a significantly higher risk of heart attack, stroke, and death one-year post-stent than those who take both aspirin and Plavix. So as it would seem, that’s one pill to surely take.

However, with the benefits of every drug come the risks. One week after her heart attack, Nicola was back in the hospital with dark, tarry stools, a sign of bleeding in her intestinal tract. She was feeling fine, but her blood count had dropped, nearly necessitating a blood transfusion. The gastroenterologists and cardiologists were called from the Emergency Room, and after she had cameras steered down her throat and up into her colon (two separate times) without much result, aspirin and Plavix were deemed the culprits. Although they work in different ways, as inhibitors of platelets (tiny cells that help organize clots) they both independently increase the chance of bleeding. In preventing life-threatening clots in the brain and around the heart, they also “thin” the blood all throughout the body. Some people get nosebleeds, some ooze from their gums, and some have microscopic bleeding from their small intestine. Nevertheless, she wasn’t dying from it, so the cardiologist wrote: Do not stop the aspirin or Plavix!

But this time, when Nicola came to the hospital, I thought her liver might be dying. We weren’t sure of the cause, but the blood tests showed profound liver damage. Her liver cells were spilling all their contents, bilirubin and ammonia were building up, and the ability of her liver to make basic proteins was failing. To corroborate the answers that Nicola gave us, we checked her blood for toxins (including illicit drugs, alcohol, and Tylenol), bacteria, viruses, and signs of autoimmune hepatitis (one’s own immune system attacking the liver). We ordered an ultrasound to look for obstruction of blood or bile flow and a CT scan to look for masses. We ran tests to fish for rare etiologies like primary biliary cirrhosis, primary sclerosing cholangitis and Wilson’s disease (too much copper). And, of course, we stopped nearly all of her medications in case they were the cause – but we didn’t stop her aspirin or Plavix.

Two days later, Nicola was in no better shape, but we had learned a lot about what was not causing her liver failure. As we initially thought, she did not have Hepatitis A, B, or C, the architecture of her liver and gallbladder looked normal, she never showed any signs of infection and she had not taken any illicit drugs, alcohol, or Tylenol. Nevertheless, all the while, her liver function was worsening. The measured time it was taking her blood to clot was climbing unnaturally because her liver was not making proteins well. Her risk of serious bleeding was going up, up, up, and with it went her our level of concern. Her gastroenterologist wanted her transferred to another medical center for a possible liver transplant. And he wanted to stop the Plavix. Yes, the Plavix!

It was at this point that several worlds of medicine collided. The cardiologists, forever concerned for her heart, still warned against stopping the Plavix. The gastroenterologists and me, fearing complete liver failure that could lead to death, wanted it stopped. According to the Food and Drug Administration (FDA), there are reports from post-market surveillance data that Plavix rarely causes acute liver failure. Of possible adverse effects, it’s so far down the list in frequency that it’s not something we typically even think of. In fact, liver failure didn’t happen even once during the controlled experiments on tens of thousands of people that proved the worth of Plavix as an effective medication. But now that the medication is being prescribed to millions, we are learning more about its possible dangers. In the case of Nicola and her Plavix we had to make a decision. How much extra benefit (to her heart) was worth the additional risk (to her liver)?

Since our medical team was calling the final shots, we stopped the Plavix and prepared for her transport downtown. And in the 24 hours or so after her last dose, her liver function seemed to stabilize. Her ammonia levels were sky-high but they caused her to hallucinate. Her bleeding times were prolonged but she never lost a lot of blood. And although her liver was failing, we were able to get her the hyper-specialized care she needed – all on account of the Plavix. I hope her heart agreed with our decision.

Reference

Food and Drug Administration. Plavix: prescribing information. NDA20-839/S-035.


LD50

Scientific knowledge can be a scary thing. It’s often said that doctors are the worst hypocondriacs, because once you get under the hood, it’s easy to see all the ways things can break down. Likewise, the more you know about what’s out there in the world, the less auspicious a place it seems for small, soft, and pink critters like us. In this column, we explore interesting corporeal glitches and Mother Nature’s sometimes viperous disposition. Just remember: science doesn’t kill people, but, um…lots of things do.

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