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http://www.postgradmed.com/issues/2000/01_00/draganov.htm

Alcohol-acetaminophen syndrome
Even moderate social drinkers are at risk
Peter Draganov, MD; Hugh Durrence, MD, RPh; Christopher Cox, MD; Adrian Reuben, MBBS, FRCP

VOL 107 / NO 1 / JANUARY 2000 / POSTGRADUATE MEDICINE

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CME learning objectives

To recognize acetaminophen toxicity in both users and nonusers of alcohol
To understand the significance of extremely high aminotransferase levels in patients with alcohol-acetaminophen syndrome
To know the importance of timely administration of acetylcysteine

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Preview: Long-time alcohol users who take acetaminophen in therapeutic or modestly excessive doses are at risk for severe hepatic injury and possibly acute liver failure. Diagnosis may be difficult because presenting symptoms are vague. The authors review management of acetaminophen toxicity in both users and nonusers of alcohol and emphasize the need for greater awareness among healthcare providers and acetaminophen users of this preventable and treatable condition.
Draganov P, Durrence H, Cox C, et al. Alcohol-acetaminophen syndrome: even moderate social drinkers are at risk. Postgrad Med 2000;107(1):189-95

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Acetaminophen is one of the most commonly used over-the-counter medications. It is advertised as being safe for pain, fever, colds, and "flu." In the United States, it is marketed both as a single agent and as a component of more than 100 combination nonprescription preparations.

Taken in doses greater than 150 mg/kg/24 hr (>10 g), acetaminophen is a well-recognized cause of acute liver failure. This is a dose-dependent phenomenon, and the potential for hepatotoxicity after acute overdose is best predicted from an acetaminophen level plotted against the time that has elapsed since ingestion (Rumack-Matthew nomogram) (1).

Chronic moderate to heavy alcohol use potentiates the toxic effects of acetaminophen. Reports in recent years have drawn attention to the development of acute toxic effects on the liver in long-term alcohol users who have ingested acetaminophen, with therapeutic intent, in doses generally considered to be nontoxic (
The incidence of the syndrome is unclear, although Lee (4) speculates that it may be the most common cause of acute liver failure in the United States. The paucity of reported cases is surprising, particularly considering that 31% of alcoholic persons use acetaminophen regularly, often daily, and that 1 in 10 of them abuses the drug (7). Thus, the extent of this association remains either poorly appreciated or underreported.

A factor other than alcohol per se may also contribute to the enhancement of acetaminophen toxicity. Recent severe fasting was found to be possibly an even more important predisposing factor than recent alcohol use in patients with acetaminophen hepatotoxicity who were taking 4 to 10 g in 24 hours (8).

Unfortunately, it is not possible to give guidelines for safe alcohol ingestion with acetaminophen use. Patients with alcohol-acetaminophen syndrome are generally regular moderate to heavy drinkers who use therapeutic or modestly excessive doses of acetaminophen and do not intend suicide (6).

How alcohol affects acetaminophen metabolism
The metabolism of acetaminophen involves three separate pathways (9). About 95% of the agent is conjugated by way of glucuronide and sulfate routes (figure 1: not shown). Only 5% is metabolized by the hepatic microsomal mixed-function oxidase enzymes, primarily cytochrome P-4502E1 (CYP2E1) (8). Such oxidation yields the avidly electrophilic compound N-acetyl-p-benzoquinoneimine (NAPQI), a product that is highly toxic to liver tissues.

Normally, the small amount of NAPQI formed after the ingestion of a therapeutic dose of acetaminophen is promptly detoxified by conjugation with glutathione. However, when high doses (>10 g) of acetaminophen are ingested, large amounts of NAPQI are formed, and the body's glutathione stores are rapidly exhausted. The unconjugated NAPQI then causes hepatic injury (10,11).

In cases of acute heavy alcohol ingestion, alcohol competes with acetaminophen for interaction with CYP2E1. With chronic alcohol use, a combination of CYP2E1 induction and glutathione depletion results in an increased accumulation of NAPQI, leading to enhanced acetaminophen toxicity from doses generally considered to be nontoxic (5,12-14).

