Increasing number of fatal acute liver failure cases linked to the popular painkiller acetaminophen (Tylenol)
- Last Updated: 20 November 2015 20 November 2015
Research published in the December 2005 issue of the medical journal Hepatology found that the annual percentage of potentially fatal acute liver failure (ALF) cases caused by acetaminophen (TYLENOL) rose from 28 percent in 1998 to 51 percent in 2003. The research was conducted by the Division of Gastroenterology at the University of Washington Medical Center, Seattle WA. The facility is part of the U.S. Acute Liver Failure Study Group (ALFSG), a consortium of 22 academic medical centers that monitor cases of liver toxicity around the country.
The ALFSG collected information on all cases of acute liver failure that occurred between Jan. 1, 1998 and Dec. 31, 2003, including outcome information. A careful history of each patient's acetaminophen use, including the total dose, the type of product used, and the duration of use, was obtained where possible.
The researchers identified a total of 662 patients during the six year study period who met the criteria for acute liver failure. Of these 662 patients, in 275 (42%) cases, liver failure was found to have resulted from acetaminophen-induced liver toxicity. The fraction rose from 28% in 1998 to 51% in 2003, almost doubling in five years. The median total dose of acetaminophen taken by these patients was 24 grams, the equivalent of 48 extra-strength acetaminophen tablets.
Unintentional overdoses were responsible for 131 (48%) of the acute liver failure cases. Intentional overdoses, or suicide attempts, accounted for 122 (44%) episodes. In 22 (8%) of the cases, the intent was unknown. Of the 131 patients who overdosed unintentionally, 38% took two or more acetaminophen containing products simultaneously, and 63% used narcotic combination painkillers that contained acetaminophen.
Overall, 178 (65%) of 275 patients identified as having acetaminophen-induced liver toxicity survived. Seventy-four (27%) died without a liver transplantation, and 23 (8%) patients underwent a liver transplantation operation.
The authors of the study concluded:
"...acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States."
Prevent accidental overdosing—read labels
They also stated that efforts to limit OTC package size and to restrict the prescription of narcotic-acetaminophen combinations (or to separate the narcotic from the acetaminophen) may be necessary to reduce the incidence of this increasingly recognized but preventable cause of ALF in the United States. Educational programs for practicing physicians, pharmacists, and consumers, involving a full discussion of the hazards of this ubiquitous pain reliever and the identification of susceptible groups, seems warranted.
In testimony before an FDA advisory committee on this topic more than three years ago, Health Research Group Deputy Director Dr. Peter Lurie made several similar suggestions, as well as some others, to reduce the terrible toll of acetaminophen-induced liver failure.
Drug induced injury or death is a tragedy because, as is the case with acetaminophen, most of the time the toxicity of the drugs causing injury or death is known. It is even more troubling when the drug-induced injury or death is unintentional.
In the case of acetaminophen, this can occur in patients who are taking a prescription narcotic combined with acetaminophen as directed by their physicians if they also take acetaminophen-containing over-the-counter (OTC) products. This can happen even if these patients follow the instructions on the label of the product.
The amount of acetaminophen contained in OTC drugs is clearly listed on the label. Always read these labels before taking any OTC drug to make sure you are not taking acetaminophen (or any other drug) in more than one product.
If you are prescribed a prescription painkiller, it is likely that it is a combination of a narcotic drug with acetaminophen. Lortab, Percocet, and Tylox are a few examples of widely-prescribed acetaminophen-containing painkillers.
If you are prescribed a painkiller, ask your pharmacist if it also contains acetaminophen. Mixing OTC drugs and prescription painkillers may result in too much acetaminophen being taken.
Alcohol in combination with acetaminophen can increase the risk of liver toxicity. All OTC drugs that contain acetaminophen have the following warning on their labels:
Alcohol warning: If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage.
What you can do
To prevent acetaminophen overdose, you should carefully read the labels on all OTC drug products to see if they contain acetaminophen. If you are prescribed a prescription painkiller, ask your pharmacist if it contains acetaminophen.
Do not take OTC products that contain acetaminophen if you are taking an acetaminophen-containing painkiller. Do not take more than one acetaminophen-containing drug, prescription or otherwise.
If you or a family member develop any of the symptoms of potential liver toxicity, stop taking all acetaminophen-containing products and call your physician immediately. These symptoms are:
Pruritus (itchy skin)
Jaundice (yellowing of the skin or whites of the eyes)
Upper right-sided abdominal tenderness (location of the liver)
Unexplained "flu-like" symptoms
- Last Updated: 02 December 2015 02 December 2015
by Dr. Richard L. Bruno
The Massachusetts CFIDS/ME & FM Association Spring 2002 UPDATE
While watching a football game President Bush swallowed a pretzel and fainted. They said it irritated his throat and made his blood pressure fall. I feel faint when food seems to get stuck behind my breastbone. I also get lightheaded and very tired after a big meal. Other people with the Chronic Fatigue and Immune Dysfunction Syndrome and fibromyalgia (CFIDS/FM) tell me they do, too. Are these CFIDS/FM symptoms?
