Intravenous acetaminophen associated with acute liver failure

Abstract

A woman in her mid-60s, without known liver disease, was admitted to the hospital with a partial malignant colonic obstruction. Over a 6-day course, she received a total of 13 g of intravenous acetaminophen not exceeding 4 g over a 24-hour period. She developed encephalopathy and an international normalised ratio of 6.1 meeting criteria for acute liver failure (ALF). She was treated with intravenous N-acetyl cysteine and other causes of liver failure were excluded. The patient was discharged with subsequent resolution of encephalopathy and improvement of her liver chemistries. Though ALF is rare, in countries where acetaminophen is readily available, almost 50% of ALF cases are acetaminophen-induced hepatotoxicity and most have been documented as oral ingestion of acetaminophen. We present a rare case of intravenous acetaminophen-induced ALF.

Background

Acute liver failure (ALF) is defined as new onset coagulopathy with international normalised ratio (INR) ≥1.5 and encephalopathy without pre-existing cirrhosis.¹ Drug-induced liver injury (DILI) is the most common cause of ALF in the USA occurring at a rate of 20 cases per 100 000 persons.^{2 3} Of all DILI cases, acetaminophen-induced hepatotoxicity accounts for up to 46% of ALF cases.² The two main aetiologies of acetaminophen overdoses are either intentional, often in context of suicide attempts, and unintentional overdoses, also known as therapeutic misadventures.^{3 4} Bower et al conducted a population-based surveillance for ALF that noted 55% of all acetaminophen-related ALF cases to be therapeutic misadventures.⁵

Current US Food and Drug Administration packaging for acetaminophen recommends total daily dose to not exceed 4 g in most adults.⁶ No evidence-based guidelines exist, but expert opinion recommends lower maximum daily dose to be 2–3 g in adults with risk factors for liver injury to include chronic liver disease, malnutrition, chronic alcohol use and concurrent use of products that induce cytochrome p450 enzymes.^{6 7}

Acetaminophen does not directly cause hepatic injury. However, when it is metabolised by the cytochrome p450 system a toxic byproduct, N-acetyl-p-benzoquinone imine (NAPQI), is produced. Normally, NAPQI would be converted to non-toxic metabolite by glutathione (GSH). In acetaminophen overdose, GSH is depleted and unable to prevent NAPQI from causing further hepatic injury.⁴ Mechanistically, intravenous formulation of acetaminophen is shown to have better safety profile than oral formulation as intravenous administration limits acetaminophen exposure to the liver up to 50% by avoiding first-pass hepatic exposure.^{4 8 9}

As there have been limited cases of therapeutic dose intravenous acetaminophen causing ALF,⁹ we present a rare case of therapeutic dose intravenous acetaminophen-induced ALF.

Case presentation

A woman in her mid-60s presented to the emergency room with progressively worsening generalised abdominal pain and constipation complicated by poor dietary intake. Medical history was notable for well-controlled seizure disorder on levetiracetam and anxiety disorder on as-needed clonazepam but with no known history of liver-associated diseases. She was an active smoker and social ethanol drinker but denied recent use. She denied any other illicit drug, supplement or over-the-counter medication use. On initial presentation, her body mass index (BMI) was 19.1 kg/m². Admission laboratory workup found aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 17 U/L and 14 U/L, respectively, with an INR of 1.0. CT scan of the abdomen and pelvis with intravenous contrast revealed sigmoid colonic bowel obstruction and the patient was made nil per os (NPO) with nasogastric tube placed and admitted to the medical floor. Her levetiracetam was transitioned to intravenous formula and clonazepam was discontinued.

The patient remained NPO for the next two hospital days. A colonic stent was placed with a biopsy of the sigmoid colon revealing adenocarcinoma with less than 165 mg of propofol used for intraoperative sedation. She received 1 g of intravenous acetaminophen at least 6 hours apart, receiving a total 13 g of intravenous acetaminophen in the course of six hospital days for primary analgesia. The patient received intravenous hydromorphone for breakthrough pain, esomeprazole for heartburn and ondansetron for nausea. The patient did not receive any other medications to include antibiotics. The patient did not have any hypotensive episodes and total parenteral nutrition was introduced on hospital day 4 while remaining NPO.