Data on the exact amount of alcohol needed to enhance the toxicity of acetaminophen are not available, but the induction of CYP2E1 subsides by the fifth day after alcohol withdrawal (12,14). Persons who regularly use alcohol are at highest risk if they take acetaminophen after brief abstinence from alcohol (at least 12 hours) (11). During that time period of abstinence, CYP2E1 is still induced but ethanol is not present to compete with acetaminophen for the CYP2E1 microsomal enzyme (11).

How much alcohol intake is needed to create the milieu for alcohol-acetaminophen syndrome (ie, induction of CYP2E1 and depletion of glutathione)? Generally, large amounts are needed, but incidents of alcohol-acetaminophen syndrome have been reported in moderate "social drinkers." In a well-publicized case, Antonio Benedi, an appointments secretary for President George Bush, sued Johnson & Johnson and was awarded $8.8 million in damages. Although Benedi regularly had three glasses of wine with dinner, he stopped drinking alcohol because of the dose. Several days later, he had "complete liver failure," which eventually necessitated a liver transplant (11).

Clinical features
Patients with acetaminophen toxicity commonly have nonspecific abdominal complaints, such as nausea, vomiting, and pain (2,5). Usually they have taken the drug for relief of headaches, dental pain, back pain, respiratory illness, abdominal pain, or hangover (2,6). Many patients are not aware that they ingested the drug, because it may have been one of the components of a cold or headache medicine (2,6). Physical examination yields nonspecific results and may reveal only abdominal tenderness and guarding (5). A minority of patients have stigmas of chronic alcoholic liver disease (eg, spider nevi, gynecomastia, parathyroid enlargement, testicular atrophy). Thus, thorough history taking, not physical examination, best raises suspicion of the alcohol-acetaminophen syndrome.

Laboratory findings
A number of abnormalities have been noted on laboratory studies, including hyperbilirubinemia, prolongation of prothrombin time, azotemia, hypoglycemia, and metabolic acidosis. The most striking finding is marked elevation of transaminase levels, with the aspartate transaminase (AST) level being significantly higher than the alanine transaminase (ALT) level. AST levels exceed 1,000 IU/L in 97% of patients and 3,000 IU/L in 90%. In more than half of cases, AST values are greater than 5,000 IU/L (2). Peak AST levels range from 1,960 to 29,700 IU/L (median, 6,888 IU/L), and ALT levels range from 12 to 12,550 IU/L (median, 2,480 IU/L) (5). Both levels decrease rapidly, usually by 50% in the first 24 hours after presentation. Extremely high transaminase levels followed by a rapid decrease are a hallmark of the alcohol-acetaminophen syndrome and are remarkably different from those observed with viral or alcoholic hepatitis (2) (figure 2: not shown). It should be kept in mind that very high transaminase levels also occur with massive ischemic injury to the liver.

Serum acetaminophen levels can be elevated, low, or undetectable, depending on the time of ingestion and dose. An elevated level is not necessary for diagnosis of alcohol-acetaminophen syndrome but can be supportive evidence. If a patient has been seen in an emergency department or a physician's office a few days before presentation, preserved serum samples should be obtained and analyzed for acetaminophen.

Diagnosis
Alcohol-acetaminophen syndrome is diagnosed on the basis of the patient's history of chronic alcohol use and recent acetaminophen intake plus the finding of towering transaminase levels. As noted, high acetaminophen levels support excess consumption, but low levels do not exclude it. This fact once more emphasizes the importance of a high index of suspicion and the need for detailed history taking with particular attention to use of over-the-counter medications. Liver biopsy is not necessary for diagnosis, but when tissue is available (eg, at autopsy), the classic centrilobular necrosis of acetaminophen injury is seen (2,5).

