Fulminant Hepatitis After 10 Days of Acetaminophen Treatment at Recommended Dosage in an Infant

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Treatment at Recommended Dosage in an Infant

abstract

Acetaminophen is considered a safe drug for children, although hepa-totoxicity may develop after overdosing. Reports of liver failure after repeated therapeutic doses of the drug have been rare. Here we de-scribe the case of an infant who developed acute liver failure after administration of acetaminophen for 10 days at a total dose of 720 mg/day (72 mg/kg per day). The patient had high levels of aspartate aminotransferase (11 735 U/L) and alanine aminotransferase (6611 U/L) accompanied by encephalopathy and an increased ammonium level (266 ␮g/dL). Intravenous N-acetylcysteine therapy resulted in rapid improvement of the child’s clinical condition and laboratory test results. Health care providers should be aware that multiple doses of acetaminophen in infants may lead to acute hepatic failure.

N-acetylcysteine therapy should be initiated in cases of drug-induced acute liver failure.Pediatrics2011;127:e494–e497

AUTHORS:Francesco Savino, MD, PhD, Maria Maddalena Lupica, MD, Valentina Tarasco, MD, Emanuela Locatelli, MD, Silvia Garazzino, MD, and Pier-Angelo Tovo, MD, PhD

Department of Paediatrics, Ospedale Infantile Regina Margherita, Turin, Italy

KEY WORDS

acetaminophen, hepatic failure, infant, toxicity

ABBREVIATIONS NAC—N-acetylcysteine CYP—cytochrome P-450

NAPQI—N-acetyl-p-benzoquinone imine

www.pediatrics.org/cgi/doi/10.1542/peds.2010-1965

doi:10.1542/peds.2010-1965

Accepted for publication Nov 16, 2010

Address correspondence to Francesco Savino, MD, PhD, Dipartimento di Scienze Pediatriche e dell’Adolescenza, Ospedale Infantile Regina Margherita, Piazza Polonia 94, 10126 Torino, Italy. E-mail: francesco.savino@unito.it

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

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Acetaminophen is the analgesic and antipyretic drug most widely used in infants. It has a narrow therapeutic in-dex, and it may exert toxic effects, pri-marily on the liver, when administered in supratherapeutic doses.1,2_Repeated

therapeutic doses of acetaminophen can also be toxic.3–5_{Here we report the}

case of an infant who presented with acute liver failure after treatment with acetaminophen for 10 days.

CASE REPORT

An 11-month-old boy was admitted to the emergency department of our hos-pital because of persistent fever and vomiting. On the day of admission, he had received three 12 mg/kg doses of acetaminophen in 3 hours (2 oral doses and 1 endorectal dose) because of vomiting after administration. Ten days earlier, the pediatrician had pre-scribed clarithromycin (15 mg/kg per day) for 7 days for upper respiratory tract infection and endorectal acet-aminophen for fever at a dosage of 125 mg (12.5 mg/kg) every 6 hours for 3 days, and then orally at a dosage of 120 mg (12 mg/kg) every 4 hours for the next 7 days (total daily dose of 720 mg/day). Parents administered the drugs according to the pediatri-cian’s prescriptions.

The infant’s birth and medical history were unremarkable. He presented dis-crete general conditions, and his tem-perature was 38.4°C. His weight was 10 kg. At physical examination, the liver was palpable 3 cm below the right cos-tal margin, and there were no other pathologic signs. His aspartate amino-transferase (11 735 U/L [normal value:

⬍41 U/L]), alanine aminotransferase (6611 U/L [normal value: ⬍41 U/L]), and ␥-glutamyltransferase (286 U/L [normal value: ⬍71 U/L]) levels were elevated, whereas his alkaline phos-phatase and total bilirubin levels were within normal range, as were pro-thrombin time-international

normal-ized ratio and activated prothrombin time. His C-reactive protein level was increased to 59.1 mg/L (normal value:

⬍10.0 mg/L). Urinalysis revealed the presence of bilirubin, proteins, and he-moglobin. A chest radiograph was normal.

