Study Shows Fasting and Heavy Drinking Associated With Liver Injury After Standard Acetaminophen Doses

Acetaminophen (also known as paracetamol) is an old drug that is available over the counter as an oral tablet or liquid, mainly as TYLENOL and multiple store-brand generics, and by prescription. It also is a component of many combination drug products, including allergy, cold and pain medications. It is widely used as a first-choice drug for fever and mild-to-moderate pain.

Acetaminophen toxicity is catastrophic to the liver. It accounts for one-half of reported drug-induced acute liver failure cases and approximately 20% of liver transplant cases in the U.S.[1] Acetylcysteine (ACETADOTE) is an effective antidote for acetaminophen poisoning, ideally when taken in the first eight hours after exposure.[2]

One would presume that acetaminophen-related liver injury is limited to intentional (suicidal) or unintentional intake of high doses (overdose) of acetaminophen. However, prior evidence suggest that acetaminophen can be harmful to the liver even at therapeutic (recommended) doses in certain circumstances.[3]

A group of French researchers conducted the first prospective study that examined a series of acute liver injury cases associated with therapeutic and high acetaminophen doses and published their findings in the May 2021 issue of Hepatology.

The new study[4]

The study researchers collected data for all patients with severe acetaminophen-related acute liver injury (without preexisting liver cirrhosis [late-stage liver disease]) who were admitted to the intensive care unit of a large French hospital from 2002 to 2019. Out of 400 identified patients that met their criteria, 89 had taken therapeutic acetaminophen dosages (therapeutic-dose patients) and the remaining 311 patients had taken acetaminophen overdoses (overdose patients). Consistent with a prior study, the researchers considered acetaminophen dosages of 6,000 milligrams (mg) or less per day as therapeutic and those higher than 6,000 mg per day as overdoses. Notably, the current maximum daily recommended dose for an average-weight adult in the U.S. is 4,000 mg.[5]

The therapeutic-dose patients were older (average age was 44 years) than the overdose patients (average age was 31 years). None of the therapeutic-dose patients reported attempting suicide by ingesting the drug, whereas 76% of the overdose patients reported taking acetaminophen with a suicidal intent.

For therapeutic-dose patients, the median maximum ingested daily dose of acetaminophen was 4,000 mg for a median duration of four days. Importantly, the researchers noted that patients rarely developed acute liver injury with therapeutic acetaminophen doses used for just one day.

In contrast, the median maximum ingested daily dose of acetaminophen for overdose patients was 16 grams for a median duration of one day. This finding supports the well-known damaging effect of high doses of acetaminophen on the liver.

Overall, therapeutic-dose patients had more severe acute liver injury than the overdose patients. Although all acetaminophen users received intravenous infusion of the antidote drug acetylcysteine, 13% of therapeutic-dose patients and 5% of overdose patients died within 30 days of their hospital admission.

Excessive drinking — defined as a daily consumption of at least 30 grams of alcohol, which is equivalent to approximately two standard alcoholic drinks (such as about 24 ounces of beer)[6] — is a known major risk factor for acetaminophen-induced liver toxicity. It was significantly more common among therapeutic-dose patients. Specifically, 93% of the therapeutic-dose patients were excessive drinkers compared with 36% of the overdose patients.

Fasting (defined as not eating for at least 24 hours before admission or having an eating disorder) was also more frequently observed in therapeutic-dose patients than in overdose patients (48% versus 26%, respectively).

In conclusion, the researchers recommended that doctors and patients be warned about the risk of acute liver injury associated with prolonged use of therapeutic acetaminophen doses in conjunction with excessive drinking or fasting.

What You Can Do

If you have a history of liver disease or alcoholism, talk to your doctor before taking acetaminophen.

If you need to take acetaminophen, try to start with regular-strength dosages (650 mg every six to eight hours), if possible, and do not exceed the recommended daily dose or interval between doses. Current Tylenol labeling instructs users not to take the drug for longer than ten days. Talk to your doctor if you need to take the drug for longer periods, such as for osteoarthritis.[7]

Carefully read the labeling of all your over-the-counter and prescription medications and check with your doctor or pharmacist about whether they contain acetaminophen. Do not take more than one product that contains acetaminophen at any given time.

Avoid drinking alcohol and fasting for 24 hours or longer when taking acetaminophen.

Beware of the symptoms of potential liver toxicity, including pruritus (itchy skin), jaundice (yellowing of the skin or whites of the eyes), dark urine, upper-right-side abdominal tenderness (where your liver is located) and unexplained “flu-like” symptoms.

If you suspect that you are experiencing an overdose or potential liver toxicity from therapeutic doses of acetaminophen, stop taking all acetaminophen-containing products and call your doctor immediately or contact a Poison Control Center by calling 800-222-1222.
 

References

[1] Burns MJ, Friedman SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. April 6, 2020.

[2] Chiew AL, Buckley NA. Acetaminophen poisoning. Crit Care Clin. 2021;37(3):543-561.

[3] Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93.

[4] Louvet A, Ntandja Wandji LC, Lemaître E, et al. Acute Liver injury with therapeutic doses of acetaminophen: A prospective study. Hepatology. 2021;73(5):1945-1955.

[5] Food and Drug Administration. FDA drug safety communication: Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. January 13, 2011. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit. Accessed August 16, 2021.

[6] National Institute on Alcohol Abuse and Alcoholism. What is a standard drink? https://www.niaaa.nih.gov/alcohols-effects-health/overview-alcohol-consumption/what-standard-drink. Accessed August 16, 2021.

[7] McNeil. Label: Acetaminophen (TYLENOL). July 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019872Orig1s048lbl.pdf. Accessed August 16, 2021.