On hospital day 5, during presurgical evaluation for partial colectomy, the INR was found to be 6.1, leading to an evaluation of her liver chemistries noting AST of 2974 U/L, ALT of 4415 U/L, bilirubin of 2.78 mg/dL, alkaline phosphatase at 142 U/L, lactate dehydrogenase >1800 U/L and albumin of 2.8 g/dL. Platelets were low at 139 k/µL. Acetaminophen serum level was 58.9 µg/mL. Intravenous acetaminophen was discontinued and a presumed diagnosis of acetaminophen-induced hepatotoxicity was made and 21-hour N-acetyl cysteine (NAC) protocol was initiated. Refer to figure 1 for full laboratory data by hospital days. The patient showed signs of psychomotor retardation consistent with grade 1 hepatic encephalopathy by West Haven Criteria and a diagnosis of ALF was made.

Figure 1.

Liver injury by hospital day showing aspartate aminotransferase (AST), alanine aminotransferase (ALT) and international normalised ratio (INR).

Investigations

Serological evaluation for other causes of liver failure to include Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus, hepatitis A/B/E virus, autoimmune hepatitis and Wilson’s disease was unremarkable. Doppler ultrasound of the liver was also unremarkable with patent vasculature. Liver biopsy was deferred given the high suspicion for acetaminophen-induced ALF.

Treatment

On hospital day 5, when presumed diagnosis of acetaminophen-induced hepatotoxicity was made, 21-hour NAC protocol was initiated. The patient received a loading dose of 150 mg/kg infused over 1 hour followed by a second dose of 50 mg/kg infused over 4 hours and a third dose of 100 mg/kg infused over 16 hours. Once diagnosis of ALF was made, the NAC therapy continued for a total 48 hours prior to discontinuation.

Outcome and follow-up

The patient remained haemodynamically stable and AST/ALT/INR continued to downtrend. In the course of 48 hours, INR downtrended from 6.1 to 4.4 to 3.2, serum ammonia from 74 mcmol/L to 62 mcmol/L, and lactate from 4.80 mmol/L to 2.56 mmol/L. In addition, AST downtrended from 2974 units/L to 836 units/L and ALT from 4414 units/L to 3180 units/L within 48 hours. After completion of the 21-hour NAC protocol, the patient remained on NAC therapy for a total of 48 hours prior to discontinuation in the setting of downtrending liver chemistries. The patient underwent sigmoid colectomy with end colostomy without complication. On hospital day 17, the patient’s AST/ALT downtrended to 96 U/L/159 U/L and INR to 1.3. She was discharged to a skilled nursing facility.

Discussion

We have identified a case of ALF associated with therapeutic dosing of intravenous acetaminophen. There were no confounders of hypotensive episodes, heart failure, vascular compromise, infectious processes, and genetic or autoimmune conditions. Medications introduced during this hospitalisation, including a short course of propofol, are less likely to have caused liver injury given the timing and lack of association with liver failure.¹⁰ The patient did not have known liver disease prior to her admission that would have been contributory.

Pharmacodynamics between intravenous and oral formulations were believed to favour intravenous acetaminophen as less hepatotoxic than oral acetaminophen. Intravenous formulations reduce first pass metabolism.⁹ Acetaminophen dosed at 1 g intravenous every 6 hours is a widely accepted dosing regimen for patients with a body weight of at least 41 kg without known liver disease.¹¹ Therapeutic dosing of intravenous acetaminophen causing hepatotoxicity has been associated with spinal muscular atrophy with reduced muscle mass. Reduced muscle mass is theorised to cause reduced stores of GSH and volume of distribution thus increasing toxic metabolite and plasma level of acetaminophen.¹² Elderly patients have smaller volumes of distribution and prolonged half-life of acetaminophen.¹³ Additional risk factors for this patient include malnutrition with poor oral intake prior to admission, intermittent NPO status during admission, lower BMI and duration of treatment.

This case is the second reported case of ALF with prolonged intravenous acetaminophen administration.¹² Lower dosing of acetaminophen may be more appropriate in this patient’s population.

Learning points.

• This is a rare case of an intravenous acetaminophen-induced acute liver failure.

• Previous pharmacodynamic understanding of intravenous formulation of acetaminophen to be less hepatotoxic than oral formulation, should be re-evaluated.

• Patients that have risk factors including elderly age, reduced muscle mass, history of malnutrition and prolonged poor oral intake should consider lower dosing of acetaminophen.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.