The day after admission, the patient’s liver enzyme levels, cytolysis indexes, and C-reactive protein level were un-changed. Moreover, his lactic dehydro-genase level was 17 337 U/L (normal value:⬍630 U/L), and his total biliru-bin concentration was 2.18 mg/dL with a predominance of the direct form (1.51 mg/dL [normal value:⬍0.25 mg/ dL]). Liver damage was also demon-strated by a reduction of the albumin level to 3.22 g/dL (normal value:⬎3.92 g/dL) and an elevation of the pro-thrombin time-international normal-ized ratio (2.07 [normal value:⬍1.20]). There was no serologic evidence of in-fection by hepatitis A, B, or C virus, cy-tomegalovirus, Epstein-Barr virus, ad-enovirus, HIV, herpes simplex virus 1 or 2, or parvovirus. His urine tested negative for drug metabolites (opium derivatives, methadone, cocaine, can-nabis derivates, amphetamine, barbi-turates, benzodiazepines, and ec-stasy). His serum acetaminophen concentration, measured 9 hours after the assumption of the last dose of the drug, was 7.2␮g/mL (reference range: 10.0 –30.0 ␮g/mL). Abdominal ultra-sonography revealed a normal liver without dilatation of intrahepatic or extrahepatic bile ducts; the gallblad-der was hypoechoic, had thick walls, and was contracted with a nonhomo-geneous content. During the second day of hospitalization, the patient de-veloped jaundice, lethargy, and retch-ing. An electroencephalogram did not reveal pathologic signs, but his ammo-nium concentration was 266 ␮g/dL (normal value:⬍125␮g/dL).

Acute acetaminophen-induced liver injury was diagnosed, and N

-acetylcysteine (NAC) was promptly started (150 mg/kg in 90 minutes in glucose solution [5%] followed by 300 mg/kg per day for 5 days). Oral feeding was stopped, and hydration was main-tained by electrolytic solution infusion. Lactulose was administered at a dos-age of 1.8 g/kg per day, and a single dose of vitamin K (5 mg intravenously) was given. The indexes of hepatic ne-crosis improved on the ﬁrst day of therapy, and his ammonium concen-tration normalized within 48 hours. Af-ter an initial worsening (albumin: 2.89 g/dL; prothrombin time-international normalized ratio: 2.07), hepatic func-tional indexes normalized within 5 days of treatment.

Molecular analysis of cytochrome P-450 (CYP) 3A4 revealed wild-type ho-mozygote status of the patient.

At the end of treatment, abdominal ul-trasonography revealed a normal liver and bile ducts. The infant was dis-charged 13 days after admission with complete resolution of all clinical and laboratory abnormalities. Results of liver-function tests remained in the normal range 1, 3, and 6 months later.

DISCUSSION

Our report highlights the possibility that multiple therapeutic doses of acetaminophen in infants may lead to acute hepatic failure. Acetaminophen is a widely used medication with a good safety proﬁle,1,6 _{although doses}

that exceed 150 mg/kg may lead to se-vere hepatic failure,2 _{particularly in}

cases with delayed presentation and treatment.7 _{The recommended daily}

dose in children is 60 mg/kg (90 mg/kg maximum),8 _which

corre-sponds to 10 to 15 mg/kg every 4 or 6 hours.9_{In June 2009, the US Food and}

Drug Administration discussed the possibility of lowering the daily rec-ommended dose of acetaminophen10_;

however, an agreement has yet not been reached.

CASE REPORTS

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been suggested that they could be a result of acetaminophen accumula-tion.11_{In a review of 47 cases of acute}

liver failure caused by chronic admin-istration of acetaminophen at thera-peutic dosage, 46.8% of the patients were younger than 2 years.12_{Muñiz et}

al3_{described the case of a 58-day-old}

infant who developed hepatotoxicity after multiple administrations of acet-aminophen at a dosage of 16.32 mg/ kg.3_{Unlike our patient, the infant had a}

high serum acetaminophen level (287

␮g/mL), and her liver abnormalities peaked on day 3. Our patient assumed therapeutic doses of acetaminophen for 10 days, and there was no elevation of serum acetaminophen level. Toxic se-rum concentrations of acetaminophen have been found in approximately three-quarters of cases with acetaminophen-induced hepatotoxicity.