President Bush swallows a pretzel that irritates his esophagus. The irritation causes his blood pressure to plummet and he faints. An unheard of experience? Not for some of the world's 20 million polio survivors and the estimated 10 million people with CFIDS/FM.
The President's problem likely had to do with the pretzel overstimulating the vagus nerve, the main highway for nerve traffic to your esophagus, your swallowing tube, and to your stomach. The vagus nerve carries commands from brain stem neurons to activate the muscles in your throat, esophagus and stomach that make swallowing possible. The vagus nerve also sends commands that tell your heart muscle to slow down and your blood vessels to open up. Vagus nerve stimulation, causing a drop in blood pressure due to blood vessels opening up, is responsible for the common faint, called vaso-vagal syncope.
But the vagus nerve is a two-way street: it both sends commands to your heart and gut and listens to the results of those commands. The vagus carries information about how much food is inside your throat, esophagus and stomach back to those same brain stem neurons. Anything that irritates the esophagus—like a pretzel getting stuck or even a full stomach—can stimulate the vagus nerve enough to drop blood pressure and cause a faint, which seems to be what happened to the President.
For Mr. Bush this is likely a one-time thing. But for polio survivors and people with CFIDS/FM, low blood pressure, lightheadedness and even fainting can be frequent occurrences. We know that the poliovirus damaged brain stem neurons that control the vagus nerve and possibly damaged the nerve itself.
We have been following a growing number of post-polio patients who feel exhausted after eating meal. Food sticking in the esophagus or a full stomach apparently overstimulates the vagus nerve, triggers a drop in blood pressure and causes feelings of severe fatigue, even though these polio survivors don't usually faint.
In 1995, pediatrician Peter Rowe found that some patients with CFIDS also have fatigue that is associated with a drop in blood pressure when they stand up, take a hot shower or are in a hot room. Rowe's observations parallel the finding from our 1985 Post-Polio Survey that fatigue increased in more than one third of polio survivors when they were exposed to heat.
Another parallel with polio survivors was Rowe's observation that a CFIDS patient had "a purple discoloration" of her feet and hands after standing. This discoloration was reported in patients with CFIDS back in 1959 and is remarkably similar to polio survivors' cold and purple "polio feet." These findings indicate that both polio survivors and some CFIDS/FM patients have lost the ability to regulate the size of their veins, which allows blood to pool, blood pressure to drop and causes feelings of fatigue.
Our 2001 International Chronic Fatigue Syndrome Survey found that those with CFIDS/FM fainted nearly twice as often as they did before having CFIDS/FM.
Our 1995 International Post-Polio Survey found that polio survivors do not faint any more frequently than those who didn't have polio. But the 1995 Survey did find that anyone who had fainted even once in their lifetime reported significantly more severe daily fatigue than those who had never fainted.
This suggests that damage to brain stem blood pressure control and vagus nerve neurons may be coupled to damage to brain activating neurons, the neurons that our and others' research suggests are responsible for symptoms of "brain fatigue" in polio survivors and those with CFIDS/FM.
So polio survivors and patients with CFIDS/FM share abnormalities of blood vessels and blood pressure that seem to be related to brain stem neurons that are not functioning normally, probably as a result of virus damage to both brain activating and blood pressure control neurons.
What's to be done? Everyone with CFS should have their heart rate and blood pressure taken lying, sitting and standing. If fatigue is associated with a drop in blood pressure, compression stockings are often helpful to stop blood from pooling in the legs.
If you need more help, go to a specialist in low blood pressure and ask about medications that increase the amount of fluid in your blood or reduce the size of your veins to stop blood from pooling in the legs.
If fatigue is associated with meals, eating small bites and washing them down with liquid, as well as eating frequent, small, higher protein meals, can stop food from sticking in the esophagus and the stomach from getting too full, prevent over stimulating the vagus nerve and prevent fatigue or even a faint.
Bou-Holaigah I, "Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia," Clinical & Experimental Rheumatology 15 (1997): 239-46.
Bruno RL. The Polio Paradox: Uncovering the Hidden History of Polio to Understand and Treat "Post-Polio Syndrome" and Chronic Fatigue. Warner Books, 2002.
Bruno RL, "Paralytic versus non-paralytic polio: A distinction without a difference?" American Journal of Physical Medicine and Rehabilitation 79 (1999): 4-12.