Clinical outcome and prognosis
Patients who have alcohol-acetaminophen syndrome have a worse prognosis than patients with acute acetaminophen overdose, even though the former have ingested a lower dose of acetaminophen (6). Reported overall mortality in alcohol-acetaminophen syndrome is 18% to 19% (2,6). If acute liver failure develops, the mortality rate exceeds 75% (5). The hospital course of patients who have acute liver failure (defined by the presence of encephalopathy and coagulopathy) is marked by the typical complications of shock, acute renal failure, adult respiratory distress syndrome, hypoglycemia, respiratory alkalosis, metabolic acidosis, hypokalemia, hyponatremia, infections, and gastrointestinal bleeding (4).

No definite prognostic criteria have been established yet for alcohol-acetaminophen syndrome. However, in cases of acute acetaminophen overdose without alcohol, poor prognostic factors include late presentation (>24 hours after ingestion), metabolic acidosis, renal failure, advanced encephalopathy, need for inotropic support, and age over 45 years (4,15) (table 1). Obviously, the presence of concomitant liver disease from chronic viral hepatitis or other causes reduces the liver's ability to tolerate acute injury when it occurs. However, patients with chronic liver disease, including cirrhosis, are not more susceptible to acetaminophen injury; for that reason, acetaminophen in the recommended dose (up to 4 g daily) can be safely given to such patients.

Table 1. Factors predicting poor outcome in patients with acute acetaminophen overdose
Acidosis (pH
Coagulopathy (INR >6.5) in addition to coma*

Renal failure (serum creatinine >3.4 mg/dL) in addition to coma*

Late presentation (>24 hr after ingestion)

Advanced coma

Need for inotropic support

Age over 45 years

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INR, international normalized ratio.

*Criteria used for consideration of liver transplantation.

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Therapy
Treatment of acetaminophen toxicity is approached according to individual circumstances.

Overdose unrelated to alcohol ingestion
Acetylcysteine (Mucomyst, Mucosil) has a well-established role in the treatment of acute acetaminophen overdose unrelated to alcohol ingestion (16). It is safe and effective, and its use correlates significantly with survival. The decision to treat with acetylcysteine is based on the Rumack-Matthew nomogram (1). The earlier the agent is given, the better the outcome, but even late administration (after 24 hours) can be of benefit (17). It is believed that acetylcysteine acts early by restoring glutathione stores and later by improving tissue oxygenation.

In the United States, a 72-hour oral regimen of repeated dosing with acetylcysteine is the standard of care. A load of 140 mg/kg is given, followed by 70 mg/kg every 4 hours for a total of 17 doses. It can be administered through a nasogastric tube, and antiemetics can be used in patients with nausea and vomiting.

An intravenous form of acetylcysteine is used worldwide. Although available in some hospitals in the United States for patients with severe vomiting, this form is not currently approved by the US Food and Drug Administration. The recommended intravenous dose is 150 mg/kg in 200 mL of 5% dextrose in water (D5W) given over 15 minutes, followed by 50 mg/kg in 500 mL of D5W over 4 hours, then 100 mg/kg in 1 L over 16 hours (16). The last dose is repeated until recovery or death occurs.

Alcohol-acetaminophen syndrome
Which is the best treatment for alcohol-acetaminophen syndrome is controversial. No regimen has been tested in a clinical trial. Nevertheless, personal experience and extrapolation from results in patients with acetaminophen overdose unrelated to alcohol ingestion suggest that therapy with acetylcysteine is preferred. Uncertainty exists regarding whom to treat and for how long. The following two approaches have evolved:

1. If the dose or time of ingestion is uncertain, treatment of all patients with a 48-hour course of acetylcysteine, regardless of acetaminophen or transaminase levels (4). The concerns with this method are that many patients may receive unnecessary treatment and that, on the other hand, some may receive insufficient therapy with only a 48-hour course of acetylcysteine (18).

2. Treatment of only those patients who have detectable acetaminophen levels or elevated AST levels, with a 72-hour course of acetylcysteine or until encephalopathy resolves or death occurs (18). The drawback of this strategy is that needed therapy may be denied to the rare patient who presents early enough to have a normal transaminase level and a low or undetectable acetaminophen level because of a small ingested dose (19).

