F Ahmad, et al. www.hepato-gastroenterology.org
DOI 10.5754/hge11107 2011; 58(110-111): Ahead of Print
Liver, Original
Hepato-Gastroenterology Open Access, Ahead of Print
CYP3A4*18 Polymorphisms and Anti-Hepatitis A Virus Seroprevalence Fazlina Ahmad1, Nor Aizal Che Hamzah1, Nazri Mustaffa1and Gan Siew Hua2 Department of Medicine, Hospital Universiti Sains Malaysia, Kelantan, Malaysia
1
2
Human Genome Centre, Hospital Universiti Sains Malaysia, Kelantan, Malaysia
Corresponding author: Siew Hua Gan, Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia; Tel.: +6097676798, Fax: +6097653370; E-mail:
[email protected]
KEY WORDS: CYP3A4*18 polymorphisms, Anti-hepatitis A. ABBREVIATIONS: Hepatitis A Virus (HAV); Chronic Liver Diseases (CLD); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); Hepatitis B Virus Surface Antigen (HBsAg); Cytochrome (CYP); Cytochrome P450 3A4 (CYP3A4); Liver Cirrhosis (LC). ABSTRACT Background/Aims: CYP3A4 is the major cytochrome in humans which shows reduced activity in chronic liver disease as well as in hepatic cirrhosis. The detection of this polymorphism may give an indication on the prognosis of patients having chronic viral hepatitis with superimposed hepatitis A infection. The aim of this study is to correlate the seroprevalence of anti-HAV antibodies in chronic liver disease patients having CYP3A4*18 polymorphisms. Methodology: This is a prospective study where patients’ (n=119) blood was tested for anti-HAVIgG and CYP3A4*18 polymorphism. Results: The overall anti-HAV seroprevalence was 88.2%. The etiology of CLD was hepatitis B in 96 patients (80.7%) and hepatitis C in 23 patients (19.3%). There was a significant increase in the age of the prevalence of this disease after 30 years of age (p=0.008). CYP3A4*18 polymorphism was detected in 3 (2.5%) of the patients with chronic liver disease. However, there was no significant association between CP3A4*18 mutation and anti-HAV serology. Conclusions: Age was the most important factor in determining anti-HAV positivity. It is concluded that CYP3A4*18 genetic polymorphism does not play a main role in influencing the seroprevalence of anti-hepatitis A among chronic viral hepatitis B and C liver disease patients.
INTRODUCTION Hepatitis A virus (HAV) is usually acquired via contaminated food or drinks. In developing countries or regions with poor standards of hygiene, the incidence of this infection is higher, with the illness usually occurring during early childhood. Hepatitis A infection among children is mostly asymptomatic and could lead to many unreported cases and underestimation of the true incidence. In Western and other industrialized countries, its prevalence is relatively low (1) when compared to Asian countries. Usually, children and young adults do not have natural immunity. Therefore, HAV infections tend to occur in community-wide outbreaks among susceptible children and young adults in high-risk group. Unlike in children, infection among adults and in those with underlying chronic liver diseases (CLD) often results in significant symptoms as well as increased morbidity and mortality (2). When compared to other causes of viral hepatitis, hepatitis A was reported to be the main cause for symptomatic clinical hepatitis (up to 66.4% in 1996) (3) and remains a significant problem in the Eastern region of Peninsular Malaysia. Over the last 20 years, the patterns of endemicity in South East Asia have changed due to improvements in living standards, with some countries shifting from high to intermediate, or intermediate to low endemicity (4). Together with Thailand and Sri Lanka, Malaysia is among the countries reported to be of intermediate endemicity (4). A local study conducted by Ton et al. (5) reported that the seroprevalence of hepatitis A among 100 healthy individuals is 78.2%. In 1985, it was reported that 100% of the Malaysian population in a study becomes anti-HAV positive once they reach 30 years of age (6). However, the scenario was different in 1992 with only 45% of the same age group being antibody positive, indicating a shifting epidemiology (6). Due to the shifting patterns of antibodies to HAV, the prevalence of HAV in Malaysia is expected to fall over time. On the other hand, as young adults are not immunized, reintroduction of the virus to non-immune population could produce a community level outbreak and this may lead to an increase in morbidity and mortality (7). In the West, vaccination against HAV has been recommended in all patients with CLD to prevent decompensation of liver disease due to super-infection with HAV. However, in countries where hepatitis A is still endemic, as in Malaysia, the usefulness of this vaccine needs to be examined as most CLD patients had acquired natural immunity (8). 2
HAV super-infections in patients with underlying chronic hepatitis or liver cirrhosis (LC) may lead to further decompensation of the liver. Acute HAV super-infection has higher morbidity and mortality when compared to isolated cases of acute HAV infection, leading to an increase in the likelihood of developing a fulminant liver failure. Based on epidemiological studies on huge hepatitis A outbreaks in Shanghai in the late 1980’s, acute hepatitis A among chronic hepatitis B has an even more severe clinical course and higher risk of death (9), where the fatality rates for acute hepatitis A were 5.6 times higher among hepatitis B virus (HBV) surface antigen (HBsAg) carriers when compared to HBsAg-negative patients (10). A similar scenario may also be true for super-infection of hepatitis A among patients with chronic hepatitis C. An observational study over a 7-year period among 432 Italian patients with chronic hepatitis C reported that amongst the 17 patients (3.9%) with acute hepatitis A super-infection, 41% eventually progressed into fulminant hepatic failures (11). Due to alteration as well as destruction of liver cells, liver disease is also associated with reduced metabolic capacity for drugs and substances that are metabolized by cytochrome (CYP) P450 (12). Since hepatic levels of CYP3A4 isoform of CYP were selectively altered in CLD, it is postulated that polymorphic variants of CYP in patients with hepatitis C may influence progression to CLD and even hepatocellular carcinoma (13). The reduced CYP3A4 activity in hepatic cirrhosis due to reduced expression of the CYP3A4 gene may lead to a decreased ability of the liver to eliminate many drugs and substrates such as harmful environmental toxins (14). Among Asian subjects, CYP3A4*18 allele is found in higher frequencies as compared to other CYP3A4 alleles (15,16). CYP3A4*18 is a variant allele in exon 10 involving T to C transition that changes Leu to Pro at site 293 (17) and may have important clinical implication in individuals carrying these variants. Dai et al. (18) for example indicated that CYP3A4*18 showed a significantly higher turnover number for both testosterone and insecticide chlorpyrifos in vitro. Ruzilawati et al. (16) however, showed that this variant allele is responsible for the metabolism reduction of repaglinide (16). It has been reported that hepatitis C and B, as well as alcoholic liver disease increase CYP3A4 activity (19). Therefore, it would be interesting to investigate if there is any correlation between CYP3A4*18 genetic polymorphism and these diseases. Furthermore, to date, there is no study that investigates the seroprevalence of anti-hepatitis A among CLD patients. The scarcity of data prompted the undertaking of these two tasks in this study. 3
MTEHODOLOGY Sample population One hundred and nineteen patients with CLD attending the gastroenterology clinic of Sains University Malaysia, Kelantan between July and September 2009 were enrolled after having signed written informed consents. The diagnosis of CLD was based on the presence of HBsAg or anti-hepatitis C virus antibody (anti-HCV) in the serum for at least 6 months duration. The underlying liver diseases were classified either into 1) LC or 2) non cirrhotic CLD. LC was evidenced by previous ultrasonography (i.e. coarse liver architecture, nodular liver surface and blunt liver edges) as well as confirmation of hypersplenism (i.e. splenomegaly on ultrasonography with a platelet count