Bruno RL. "Fainting and Fatigue: Causation or Coincidence?" CFIDS Chronicle 9(2) (1996): 37-39.
Bruno RL. "Chronic fatigue, fainting and autonomic dysfunction: Further similarities between post-polio fatigue and Chronic Fatigue Syndrome?" Journal of Chronic Fatigue Syndrome 3 (1997): 107-117.
Bruno RL, Frick NM. Stress and "Type A" behavior as precipitants of Post-Polio Sequelae. In Research and Clinical Aspects of the Late Effects of Poliomyelitis. White Plains: March of Dimes Research Foundation, 1987.
Manyari D, "Abnormal reflex venous function in patients with neurally mediated syncope," J Am College Cardiology 27 (1996): 1730-5.
Palmer E, "The upper gastrointestinal vasovagal reflexes that affect the heart" Am J Gastroenterology 66 (1976): 513-22.
Rowe P, "Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome," J Pediatrics 135 (1999): 494-9.
Dr. Bruno is the Director of Fatigue Management Programs and The Post-Polio Institute at Englewood (NJ) Hospital and Medical Center. His book is The Polio Paradox: Uncovering The Hidden History of Polio to Understand and Treat "Post-Polio Syndrome" and Chronic Fatigue . See his website at www.postpolioinfo.com.
- Last Updated: 07 November 2015 07 November 2015
by Dr. Peter Rowe, Johns Hopkins Medical School
This is an editorial from The Journal of Pediatrics Apri1 40(4) (2002):387-9. Dr. Rowe has done research into orthostatic hypotension and its role in ME/CFS, especially in adolescents.
Chronic fatigue is a prominent symptom in a variety of overlapping syndromes of circulatory dysfunction, the most notable examples of which are neurally mediated hypotension (NMH) and postural tachycardia syndrome (POTS).
An early suggestion that such abnormalities were treatable causes of symptoms in what we now call chronic fatigue syndrome (CFS) was made in 1940 by Alexander MacLean and Edgar Allen. They described a group of patients who experienced excessive acceleration of the heart and hypotension after moving from the recumbent to the erect posture, usually associated with symptoms of orthostatic exhaustion, blurring of vision, weakness on exercise, and syncopal episodes.
McLean and Allen attributed the tachycardia to a reduced venous return to the heart, in part because symptoms and hemodynamic changes could be provoked within 10 seconds by Flack's test, which involved forced expiration into a tube to maintain a mercury column at 40 mm, thereby reducing blood flow into the thorax. They concluded that this orthostatic tachycardia syndrome seemed similar to "effort syndrome, irritable heart, or neurocirculatory asthenia" the synonyms of the day for what we now call CFS.
McLean and Allen reported that patients improved by increasing their intake of fluids and sodium, and by sleeping with the head of the bed elevated. The head-up bed may have helped to conserve intravascular volume by reducing blood flow to the kidney at night. It is a medical curiosity that these detailed observations were largely ignored for several decades.
In this issue of The Journal of Pediatrics, 3 articles address related aspects of orthostatic control of blood pressure and heart rate, two of which take advantage of newer methodologic tools to better understand microvascular flow and cerebral oxygenation. In 23 healthy adolescents, Stewart noted that 44% had reductions in blood pressure of >20 mm Hg systolic in the first minute of upright tilt to 70 degrees, associated with transient symptoms of lightheadedness. At a formal level, these patients met the adult criteria for orthostatic hypotension, but in contrast to the usual course in adults, the hemodynamic changes resolved during one minute and did not require treatment. The reduction in blood pressure correlated with increased calf blood flow measured by strain gauge plethysmography.
These valuable observations provide a physiologic explanation for common and self-limited episodes of lightheadedness in adolescents, and they support a conservative approach to treatment, provided resolution of symptoms is rapid. Stewart suggests a need for better pediatric norms for the response to orthostatic stress, and as we generate these, we will be wise to make them age-specific. There is now good evidence that pubertal children have a greater susceptibility to orthostatic stress than prepubertal children. Although the mechanisms for this change in susceptibility during adolescence are as yet unclear, the observation is in agreement with epidemiologic and clinical impressions that orthostatic intolerance syndromes and CFS are much less prevalent in prepubertal children.
The paper by Tanaka et al brings further insight to the pathophysiologic features of symptoms during upright posture in patients with CFS. In orthostatic intolerance syndromes, it has been widely assumed that lightheadedness and other symptoms are caused by a reduction in cerebral blood flow. Our own studies using transcranial Doppler ultrasonography do not identify a distinctive pattern of cerebral blood flow velocity during upright tilt in adolescents and adults with CFS and orthostatic intolerance compared with controls. The much earlier onset of symptoms during head-up tilt in patients with CFS suggests that other factors not measured by transcranial Doppler may play an important role.