Until further research examines specific protocols of acetylcysteine administration and clarifies which patients will benefit from therapy, it seems reasonable to individualize regimens (18). Despite the lack of randomized controlled trials, we believe that one should err on the side of treatment with acetylcysteine. If there is uncertainty regarding the dose or time of ingestion, a full 72-hour regimen, regardless of acetaminophen or transaminase levels, is prudent. With this strategy, many patients may be overtreated. However, potentially preventable acute liver failure is too high a price to pay for a more conservative approach.

Acute liver failure
If acute liver failure develops, treatment consists of general support, and liver transplantation may be considered. Optimal care of the comatose patient should be provided in an intensive-care setting. For encephalopathy, lactulose and neomycin sulfate can be given and protein restricted. In patients in advanced coma who are liver transplantation candidates, intracranial pressure should be monitored to avoid damage from cerebral edema and herniation. Coagulopathy needs to be treated with fresh frozen plasma only if bleeding is active or an invasive procedure is performed. Vigilance for hypogly-cemia, infections, electrolyte abnormalities, and gastrointestinal bleeding should be maintained.

Liver transplantation
The decision for liver transplantation must be individualized, but some guidelines are available. Criteria for consideration of liver transplantation in cases of acetaminophen overdose without concomitant alcohol consumption are based on the severity of acidosis, coma grade, prolongation of prothrombin time, and elevation of serum creatinine levels (King's College criteria) (20) (table 1). Adequate funding and availability of a donor organ are also important issues.

The decision for liver transplantation in a patient with alcohol-acetaminophen syndrome is complicated by the underlying chronic alcohol use. Most centers in the United States do not use transplantation if a patient is an alcohol abuser or alcoholic. It may be difficult to distinguish a moderately heavy "social drinker" from an abuser, especially when a patient is confused or comatose. In such cases, the decision must be individualized according to the policy of the respective transplantation center.

If transplantation is considered, it should be done early; patients must be transferred to a transplantation center while still fit to travel. Transporting a patient in advanced coma can be hazardous, because cerebral edema can be exacerbated by movement in an ambulance or changes in pressure in an airplane (4).

Liver transplantation offers a reasonably good survival rate of 65% after 1 year but does carry its own morbidity and mortality rates for what was originally a self-limited illness. A newer experimental approach is to provide a heterotopic liver graft as a "bridge" until the native liver recovers.

Summary
In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen taken in therapeutic or modestly excessive doses is distinctive. It is characterized by striking elevation of transaminase levels and the potential for acute liver failure with high morbidity and mortality rates. A high index of suspicion should be maintained; in any patient with evidence of acute hepatic injury, a complete history of over-the-counter drug use should be obtained and acetaminophen levels checked.

If there is doubt about the dose or time of ingestion, one should err on the side of treatment with acetylcysteine, because it is both effective and safe. Therapy should be initiated as early as possible, but even late administration may be of benefit. Timely contact with a medical center that has liver transplantation capabilities should be made before encephalopathy becomes advanced.

Heightened awareness of this preventable and treatable condition is needed by healthcare providers and acetaminophen users alike. Because the minimum safe dose of acetaminophen is not known in the setting of chronic alcohol use, it seems prudent in such situations to avoid acetaminophen altogether, especially during brief periods of abstinence.

References
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Dr Draganov is assistant professor of medicine, division of gastroenterology, hepatology, and nutrition, University of Florida College of Medicine, Gainesville. He was formerly a fellow in gastroenterology and hepatology, department of medicine, Medical University of South Carolina College of Medicine, Charleston. Dr Durrence is in community family medicine practice in Charleston. Dr Cox is a resident in internal medicine, New York University Medical Center, New York City. Dr Reuben is professor of medicine, director of liver studies, and medical director of liver transplantation, division of gastroenterology/hepatology, Medical University of South Carolina College of Medicine. Correspondence: Peter Draganov, MD, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, PO Box 100214, Gainesville, FL 32610-0214. E-mail:

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