Year : 2001 | Volume
: 7 | Issue : 3 | Page : 95--102
Serological profile of sporadic acute viral hepatitis in an area of hyper-endemic hepatitis B virus infection
Ayobanji Ayoola1, Aderemi Aderoju1, Mohammed Osman El-Hassan Gadour1, Mohammed Al-Hazmi1, Mirghani Khalifa Hamza1, Dan Ene1, Magdy Hafeez1, David Anderson2, Michelle Riddell2,
1 Department of Medicine, Gizan Central Hospital, Saudi Arabia
2 Hepatitis Research Unit, Macferlene Bumet Centre Fiarfield, Victoria, Australia
Department of Medicine, King Fahad Central Hospital, P. 0. Box 235, Abu Arish
Background: Located in the south western part of Saudi Arabia, the Gizan region is largely a rural community in which hepatitis B and chronic liver disease including hepatocellular carcinoma are highly prevalent. Aim of study: To determine the relative frequencies of acute hepatitis A, B, C and E in acute viral hepatitis in an area of hyperendemic hepatitis B infection. Methods and materials: In a prospective study 246 consecutive patients (179 males and 67 females) diagnosed in a 2-year period were tested for markers of Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C (HCV) and hepatitis E virus (HEV). Results: Of the patients tested, 131 (53.3%) were children (<10 years), and 42 (17%) were 11 - 20 years in age. Ig M anti -HAV, IgM anti-HBV, anti- HCV and IgM anti-HEV were positive in 37%, 19.1%, 3.7% and 13.7% respectively. Markers of these viruses were absent in 24.4%. Among 131 children (< 10 years) the commonest cause of AVH was HAV occurring in 57.3% of the cases. In adults (> 21 years) HBV was found in 35.6% and IgM anti -HAV was detected in only 6.8%. In contrast to the age- related decline in the frequency of acute HA, the proportion of acute HE were similar in all age groups (13.7% in children, 16.7% in adolescents and 11.0% in adults). Conclusion: The study indicated that HAV is still a common cause of AVH particularly among children in Gizan. Acute 1-113 had a low occurrence among the children, evidently as a consequence of the integration of HB vaccine into the Saudi Arabian national EPI, 10 years ago. With the availability of combined HB and HA vaccines, It should be possible to graft the vaccination against HAV on to the existing program in Saudi Arabia. Affecting 13.4% of the group studied, sporadic HEV constitute a significant cause of AVH in this population. Until HEV vaccine becomes widely available, its prevention would be mainly by the improvement of socio - economic and hygienic standards of the population.
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Ayoola A, Aderoju A, Gadour ME, Al-Hazmi M, Hamza MK, Ene D, Hafeez M, Anderson D, Riddell M. Serological profile of sporadic acute viral hepatitis in an area of hyper-endemic hepatitis B virus infection.Saudi J Gastroenterol 2001;7:95-102
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Ayoola A, Aderoju A, Gadour ME, Al-Hazmi M, Hamza MK, Ene D, Hafeez M, Anderson D, Riddell M. Serological profile of sporadic acute viral hepatitis in an area of hyper-endemic hepatitis B virus infection. Saudi J Gastroenterol [serial online] 2001 [cited 2020 Jul 15 ];7:95-102
Available from: http://www.saudijgastro.com/text.asp?2001/7/3/95/33419
In spite of the rapid progress in research, surveillance, therapy and preventive strategies, viral hepatitis continues to be a serious public health problem in many parts of world  . An estimated incidence of all types of acute viral hepatitis varies between 100-200 per 100,000 especially among the inhabitants of developing countries and the number of cases of acute viral hepatitis has been estimated to be about 1-2 million per year in these populations  . In many developing countries, the system of notification of infectious diseases may be nonexistent, unreliable or rudimentary. Therefore, the clinical and epidemiological characteristics of acute viral hepatitis, with particular emphasis on the prevalence of various forms in these populations can only be inferred from studies of hospitalized patients.
Viral hepatitis is common in Saudi Arabia. By adult age, about 90 % of Saudis have antibodies to hepatitis A virus (anti-HAV). The average prevalence of hepatitis B surface antigen (HBsAg) in the asymptomatic population is 7% and about 70% have evidence of past exposure to hepatitis B virus (HBV) , . The prevalence of HBsAg in Gizan region of the country has been reported to be as high as 12-28% , . In contrast, antibody to hepatitis C virus (anti-HCV) is detectable in only 1-3% of asymptomatic Saudis , . Information on the epidemiological pattern of hepatitis E virus (HEV) in Saudi Arabia is scanty , . The availability of sensitive and specific assays for the detection of viral markers has made it possible to determine the relative frequencies of the various forms of viral hepatitis with significant accuracy and reliability. We report the results of a study carried out to determine the prevalence of HAV, HBV, HCV and HEV among patients with sporadic AVH in Gizan region, Saudi Arabia.