Acetaminophen is metabolized in the liver via 3 main pathways: sulfation, glucuronidation, and oxidation. The ﬁrst 2 pathways are quantitatively more important, but the oxidative pathway is implicated in toxicity.13,14

The sulfate pathway can become satu-rated at low acetaminophen doses,15_and

the sulfate substrate may become de-pleted during multiple administrations of therapeutic doses of acetamino-phen,16_{which results in hepatotoxicity.}

The drug is oxidized by CYP (CYP 2E1, 3A4, and 1A2) to a toxic metabolite (N -acetyl-p-benzoquinone imine [NAPQI]) that is detoxiﬁed by glutathione and eliminated in the urine or bile. Al-though at toxic acetaminophen doses

lite NAPQI, CYP 2A6 can also contribute signiﬁcantly to NAPQI production.17_The

NAPQI fraction that is not detoxiﬁed may bind the hepatocytes and produce necrosis as a result of various intra-cellular events including deranged cel-lular calcium homeostasis, mitochon-drial oxidative stress, and formation of peroxynitrite.18_{The innate immune}

re-sponse has also been implicated in the pathophysiology of acetaminophen hepatotoxicity. In fact, this condition has been associated with the activa-tion of resident innate immune cells in the liver, the release of inﬂammatory mediators such as cytokines, chemo-kines, and reactive oxygen and nitro-gen species, and the recruitment of inﬂammatory cells.19

Marked interindividual differences in the expression levels of enzymes in-volved in acetaminophen metabolism in humans may be attributed to ge-netic polymorphisms.20_{An inherited}

in-creased activity of CYP 2E1 or 3A4 may increase conversion of acet-aminophen to its toxic metabolite.21,22

People who are heterozygous for glu-tathione synthetase deﬁciency may have a limited NAPQI detoxiﬁcation capacity.23 _{Molecular analysis}

re-vealed that CYP 3A4 was not altered in our patient. Little is known about the pathways of acetaminophen me-tabolism in infants younger than 12 months.

Intravenous administration of NAC pre-vents the progression of hepatic ne-crosis by replenishing reduced stores of glutathione.24_{The interval between}

preventing the progression of liver damage. Indeed, in 2 multicenter stud-ies, treatment with NAC resulted in no acetaminophen toxicity-related deaths when administered within 16 to 24 hours.25,26 _{In another study, efﬁcacy}

was highest when NAC was adminis-tered within 8 to 10 hours.27_{Prescott et}

al28_{reported that intravenous NAC 300}

mg/kg for 20 hours (a loading dose of 150 mg/kg infused for 15 minutes, fol-lowed by 50 mg/kg for 4 hours and then 100 mg/kg for 16 hours) was ef-fective in counteracting acetamino-phen poisoning. Our patient was treated with NAC at a loading dose of 150 mg/kg, followed by 300 mg/kg per day for 5 days. This treatment resulted in a rapid improvement of hepatic ne-crosis and function indexes without any adverse reaction.

CONCLUSIONS

Although acetaminophen toxicity is rare, health care providers need to be aware that children who receive multi-ple therapeutic doses of the drug may develop acute hepatic failure. When there is a high index of suspicion of acetaminophen toxicity, NAC treatment should be initiated because of its low toxicity and beneﬁcial effects.

ACKNOWLEDGMENTS

We are grateful to Jean Ann Gilder for editing the text and Antonio D’Avolio (Amedeo di Savoia Hospital, Department of Infectious Disease, Turin, Italy) for the cytochrome analyses.

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CASE REPORTS

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DOI: 10.1542/peds.2010-1965 originally published online January 17, 2011;

2011;127;e494

Pediatrics

Silvia Garazzino and Pier-Angelo Tovo

Francesco Savino, Maria Maddalena Lupica, Valentina Tarasco, Emanuela Locatelli,

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DOI: 10.1542/peds.2010-1965 originally published online January 17, 2011;

2011;127;e494

Pediatrics

Silvia Garazzino and Pier-Angelo Tovo

Francesco Savino, Maria Maddalena Lupica, Valentina Tarasco, Emanuela Locatelli,

Recommended Dosage in an Infant

Fulminant Hepatitis After 10 Days of Acetaminophen Treatment at

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