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Pediatric Oncall Journal

Usefulness of N-acetylcysteine as Hepatoprotective Agent in Children Infected by Hepatitis A virus 04/25/2018 00:00:00

Usefulness of N-acetylcysteine as Hepatoprotective Agent in Children Infected by Hepatitis A virus

María de los Ángeles Durazo-Arvizu1, Karina Azpeitia-Cruz1, Roberto Dórame Castillo1, Manuel Alberto Cano-Rangel1, Norberto Sotelo-Cruz2.
1Servicio de Infectología, del Hospital Infantil del Estado de Sonora, Hermosillo Sonora, México,
2Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo Sonora, México.

Dr. Norberto Sotelo-Cruz, Professor Investigador Titular “B”. Departamento de Medicina y Ciencias de la Salud de la Universidad de Sonora, Av. Luis Donaldo Colosio S/N entre Reforma y Francisco Q. Salazar, Colonia Centro, Hermosillo Sonora, México C.P.83000.
Introduction: All forms of viral hepatitis are acute and/or chronic and transmissible. In less developed countries, they are considered a public health problem. The objective of this study was to examine the clinical effects of the oral administration of N-acetylcysteine (NAC) as hepatoprotective agent in pediatric patients infected with hepatitis A virus.
Materials and Methods: Fifty patients were studied. Group A (20 children) received N-acetylcysteine (50mg/kg) orally for 7 days. Group B (30 children) received no medication. The variables studied were: age, hepatitis-related signs and symptoms, fever, malaise, anorexia, nausea, vomiting, abdominal pain, jaundice, choluria, acholia, and undesirable effects of the drug. Laboratory tests were performed at baseline and 8 days later: complete blood count (CBC), glucose, total protein, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), bilirubin, urinalysis, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The results were analyzed using parametric and non-parametric statistical tests.
Results: In group A, the mean age was 8 years (65% male); in group B, the mean age was 8.3 years (56.6% male). There were no differences in clinical or laboratory manifestations. After 7 days of therapy, ALT (324 + 250.9 vs. 720.2 + 582 IU/L) and AST (134.2 + 108 vs. 502.4 + 518.3) were much lower in the patients who received NAC as compared to the controls (p<0.006 and p<0.003 respectively). No adverse effects were noted in the treated cases.
Conclusion: The oral administration of NAC helps to significantly reduce liver enzymes and is safe.
Hepatitis A, N-acetylcysteine, cytoprotection, aminotransferases, acute liver failure
All forms of viral hepatitis are transmissible, acute and/or chronic diseases; they have become particularly important worldwide due to their significant morbidity and mortality, and are considered a public health problem. (1,2) Hepatitis A virus infection (HAV) follows the fecal-oral route from person to person; risk factors include ingesting food or drinks contaminated by feces containing HAV, unhealthy practices such as not washing hands properly after using the bathroom, and sex acts involving both oral and anal contact. HAV has a high prevalence in some countries, particularly in the South Asia or Latin America. (1-5) Some people are highly exposed due to their work activity: health workers, food handlers, people involved in wastewater control, military personnel, nursery employees and childcare centers, as well as the children attending these places. (1,3,4) In 2005, HAV infection caused the death of 34,000 people around the world. Between 2012 – 2013, in Mexico, it affected 39,774 patients, 75% of which were children. The mortality associated with this disease is 1% (1-3); furthermore 1% of those infected will develop acute liver failure (ALF). Mortality rate of ALF is 65-90%. Between 15 and 26% of the subjects accepted in liver transplant centers had developed acute liver failure caused by HAV. (6-16)
When an HAV infection is diagnosed, it usually does not receive any treatment and is allowed to evolve naturally; it is thus necessary to offer hepatoprotective agent that prevent a child with this condition from evolving to ALF. In this regard, uncontrolled observations of patients of an outpatient clinic in Sonora showed that the oral administration of N-acetylcysteine (NAC) induced a decrease of aminotransferases in a shorter time than the natural course of the disease. NAC has shown benefit in previous studies. (7,11-13). This work had the aim of evaluating the clinical usefulness of this drug in children with hepatitis A.
Methods & Materials
This was a longitudinal and comparative study of 50 patients (aged from 1 to 17 years), of a public pediatric hospital in northwestern Mexico that attended the outpatient clinic or the hospital emergency room. The study was approved by the hospital ethics committee. The clinical signs of patients with suspected infection of HAV (clinical or prodromal, evidence or association with a family member with HAV infection or with an outbreak of HAV infection) were recorded and the following tests were requested: complete blood count (CBC), urinalysis, bilirubin, glucose, total proteins, prothrombin time (PT), partial thromboplastin time (PTT), International Normalized Ratio (INR), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as serologic tests for hepatitis viruses A, B and C. The clinical signs were obtained by systematic sampling, prior authorization and informed consent of parents and adolescents. Fifty patients with confirmed diagnosis by clinical features, laboratory tests and by serological, antibodies IgM against hepatitis A Virus (IgM-HAV) were divided randomly into two groups: 20 patients in group A received N-acetylcysteine (50 mg/kg) orally in three doses for 7 days and 30 patients in group B did not receive NAC. The greater number of controls was with the purpose to have greater statistical solidity.In previous studies, NAC has been administered in doses ranging from 15 to 100 mg/kg/day. (9,12) For the purpose of the study, we decided to use an average dose of 50 mg/kg/day. Patients with signs of acute liver failure (ALF) (10,12) and those who declined to participate in the study were excluded from the study. The collection of data was performed using a data-collection instrument designed for this purpose. Laboratory tests were performed on the eighth day after starting treatment; clinical signs and manifestations associated with tolerance and effects of the medication were also recorded at this time.

