Acute viral hepatitis A, which is caused by the hepatitis A virus (HAV), is an infectious disease that is prevalent worldwide, but more in underdeveloped and developing countries, and which can be prevented through vaccination. It is the most common cause of hepatitis worldwide 1. Although it is usually asymptomatic and subclinical in children, it can appear in a variety of clinical forms ranging from a mild flu-like condition to a fulminant hepatitis 2. A severe disease and fulminant liver failure because of HAV may occur in adulthood or in the elderly population and in patients with chronic liver disease (CLD) 3.
Although the seroprevalence of anti-HAV IgG has decreased in many countries, it is still quite high in underdeveloped countries 4. The HAV seroprevalence is known to increase as much as 100% before 10 years of age in regions with a high endemicity, whereas in regions with moderate and low endemicity, this rate is around 10% until mid-adolescence 5. Turkey is in the moderately endemic group in terms of the epidemiology of HAV infection. The most recent data show that the HAV is still widely circulating endemically in our country, but the age of encountering the virus shifts towards adolescence and young adulthood particularly in the Western Anatolia region of our country and in other regions of higher socioeconomic level 6. Decreasing hepatitis A incidence in line with accelerating development in our country makes vaccination against HAV more important in CLD patients who are at risk. Clean water and food, adherence to personal hygiene practices, and vaccination with the hepatitis A vaccine are important for protection from hepatitis A infection.
Konya is a province located in the Central Anatolia region of our country. Its socioeconomic status is better compared with the provinces in Eastern Anatolia and moderate compared with the provinces in Western Anatolia. The present study explores the rates of exposure to HAV by age groups and the need for vaccination in patients being monitored for chronic viral hepatitis diagnosis in our province.
Materials and methods
We included 537 individuals in our study who presented between January 2011 and December 2014 to the Infectious Diseases and Clinical Microbiology Outpatient Clinic of Baskent University Konya Medical and Research Hospital and who were diagnosed with chronic hepatitis B or chronic hepatitis C and/or liver cirrhosis. Patients whose hepatitis B surface antigen (HBsAg) was positive for 6 months and those whose hepatitis C virus antibody (anti-HCV) and HCV-RNA value were positive twice within an interval of at least 6 months were enrolled in the study. Patients who had received the hepatitis A vaccine previously and those who had nonviral or autoimmune hepatitis were excluded from the study. The status of underlying liver disease was classified into chronic hepatitis and liver cirrhosis. The diagnosis of liver cirrhosis was made if any one of the following findings was encountered: (i) compatible intraoperative gross findings or histologically compatible findings; (ii) evidence of portal hypertension in patients with liver disease; and (iii) compatible radiologic findings and platelet counts less than 100 000/mm3.
Blood samples of 10 ml were obtained from each patient. The samples were analyzed for the HBsAg, anti-HCV, and anti-HAV IgG parameters using the chemiluminescent microparticle immunoassay method in line with the procedure suggested by the manufacturing company (Architect i2000; Abbott Diagnostics, Abbott Park, Illinois, USA). Recurrent reactive results were considered positive. HCV-RNA detection in serum samples was performed using real-time PCR with a commercial kit (Fluorion; Iontek, Istanbul, Turkey). For RNA extraction, the QIAamp, Viral RNA Mini Extraction Kit (Qiagen, Hilden, Germany) was used in accordance with the instructions of the manufacturer.
The distribution of the patients by age and sex was assessed. The patients were divided into age groups of 10 years each.
The data were statistically analyzed using the SPSS (version 15.0; SPSS Inc., Chicago, Illinois, USA) statistical program. The data were described as numbers, percentages, and mean±SD. The χ 2-test was used for qualitative changes and Student’s t-test, one-way ANOVA, and variance analysis were used for quantitative changes when assessing the data. A χ 2-test was used to determine whether significant differences existed between two categorical variables. For multivariate analyses, a stepwise multivariate logistic regression model was used to assess the relative importance of variables showing a significant association (P<0.05). The results of all multivariable analyses were reported as adjusted odds ratio, 95% confidence interval, and exact P value.
A total of 537 patients were included in the study. A total of 437 patients were diagnosed with chronic hepatitis B, 60 with chronic hepatitis C, 18 with liver cirrhosis associated with chronic hepatitis B, and 22 with liver cirrhosis associated with chronic hepatitis C. A total of 297 (55.3%) of the patients were men and 240 (44.7%) were women. Their mean age was 45.9±14 years (15–81 years). Anti-HAV IgG was found to be positive in 506 (94.2%) patients and negative in 31 (5.8%) patients. The demographic characteristics of the patients are shown in Table 1.
