Role of N-acetylcysteine in liver injury due to dengue fever

Introduction

Dengue fever (DF) can be caused by any of the four serotypes (DEN 1-4) of the dengue virus of the Flaviviridae family, which are transmitted by the Aedes aegypti mosquito. ¹ Liver involvement is a common manifestation, mostly associated with serotypes 3 and 4. ² Exposure to any one serotype results in immunity against that same serotype, while a second exposure from a different serotype will produce a more serious outcome. ³ Though usually mild and self-limiting, severe hepatitis (DISH) may occur with an incidence of 4%–15%, with a rise of transaminases to more than 10 times normal levels. ⁴

A study from Brazil in 1585 patients showed a rise in aspartate aminotransferase (AST) in 88% and in alanine aminotransferase (ALT) in 69% of cases of DF, though only 4%–7% had acute hepatitis. ⁵ However, with such severe liver involvement, mortality can rise to 50% owing to significant bleeding, hepatic encephalopathy, kidney injury, and metabolic acidosis. ⁶ Unfortunately, neither DF or associated dengue-induced liver injury has any specific antiviral treatment available to slow, stop, or reverse its disease course up till now. Supportive strategies focus on managing coagulopathy, hypoglycaemia, encephalopathy, and cerebral oedema.

NAC therapy has been studied in facilities where liver transplantation is either unavailable or expensive.^7,8 Its major benefit is among patients presenting in early phases of hepatic injury and encephalopathy. NAC has a definitive role in the treatment of paracetamol toxicity and nasal mucociliary clearance. Artificial liver support in the form of Molecular Adsorbent Recirculating System (MARS) or as Single Pass Albumin Dialysis (SPAD) requires complicated machinery and trained staff.^9,10

Methods

Research articles regarding the use of NAC in dengue-induced acute liver disease were searched on PubMed, Google Scholar and EMBASE using the terms, “dengue fever AND acute liver injury”, “acute hepatitis AND dengue fever”, “N-acetylcysteine AND dengue fever”, and “N-acetylcysteine AND non-acetaminophen liver injury”. All relevant research articles including original papers, case reports, and reviews were incorporated into the study. The studies in children were also included. Cross references to older studies were included. We thus identified 36266 articles, of which 33 were included in the final review (Figure 1).

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Figure 1.

The flowchart demonstrating literature selection process.

Pathogenesis of liver injury in dengue fever

The precise pathogenesis of dengue-induced liver injury is not clearly known and is multifaceted.^11,12 The replication of DF virus in hepatocytes results in cell death. An unbalanced host immune response also leads to liver injury. ¹³ The role of oxidative stress has also been described in the acute viral phase. ¹⁴ Further, the role of inflammatory cytokines such as interleukin IL-17 and IL-22 has also been reported. ¹⁵ IL-2, IL-6 and IL-8 and tumour necrosis factor (TNF) alpha levels are raised in early DF infection whereas IL-5 and IL-10 are increased subsequently. ¹⁶ In dengue shock syndrome, a multitude of factors are again involved but ischaemic injury seems to be a subsidiary factor of liver dysfunction. ¹⁷

Degeneration of middle zonal cells and centrilobular area with typical Councilman bodies are seen. These represent the process of hepatic cell apoptosis. Some liver biopsies from DF patients show viral antigens in hepatocytes and Kupffer cells. ¹⁸

NAC raises glutathione levels intracellularly as a result of enhancing the activity of glutathione S-transferase enzyme predominantly in the liver. The antioxidant effect of NAC is perhaps due to increased plasma glutathione peroxidase and glutathione reductase. In acute DF, these enzymes are shown to be reduced, suggesting a putative role of NAC. ¹⁵

Additionally, NAC also has anti-inflammatory and vasodilatory effects, counteracting the adverse effects of impaired liver perfusion and thus, decreasing apoptosis of hepatocytes due to oxidative stress and immune-mediated injury. ¹⁹ Indeed, in a prospective trial, NAC in non-paracetamol-induced ALF had survival benefit in the initial stages of hepatic coma. ⁷ A limited number of case reports and case series have shown the beneficial effects of NAC in DF-associated acute severe hepatitis.^8,9,20,21

Data regarding the optimal dosage, loading dose, infusion rate, and duration of NAC therapy are subjective since no guidelines exist. It is, however, a relatively safe drug with minimal side effects. A summary is appended in Tables 1 and 2.