Statistical Analysis: The data obtained were subjected to the following statistical tests: Chi square test to compare proportions between groups; Student's T-test to compare means between groups; variance analysis, and correlation coefficients to analyses the association between variables.
The baseline clinical and laboratory characteristics in both the groups are depicted in Table 1. After 7 days of therapy, ALT and AST were much lower in the patients who received NAC as compared to the controls (p<0.006 and p<0.003 respectively). (Table 2). No adverse effects were noted in the treated cases.

Table 1. Signs and symptoms in patients with hepatitis A in both the groups
CHARACTERISTICS Group A (N=20) (%) Group B (N = 30) (%) P value
Age (years) 8 + 4.2 8.3 + 3.7 0.76
Female 7 (35) 13 (43.3) 0.38
Male 13 (65) 17 (56.66)
Clinical Features      
Asthenia 9 (45) 10 (33.33) 0.2
Hepatomegaly 13 (65) 18 (60) 0.47
Malaise 11 (55) 8 (26.66) 0.042
Nausea 13 (65) 22 (73.33) 0.42
Vomiting 4 (29) 8 (26.66) 0.37
Myalgia 3 (15) 0 0.05
Diarrhea 3 (15) 5 (16.66) 0.59
Pruritus 0 0 -
Jaundice 18 (90) 29 (96.66) 0.34
Acholia 4 (29) 5 (16.66) 0.52
Choluria 10 (50) 11 (36.66) 0.26
Hepatomegaly 4 (29) 4 (13.33) 0.4
Splenomegaly 2 (10) 0 0.15
Laboratory Features      
Prothrombin time (sec) 15.8 + 3.1 15.2 + 2.1 0.42
Blood glucose (mg/dl) 85 + 13 88.9 + 15.4 0.3
Direct Bilirubin (mg/d1) 4.7 + 3.2 6.4 + 4.7 0.15
ALT (IU/L) 1522.4 + 1009.3 1527.4 + 1217 0.98
AST(IU/L) 1459.6 + 829.8 1286.7 + 897.9 0.58
INR 1.2 + 0.3 1.2 + 0.2 0.88
LDH 986.9 + 817 813.5 + 343.5 0.3
Albumin (g/dl) 4 + 0.4 3.8 + 0.4 0.3