Near infrared spectroscopy (NIRS) offers a different insight into cerebral changes during upright posture. This noninvasive technique measures changes in the absorption of near infra-red light by oxygenated or deoxygenated hemoglobin and can be used to assess changes in cerebral tissue oxygenation rather than the changes in blood flow velocity that are available through transcranial Doppler studies. NIRS has been used to study cerebral oxygenation in a variety of settings, including upright tilt in patients with syncope, during lower body negative pressure (a simulated orthostatic stress), and in neonates.
Tanaka et al used NIRS to compare cerebral oxygenation between 20 healthy controls and 28 patients with either CFS or idiopathic chronic fatigue. Sixteen patients with chronic fatigue had hemodynamic evidence of orthostatic intolerance during a brief 7-minute period of active standing, compared with 2 of 20 controls of a similar age. After an initial drop in cerebral oxyhemoglobin at the onset of standing in most controls, 18 of 20 experienced a rapid recovery. In contrast, only 7 of 28 patients with chronic fatigue had a rapid recovery, and reductions below the basal level were more common in patients with CFS than in controls. Of interest, 6 of 12 patients with chronic fatigue and abnormal cerebral oxygenation had no evidence of orthostatic intolerance during the 7 minutes of standing, although it is impossible to know whether these patients would have gone on to develop hypotension after a longer period of orthostatic stress.
The results of this study are intriguing but will need to be corroborated by others. Further support for the relevance of reduced cerebral oxygenation to the development of CFS symptoms will depend on showing whether cerebral oxygenation normalizes in patients whose CFS symptoms improve either spontaneously or with treatment of the orthostatic intolerance. It will be important in future studies to ensure that the orthostatic stress is sufficiently long to identify clinically important NMH, which in most cases would be missed by a 7-minute test. Another noninvasive technique that would add to such studies would be the incorporation of end-tidal carbon dioxide measures, to assess the effect of changes in carbon dioxide tensions on cerebral blood flow and oxygenation.
In the third article, Stewart provides a concise summary of the growing literature on the pathophysiology and current treatment of common syndromes of orthostatic intolerance. Treatment of these disorders begins, as it did in 1940, with education, reassurance, dietary measures, postural maneuvers to prevent blood from pooling in the limbs, the use of compression garments, and avoidance of situations that provoke symptoms.
An underappreciated aspect of management is the need for effective control of other comorbid conditions that may independently contribute to orthostatic intolerance, including allergies, asthma, dysmenorrhea, migraine headaches, movement dysfunctions (especially those associated with joint hypermobility), and anxiety and depression. Failure to bring these problems under adequate control in the setting of clinical trials will lead to underestimates of the effect size of any intervention.
Of the medications that have been proposed, stimulant medications may have received less attention than they may deserve in the treatment of pediatric orthostatic intolerance, despite being used as therapy for hypotension long before their discovery for the treatment of attention deficit disorder and hyperactivity.
As Stewart notes, clinicians have few randomized controlled trials available to guide their decisions about treating orthostatic intolerance, and even fewer when it comes to medications targeted to adolescents. Further progress is likely to come as we gain an improved understanding of the pathophysiologic heterogeneity of these syndromes, but in the interim, a much greater effort needs to be devoted to treatment trials.
One methodologic challenge posed by the heterogeneity of these disorders is that randomized trials of single agents will need large sample sizes, thereby making them rather unwieldy to conduct and expensive for funding agencies. A more economic design for the determination of efficacy of medications may be to study treated patients at a stable point in their illness. Persons who have improved by using a medication assumed, but not proven, to be efficacious could be randomized to either active medication or placebo. This randomized withdrawal design would have the advantage of being relatively brief in duration, less costly, and low in new adverse events. If cerebral oxygenation is consistently abnormal in patients with orthostatic intolerance and CFS, its measurement may prove useful as a more objective marker of the response to treatment than self-report of symptoms."
(Source: This is an editorial from The Journal of Pediatrics Apri1 40(4) (2002):387-9)
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Notice about names
The Massachusetts ME/CFS & FM Association would like to clarify the use of the various acronyms for Chronic Fatigue Syndrome (CFS), Chronic Fatigue & Immune Dysfunction Syndrome (CFIDS) and Myalgic Encephalomyelitis (ME) on this site. When we generate our own articles on the illness, we will refer to it as ME/CFS, the term now generally used in the United States. When we are reporting on someone else’s report, we will use the term they use. The National Institutes of Health (NIH) and other federal agencies, including the CDC, are currently using ME/CFS.
Massachusetts ME/CFS & FM Association changed its name in July, 2018, to reflect this consensus.