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Table 1.

Research studies on efficacy of NAC in dengue fever with severe hepatitis.

Study	Study Type	Description	Treatment given	Time to recovery	Mortality	Remark
Ishtiaq et al. 2019 22	Descriptive cross-sectional study	63 admitted patients with dengue-associate during 18-month period	NAC infusion PCV transfusion	Not specified	None	Possibly effective
Dissanayake et al. 2021 23	Retrospective analysis	30 adults with severe DF and severe hepatitis	NAC infusion	mean length of hospital stay: 6.2  ±  1.27 days.	One patient	Effective with faster clinical and biochemical recovery
Sriphongphankul et al. 2021 24	Retrospective cohort study	33 patients with DF associated ALF; 33/16 received NAC	NAC infusion	median duration of ALF was 5 days in the NAC group and 4 days in the non-NAC treatment (p  =  0.91). The length of hospital stay in the NAC treatment group was 25 days vs. 22.7 days in the non- NAC treatment group	Two patients (one case of each group) had ALF resolution but died from other complications (one child with uncontrolled invasive aspergillosis pneumonia and acute renal failure in the NAC group and another child with intracranial bleeding in the non-NAC group).	Maybe beneficial in paediatric population

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Table 2.

Studies on efficacy of NAC in dengue fever with severe hepatitis.

Reference	Article type	Case description	Treatment given	Efficacy of NAC
Arunpriyandan et al. 2022 25	Case report	16-year-old male with severe DF with ALF	NAC infusion IV methylprednisolone three cycles TPE FFP and cryoprecipitate	Inconclusive
Tafere et al. 2020 26	Literature review	Variable	NAC infusion	Potential as a definitive therapy
Suganthan et al. 2020 27	Case report	34-year-old male, ethanol user with binge drinking with ALF with HE-3	NAC infusion Lactulose Metronidazole IV thiamine Short acting benzodiazepines	Inconclusive
Dalugama et al. 2018 20	Case report	43-year-old diabetic women with dyslipidemia with DF induced ALF with AKI with anuria and lactic acidosis	NAC infusion Metronidazole Lactulose Tranexamic acid Norethisterone IV vitamin K FFP, cryoprecipitate, platelets CVVHD	Inconclusive
Dalugama et al. 2017 28	Case report	53-year-old male with severe DF with ALF	NACinfusion Metronidazole Lactulose IV vitamin K	Possibly beneficial in conjunction with PCV
Habaragamuwa et al. 2014 9	Case report	54-year-old women with DHF with severe hepatitis with HE-2	NAC infusion	Effective
Manoj et al. 2014 21	Case report	37-year-old male with DHF with severe hepatitis with HE-3	NAC infusion IV vitamin K Thiamine Lactulose Oral metronidazole Platelets and FFP transfusion Mannitol infusion rFVIIa	Potential benefit of NAC with rFVIIa
Abeysekera et al. 2012 29	Case report	52-year-old hypertensive women with DHF	NAC infusion IV thiamine Oral metronidazole IV vitamin K Broad spectrum antibiotics	Inconclusive

NAC: N-Acetylcysteine; ALF: Acute Liver Failure; IV: Intravenous; TPE: Therapeutic Plasma Exchange; FFP: Fresh Frozen Plasma; INR: International Standardised ration; HE: Hepatic Encephalopathy; HE-3: Hepatic Encephalopathy grade 3; D5%: 5% dextrose; PCV: Packed Cell Volume; AKI: Acute Kidney Injury; CVVHD: Continuous Veno-Venous Hemodialysis; DHF: Dengue Hemorrhagic Fever; HE-2: Hepatic Encephalopathy grade 2; rFVIIa: recombinant Factor VIIa; NS: Normal Saline.

Conclusion

From the data gathered from several studies, there is no large, randomised, double-blind, controlled trial on the efficacy of NAC in dengue-induced liver involvement. Existing evidence relies on anecdotal reports. No large comparisons of NAC with or without supportive care exists, though it may have at least an incremental benefit; however, this is not substantial enough to recommend its routine administration. Furthermore, the costs of IV NAC are prohibitive. Thus, we cannot recommend its routine use as yet.