N-acetyl Cysteine Therapy as Adjunctive Therapy for Treatment of Acute Hepatitis A

Background and study aim: Hepatitis A is an acute, usually mild and self-limiting disease affecting the liver. We aim to assess the effect of oral N-acetyl cysteine compared with placebo on length of hospital stay in adult patients who were admitted to the hospital with acute hepatitis A which might cause earlier resolution of hepatitis. 
Subjects and Methods: 40 patients were diagnosed as acute hepatitis A and classified into two groups, the first one involved 20 patients who received oral N-acetyl cysteine and supportive treatment, and the second one involved also 20 patients but they received placebo and supportive treatment. We measured complete blood count (CBC), kidney profile (KP), liver function test (LFT),  blood glucose, C-reactive protein (CRP) and coagulation profiles  on the day of presentation, and every other day till the day of discharge from the hospital. Serological tests were done for HAV Immunoglobulin M (IgM), HEV IgM, HBsAg, HBcIgM, antibody to Hepatitis C virus. 
Results: The mean length of hospital stay in the NAC group was 13.2 days compared with 14.3 days in the placebo group. Length of hospital stay differed significantly between groups.  The mean time of reliving symptoms at presentation was 3.6 days in the NAC group and 4.4 days in the placebo group. The mean time of reliving symptoms at presentation was significantly lower in NAC group than in placebo group. 
Conclusion: use of oral NAC as adjunctive therapy for treatment of acute hepatitis A was safe in these patients and was associated with a shorter length of patient stay in the hospital.


INTRODUCTION
Hepatitis A is an acute, usually mild and self-limiting disease of the liver caused by the hepatitis A virus (HAV) [1].The disease varies in clinical severity from a mild illness lasting 1-2 weeks to a severely disabling disease lasting several months.Most patients make a complete recovery [2].HAV hepatitis does not progress to chronic liver disease and there is no chronic carrier state.On rare occasions the disease may be very severe, with fulminant hepatitis, liver coma and death [2].Severity of illness is strongly age dependent.Young children who are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1-3 weeks, whereas adults tend to experience a much more severe form of the disease [3].Case fatality can reach 2% for adults over 50 years of age.Persons with pre-existing chronic liver diseases have an increased risk of death from fulminant hepatitis A. Infection with HAV confer life-long immunity [3].
Globally, hepatitis A is more common in regions of the world with poor sanitation and no enough safe water [4] and around 1. 4  The objective of this study was to assess the effect of oral N-acetyl cysteine compared with placebo on length of hospital stay in adult patients who were admitted to hospital with acute hepatitis A which might cause earlier resolution of hepatitis.

SUBJECTS AND METHODS
This study was conducted between February 2014 and July 2015, at the Infectious Disease Hospital (IDH).The patients included in this study were diagnosed as acute hepatitis A. Diagnosis of acute hepatitis A was clinically based on the presence of symptoms, e.g.anorexia, nausea, vomiting, abdominal discomfort, fever, fatigue and jaundice and confirmed serologically by positive of HAV Immunoglobulin M (IgM) antibodies, indicating acute disease.40 patients were diagnosed as acute hepatitis A and divided into two groups, the first one involved 20 patients who received oral N-acetyl cysteine and supportive treatment, and the second one involved also 20 patients but they received placebo and supportive treatment.All patients were subjected to history taking and thorough clinical examination.We measured liver function test (LFT), kidney profile (KP), complete blood count (CBC), blood glucose, Creactive protein (CRP) and coagulation profiles on the day of presentation, and every other day till the day of discharge from the hospital.Also, Serological tests were done for HBsAg, HBcIgM, antibody to Hepatitis C virus and antibody to hepatitis delta virus to exclude other causes of acute viral hepatitis.
Patients in the first group (NAC group) were given 600 mg NAC effervescent tablet orally once daily (600 mg/day), NAC was continued as long as required for normalization of laboratory investigations and the patients in the second group were given placebo orally 3 times a day (placebo group).All patients received supportive treatment, according to individual needs.The study protocol was approved by the local ethics committee.All patients were informed to participate in by an inscription form in the study.

Statistical Analysis :
The data were analyzed using the statistical package for social sciences (SPSS) version 8.0 software.The significance of differences between mean values of the study variables was evaluated by using t-test.The significance of differences between proportions was performed using the Chi-square test.Significant differences were expressed at P<0.05.

RESULTS
Forty patients were enrolled in this study, they were divided into two groups, N-acetyl cysteine group and placebo group, each of them involved 20 male patients varying in age from 14 years to 29 years.Of these, 11 patients were Indian, 10 Egyptian, 2 Indonesian, 8 Syrian, and 9 Kuwaiti.Symptoms at presentation included fever, anorexia, nausea, vomiting, abdominal discomfort, fatigue, dark urine and jaundice.
At the time of admission, there were no significant differences between the NAC group and the placebo group as regard to liver enzymes, Total bilirubin, direct bilirubin, INR, platelets, white blood cells, C-reactive protein, and serum creatinine (Table I).
After 5 days of admission, we noted a significant decline in liver enzymes (ALT & AST) and total bilirubin in the NAC group than the placebo group (table II).At time of discharge, there were no significant differences between the two groups as regard liver enzymes, total bilirubin, direct bilirubin, INR, platelets, white blood cells, Creactive protein, and serum creatinine (Table III).
The mean length of hospital stay in the NAC group was 13.2 days (±0.67) compared with 14.3 days (±0.75) in the placebo group.Length of hospital stay differed significantly between groups (p-value = 0.03, table III).All patients were started the treatment within one hour of admission to hospital.The mean time of reliving symptoms at presentation was 3.6 days in the NAC group and 4.4 days in the placebo group.The mean time of reliving symptoms at presentation was significantly lower in NAC group than in the placebo group (p-value = 0.05, Table II).

CONCLUSION
This study reported that the use of oral NAC as adjunctive therapy for treatment of acute hepatitis A was associated with a shorter length of hospital stay.We also found that the use of NAC was safe in these patients.There is an undoubted necessity for further research into the treatment of hepatitis A, and this study has identified a promising compound NAC, that may be an integral component of future HAV management.
Funding: None.Conflicts of interest: None.Ethical Approval:Approved.

Table II :
Comparison between studied groups after 5 days from admission

Table III :
Comparison between studied groups at time of dischargeThere are limited data addressing the use of oral NAC in the treatment of AHA.We could not find any study that focused on the effects of NAC on AHA except one published study investigating the effect of NAC on AVH (A & B), it was determined that NAC had no effect on the jaundice duration in AVH infection and the period in which the ALT value came back to normal and accordingly hospitalization duration of AVH patients and the prognosis of biochemical parameters [9].
DISCUSSIONN-acetyl cysteine (NAC) is a specially modified form of the dietary amino acid cysteine.When taken orally, NAC is thought to help the body make the important antioxidant enzyme glutathione.It has shown promise for a number of conditions, especially chronic bronchitis [13,14].