Hepatol Int. 2010 Jun; 4(2): 533534.

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, 2864 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 IIIIV). Time from disease onset to
appearance of encephalopathy was 58 days. Worst recorded pretreatment value ranges for the
eight patients were as follows: platelet count = 6,00030,000/mm3; international normalized
ratio = 1.63.2; serum bilirubin = 2.712.2 mg/dL; alanine aminotransferase = 4,070
19,800 IU/L; aspartate aminotransferase = 4,45526,500 IU/L; serum albumin = 2.73.9 g/dL;
serum globulin = 3.13.9 g/dL; and serum creatinine = 0.72.5 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 III recovered completely
and were well at follow-up after at least 2 months, whereas the three patients with coma grades
IIIIV 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): 181182.

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 acetylcysteines antioxidant and vasodilating effects.