When the study participants were classified by decade of age into seven groups, from less than 20 years to older than 70 years old, most of the chronic hepatitis patients were found to be in the 51–60 age interval and 64.6% of them were 40 years of age and older. Anti-HAV IgG seropositivity was 23.8% in the age group younger than 20 years, 82% in the 21–30 age group, and 90.5% in the 31–40 age group. The positivity rate for anti-HAV in the patients in their 40, 50, 60s, and those older than 71 years was 100, 99.1, 100, and 100%, respectively (Fig. 1). Anti-HAV IgG seropositivity in chronic hepatitis B and chronic hepatitis C patients is shown in Table 2 by age groups. The anti-HAV seroprevalence was significantly higher in patients older than 40 years compared with those patients younger than 40 years of age (99.7 vs. 80.4%, respectively, P<0.05) (Table 3).
Anti-HAV IgG seropositivity was found in 94.3% of male patients and 94.2% in female patients, and the difference was not statistically significant (P>0.05; Table 3). With respect to the etiology of liver disease and the status of liver disease, anti-HAV IgG was positive in 93.6% of the chronic hepatitis B patients and in 97.5% of the chronic hepatitis C patients (P>0.05). Anti-HAV IgG positivity was found to be 97.4% in cirrhotic patients and 93.9% in noncirrhotic patients, the difference being statistically insignificant (Table 3).
With respect to the residences of the patients with chronic viral hepatitis, anti-HAV IgG positivity was found to be significantly higher in those living in rural areas than in patients living in cities (P<0.05; Table 3).
Multivariable analysis of the factors for anti-HAV seropositivity is shown in Table 3. At the end of the study, being older than 40 years and living in a rural area were found to be independent risk factors for anti-HAV IgG seropositivity.
Two doses (at months 0 and 6) of the hepatitis A vaccine were administered to 21 of the 31 patients who had been found to be anti-HAV IgG negative. Only eight of these 21 patients could be examined for the outcome and anti-HAV IgG was found to be positive in all of them.
Developing countries are currently facing a change in the epidemiological pattern of HAV infection. Improved socioeconomic statuses, more sanitary environments, and advanced hygienic practices all play a role in steadily reducing the incidence of HAV infection and age-specific HAV seroprevalence in the general population. Declining HAV infections particularly in young adults have led to a decrease in the number of individuals with protective antibodies, resulting in an increase in the prevalence of hepatitis A in this population 7. With the improvements in the sanitation and hygiene conditions in our country in recent years, the age of exposure to hepatitis A has been reported to shift from childhood to adolescent or adult age groups 5. The statistical works carried out by the Ministry of Health between 1990 and 2005 show that the incidence of hepatitis A infections has decreased from 5325/100 000 to 1281/100 000 and the rate of mortality has decreased from 0.78/1 000 000 to 0.03/1 000 000 8.
In a recent multicentered study carried out in our country, but that did not include the province of Konya, 4793 patients with chronic hepatitis B were investigated and the rate of anti-HAV IgG positivity was found to be 93.5% 9. This rate is very close to the rate of anti-HAV IgG positivity that we found in chronic hepatitis B patients, which was 93.6%.
The anti-HAV IgG seropositivity in patients with a CLD has been reported in largely varying rates in the studies carried out in various countries of the world. In three different studies carried out in Italy on patients with a CLD, anti-HAV IgG seropositivity has been reported to be 79.3% 10 and 85.7% 11, and 97.64% in patients with chronic hepatitis C only 12. In another multicenter study carried out in Italy, the rate of anti-HAV IgG seropositivity was 53.5% in 2830 patients with a CLD, the rate being higher in the south and middle provinces of the country and lower in the north 13. The anti-HAV IgG seropositivity was 55% in patients with a CLD in the USA, another developed country 14.
In a study carried out in Saudi Arabia, anti-HAV IgG positivity was found to be as high as 98.5% in a group of 136 CLD patients whose mean age was 39.1±17.6 years and it was concluded at the end of the study that the hepatitis A vaccine was not necessary for adult patients with CLD 15.
In another study carried out in the Kerala region of India, anti-HAV IgG positivity was found to be 93.3% in 300 CLD patients whose mean age was 53±4 years, and at the end of the study it was suggested that routine vaccination should not be attempted before anti-HAV IgG was tested 16.