Note: INR - International Normalized Ratio, AST - aspartate aminotransferase, ALT - alanine aminotransferase, LDH- lactate dehydrogenase

Table 2: Effects of N-acetylcysteine in children with Hepatitis A after 8 days of treatment
  Group A (n= 20) Group B (n= 30) P value
Prothrombin time (sec) 13.9 + 1.3 14.1 + 1.0 0.68
Glucose (mg/dl) 91 + 10 92.3 + 8.5 0.61
Direct bilirubin (mg/dl) 2.6 + 2.1 10 + 3.1 0.19
ALT (IU/L) 324 + 250.9 720.2 + 582 0.006
AST (IU/L) 134.2 + 108 502.4 + 518.3 0.003
INR 1.1 + 0.1 1.2 + 0.6 0.28
Albumin (gm/dl) 4.1 + 0.5 4 + 0.5 0.82
LDH 476.7 + 148.7 641.9 + 372.7 0.06

Note: INR - International Normalized Ratio, AST - aspartate aminotransferase, ALT - alanine aminotransferase, LDH- lactate dehydrogenase
One of the complications that may suddenly appear in patients with HAV infection is ALF. NAC, due to its cytoprotective effect has reduced the number of patients who develop this complication. (9,10,12) NAC is derived from cysteine, in which an acetyl group is attached to a nitrogen atom of the thiol type; it can be oxidized by a large variety of radicals and also serve as a nucleophile (electron donor pair). When thiolate anions that transport nitrogen dioxide in the form of toxic azide-type (N3) carbonate ions, or excess superoxide electrons, are added to thiols and hydroxyl radicals (OH), they efficiently reduce hydrogen atoms from sulphide radicals. In this reaction, thiolate anions also transport radicals that are not oxidants, such as hydrogen peroxide, nitrites, hypochlorous acid and excess thiols. (11,12,14-21) The intravenous use of NAC improves hepatic serological biomarkers in patients with liver failure of various kinds, especially in the early stages, inducing hemodynamic and oxygen transport improvements in cases of fulminant hepatic failure. (14)
NAC seems to help limit liver damage by accelerating the reduction in the levels of aminotransferases. (6-22)This agrees with the findings of this study regarding the decrease of the markers AST and ALT in less time than in patients receiving other drugs or no treatment. A study on the use of NAC in children aged 1 month and 16 years with fulminant liver failure secondary to HAV and who received treatment in a tertiary care center of a developing country, showed that the evolution of the patients was significantly associated with improvement in liver function tests. (22, 23)
In the present study, it was evident that the group that received NAC showed a significant reduction in liver enzymes. Furthermore, NAC is a safe drug that can be orally administered in pediatric ages, as was shown here; no patient showed any adverse effects such as nausea, stomatitis, vomiting, tinnitus, fever or hemoptysis, as has been suggested by the literature. (24) This will probably encourage other physicians to follow this line of work and recommend strong hepatoprotective alternatives to children living in countries with a high incidence of HAV infection but who do not benefit from a formal program of immunization against this disease. Using NAC could at least prevent the infection from developing into ALF. (5,16, 25-27)
The oral administration of NAC to patients with hepatitis A infection, showed no adverse effects and significantly reduced the levels of aminotransferases. This makes it possible to assume that NAC has an hepatoprotective effect on children with HAV infection.
Compliance with Ethical Standards
Funding None
Conflict of Interest None
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Cite this article as:
Durazo-Arvizu M d l Á, Azpeitia-Cruz K, Castillo R D, Cano-Rangel M A, Sotelo-Cruz N. Usefulness of N-acetylcysteine as Hepatoprotective Agent in Children Infected by Hepatitis A virus. Pediatr Oncall J. 2018;15: 37-40. doi: 10.7199/ped.oncall.2018.14
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