Hepatol Int. 2010 Jun; 4(2): 533–534.

Published online 2010 May 28. doi: 10.1007/s12072-010-9176-4

PMCID: PMC2900558

Intravenous N-acetylcysteine in dengue-associated acute

liver failure
We retrospectively analyzed the outcome of eight consecutive adult patients (5 men and 3
women; age range, 28–64 years) presenting during the current epidemic with serologically
confirmed dengue-associated acute liver failure. In addition to other supportive management
[6, 7], they received NAC 150 mg/kg loading dose by intravenous administration over 15 min
followed by 12.5 mg/kg/h for 4 h and then 6.25 mg/kg/h for up to 72 h. Two patients had dengue
hemorrhagic fever [6], six had dengue shock syndrome [6], seven had pleural effusions, and five
had ascites. Five patients had early-stage pretreatment hepatic encephalopathy (coma grades I–
II), and three had advanced encephalopathy (coma grades III–IV). Time from disease onset to
appearance of encephalopathy was 5–8 days. Worst recorded pretreatment value ranges for the
eight patients were as follows: platelet count = 6,000–30,000/mm3; international normalized
ratio = 1.6–3.2; serum bilirubin = 2.7–12.2 mg/dL; alanine aminotransferase = 4,070–
19,800 IU/L; aspartate aminotransferase = 4,455–26,500 IU/L; serum albumin = 2.7–3.9 g/dL;
serum globulin = 3.1–3.9 g/dL; and serum creatinine = 0.7–2.5 mg/dL. None had taken
acetaminophen more than the prescribed therapeutic dose, used hepatotoxic drugs, or had a
history of alcohol abuse. Serology was negative for hepatitis A, B, C, and E, leptospira, and
rickettsiae. All patients underwent computerized tomography of the brain to exclude intracranial
hemorrhage and cerebral edema. All five patients with coma grades I–II recovered completely
and were well at follow-up after at least 2 months, whereas the three patients with coma grades
III–IV died. No patient had adverse effects attributable to NAC.

Liver dysfunction in dengue infection may be a direct viral effect on liver cells, an adverse
consequence of dysregulated host-immune responses against the virus, ischemic hepatic injury
due to circulatory collapse in dengue shock syndrome, or a combination of any of these factors
[3]. NAC may benefit patients with nonacetaminophen acute liver failure by improving systemic
hemodynamics, by tissue oxygen delivery, or via other favorable effects on the acutely injured
liver [2, 8, 9]. Lee et al. [2] conclude that benefit is seen when NAC is used in the early stages of
liver failure but not when it is advanced. Our preliminary observations support their view and
suggest that the intravenous administration of NAC in the early stages of dengue-associated liver
failure is safe and may benefit patients. Larger randomized clinical trials must investigate this
further, but until then, we recommend its use, especially in situations in which liver
transplantation is not available.
Indian J Crit Care Med. 2014 Mar; 18(3): 181–182.

doi: 10.4103/0972-5229.128712

PMCID: PMC3963205

N-acetylcystein in dengue associated severe hepatitis

Although, N-acetylcystein (NAC) has shown benefit in non-acetaminophen related liver failure, it was
not well studies in dengue associated severe hepatitis. We report a case of dengue hemorrhagic fever
associated severe hepatitis (encephalopathy grade 2-drowsy and intermittent disorientation) treated
with NAC resulted in good outcome without hepatic transplantation.

Lee et al. found a significantly improved transplantation free survival at 3 weeks and at 1 year with the
use of NAC in non-acetaminophen related liver failure, the benefit being confined to those with early
hepatic encephalopathy.

The elevation of transaminases is usually less than five-fold greater than upper limit of normal.
However, levels more than five-fold were reported 36.8% and 74.4% of patients with classical dengue
and dengue hemorrhagic fever (DHF) respectively. Fulminant hepatitis tends to occur more often in DHF
or dengue shock syndrome compared to classic dengue infection and case fatality rate of 50% being
reported.[3] Although, NAC has shown benefit in non-acetaminophen related liver failure, it was not
well studied in dengue associated severe hepatitis.

Intravenous NAC was started at 100 mg/kg/day as an infusion and continued for 5 days with liver failure
regime.

Pathogenesis of liver involvement in dengue fever is complex and is poorly understood. Both
virus itself and dysregulated immune response to virus are being described as possible
mechanisms of liver damage in literature.[3] Although, severe hepatitis associated with dengue
fever is a rare occurrence, it carries significant mortality and morbidity.

NAC, mostly used in acetaminophen poisoning, acts through its antidote effect of repletion of
hepatocellular glutathione stores. NAC scavenges free radicals, improves antioxidant defense
and acts as a vasodilator to improve oxygen delivery and consumption.[4] These properties of
NAC have been postulated to improve outcome in patient with dengue associated acute liver
dysfunction. Lee et al. concluded that benefit is seen when NAC is used early stage of liver
failure rather than late stage.[2] A retrospective analysis on NAC in dengue associated liver
failure by Kumarasena et al. showed that 5 patients who survived out of 8 were in early (coma
grade 1, 11) liver failure stage at the time when NAC was started.[5] This case report also
supports the view that intravenous administration of NAC is safe and benefits patients, if started
in early stage of liver failure.
This patient was treated with intravenous NAC 100 mg/kg/day infusion for 5 days compared to 150
mg/kg bolus over 15 min followed by 12.5 mg/kg/h for 4 h and then 6.25 mg/kg/h for 72 h was given by
Kumarasena et al. in their retrospective analysis. Lim et al. reported a pediatric patient with dengue
associated liver failure successfully treated with NAC and they have given intravenous NAC 100
mg/kg/day for 6 days. Thus, ideal regime of NAC in this situation needs to be determined.

Large randomized trials should be carried out to establish its efficacy along with appropriate dosage,
timing, and duration of treatment.

Standard definition for ALF includes evidence of abnormal coagulation, with INR of 1.5 or greater along
with any degree of hepatic encephalopathy in a patient without preexisting cirrhosis with the length of
illness less than 26 weeks in duration.

Fulminant liver failure is defined as rapid onset of acute encephalopathy and coagulopathy (INR 1.5) in the setting of
liver failure less than 6 weeks duration.
Mechanism by which acetylcysteine improves liver function in NAI-ALF has not been fully elucidated,
however the resultant tissue hypoxia observed is believed to be ameliorated by acetylcysteine’s
antioxidant and vasodilating effects.