Anti-HAV IgG positivity was found to be 98.1% in adult patients with liver cirrhosis in Brazil and no routine vaccination was recommended at the end of the study 17.
In a study carried out in Iran, the anti-HAV IgG positivity was 79.2% in patients with chronic viral hepatitis, and hepatitis A vaccination was recommended for patients with chronic viral hepatitis who were younger than 30 years old 18.
A large number of studies have been carried out in Korea on this subject 19–24. In one of the two recent studies, the anti-HAV IgG positivity was found to be 86.61% in patients with chronic viral hepatitis 19 and the anti-HAV IgG positivity was found at to be 49.1% in the other study where only patients with chronic hepatitis B were assessed 20.
At the end of the study, being older than 40 years and living in a rural area were found to be independent risk factors for anti-HAV IgG seropositivity. The anti-HAV IgG positivity was found to be statistically higher in our study in patients older than 40 years compared with those younger than 40 years of age. Although an age above 40 years was found to be a risk factor for anti-HAV IgG seropositivity in the Korean study 19, the anti-HAV IgG seropositivity was found to be significantly higher in chronic hepatitis patients older than 30 years of age in a study carried out in Iran 18. A study carried out by Saab et al. 14 in the USA has shown that patients aged between 51 and 70 years have a higher risk of being exposed to HAV than patients younger than 51 years of age. Studies have shown that the ages at which individuals become infected have been shifting from young to old in developing countries 25,26.
When anti-HAV IgG positivity was assessed in terms of sex, no difference was found in most of the studies as in our study 13,14,20,21, but there are also study results showing that female sex is an independent risk factor 18,19. More anti-HAV IgG seropositivity was found in female patients in the study carried out in Korea. They explained this finding by the fact that female patients in Korea have a larger number of social and household contacts and thus probably more exposure to HAV 19.
With respect to place of residence, we found in our study that living in a rural area was an independent risk factor for anti-HAV IgG seropositivity. Although in the study carried out in Korea the anti-HAV IgG seroprevalence was found to be the lowest in Seoul, the most developed city of Korea, the rate was found to be higher in rural areas as in our study 19. In the study carried out in Italy, seroprevalence was found to be higher in the South of Italy than in the North and this was linked to improving hygiene and socioeconomic conditions in Northern Italy 13. Such variances in seroprevalence may be associated with differences in living conditions.
No correlation was found in the present study between anti-HAV IgG seropositivity and hepatitis B/hepatitis C. This result is in agreement with those of other studies 14,18,19. This finding may indicate that the immune response to HAV infection is not affected by either hepatitis B virus or HCV.
There was also no difference between cirrhotic and noncirrhotic patients with respect to anti-HAV IgG seropositivity. However, the results of some studies indicate that the anti-HAV IgG seropositivity is higher in patients with liver cirrhosis than in those with chronic viral hepatitis 18,19. They point out that the higher seropositivity of anti-HAV in older individuals may be explained by the fact that they lacked good hygiene practices in the past and were probably exposed to HAV, leading to the production of anti-HAV 18. The result that we found may be linked to the fact that the number of cirrhotic patients was smaller than the number of patients with chronic hepatitis in our study.
Two doses (at months 0 and 6) of the hepatitis A vaccine were administered to 21 of the 31 patients who had been found to be anti-HAV IgG negative. Only eight of these 21 patients could be examined for the outcome and anti-HAV IgG was found to be positive in all of them. In a study, the IgG seroconversion was found to be 86.17% in patients with chronic hepatitis B after their hepatitis A vaccination 27. However, no interpretation was attempted in this study on this issue because we could not vaccinate all the chronic viral hepatitis patients who were anti-HAV IgG negative and not all the patients that we could vaccinate attended follow-up.
Hepatitis A vaccines, which had initially been licensed to be used after age 2 as maternal antibodies showed persistence, were licensed by the Food and Drug Administration (FDA) after 2005 to be administered to children older than a year. Hepatitis A vaccine is recommended in the USA today for all children older than 1 year 28. In 2012, the Ministry of Health in Turkey included the hepatitis A vaccine in the routine vaccination program to be administered at the end of month 18 as the first dose and at the end of month 24 as the second in infancy 6. This routine vaccination program is good news for the coming years for our country, which is in moderate endemicity for particularly chronic hepatitis B.
In conclusion, patients with CLD who are younger than 40 and/or living in cities may be at risk for hepatitis A infection. Such patients should be advised to seek hepatitis A vaccination following an anti-HAV IgG test.
Conflicts of interest
There are no conflicts of interest.
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