Patients and methods
Location: Gizan region is located on the Red Sea on the South -Western part of Saudi Arabia.
Its one million inhabitants receive free and effective health care service through a network of primary health care centers, eight general hospitals and a tertiary (referral) hospital, King Fahad Central Hospital (KFCH) Gizan, a-500-bedded hospital with modern facilities, well-equipped departments of gastroenterology and virology. King Fahad Central Hospital provides special diagnostic and therapeutic services to all the primary health care centers and general hospitals.
The services include serological assays for the detection of all hepatitis viruses. The results of these tests are reported to the regional directorate of the ministry of health (MOH) on a monthly basis as a part of a surveillance program. When the assay kits for IgM anti-HEV and IgG anti-HEV were available, a directive was issued by the directorate to the various hospitals to refer all the patients with the diagnosis of acute hepatitis to KFCH. In addition to direct referrals, patients meeting the diagnostic criteria were identified and recruited through the registry of daily serological and biochemical tests in the KFCH as well as Samtah General Hospital. The latter is a 100-bed hospital that serves a large catchment area in the region Patients: The subjects comprised consecutive patients who were diagnosed as cases of acute viral hepatitis (AVH) between January 1997 and November 1998. All were residents of Gizan. Serum samples obtained during the acute phase of the illness were tested immediately or frozen at -70°C until needed for testing. Methods: Acute viral hepatitis was diagnosed by symptoms (jaundice, arthralgia, abdominal pain), signs (icterus, hepatomegaly) elevated aminotransferase (ALT) levels of >2.5 times the upper limit of normal values, and the exclusion of other causes of hepatic injury such as drugs, toxins, cardiovascular diseases, malignancy, malaria and alcohol. History of blood transfusion, drug use, family contacts with jaundice and prior hospitalization was obtained from the patients or their parents, in the cases of children.
Acute hepatitis A (AVHA) and acute hepatitis E (AVHE) were diagnosed by the detection of serum IgM-antibody to HAV (IgM-anti HAV) and IgM antibody to HEV (IgM-anti HEV) respectively. Patients were categorized as having acute hepatitis B (AVHB) by positive IgM antibody to hepatitis B core antigen (IgM-anti-HBC) with or without HbsAg. Acute hepatitis C was diagnosed by the detection of anti-HCV in the acute phase or its appearance during the convalescent stage (within six months of the follow-up). A diagnosis of nonABCDE was made if none of the markers was detected in the acute phase samples or during the subsequent follow-up period.
Commercially available enzyme immunoassays (EIA) (Abbott Laboratories Chicago Ill.) were used for the detection of IgM anti-HAV, HBsAg, IgManti-HBc and antibody to hepatitis B surface antigen (anti-HBs). Anti-HCV was detected by a third generation EIA (Murex III) which utilizes antigens from the putative core (C, structural), protease/helicase (NS3, non- structural) NS4 (nonstructural) and replicase (NS5, non-structural) regions of the virus, providing a sensitive diagnostic test. Reactive samples were re-tested by immunoblot assays (HCV Blot 3.0 Genelabs Diagnostics and Ortho Diagnostics Systems Raritan NJ) Tests for IgG- and IgM - antibodies to HEV (anti HEV) were performed using commercially available ELISA kits (Abbott laboratories, North Chicago USA). These tests use as solid phase antigens, two recombinant proteins (SG-3 and antigen 8-5), derived from the open reading frames of the Burma strain of HEV expressed in E coli. (Genelabs Diagnostics). In addition IgM anti-HEV was detected by a new EIA system (Australia; utilizing recombinant antigens expressed in E. coli (HEV-IgM EIA; AMRAD Biotech Victoria  . All tests were carried out according to the manufacturers' instructions. The AMRAD Biotech (Victoria Australia) kindly supplied all the reagents and test kits. Statistical analysis: Proportions were compared using the chi square or the Fisher's exact tests. Mean values were compared by the student's t test. A p value of , . However, there is evidence that HEV infection is endemic in some areas of the Middle East , . The finding in the present study is consistent with this observation and may indicate that the infection may be more common in its sporadic forms than hitherto reported. Similar to the rate of HEV infection in Gizan patients (13.4%), an earlier study among Saudi Arab samples of patients presumed to have had AVH found a seroprevalence of 14.4%  . However, the locations or clinical details about the patients' illnesses were not provided in that report. In contrast, Knawy et al  reported that none of 132 patients with sporadic AVH in the Asir region (Southern part) of Saudi Arabia was positive for IgM-anti-HEV and concluded that HEV infection played no role in the etiology of AVH in that population.
Regional variations in the prevalence of viral hepatitis within the same country or continent are well known ,,,, . Although the population of Saudi Arabia is homogenous in culture and religion, the level of social and economic development remains uneven. Gizan population is mainly rural with the water supply and sewage disposal systems not yet as developed as in other urban areas of the country ,, . Apart from a large sector of expatriate work force from Asia, there is a constant influx of immigrants from neighboring countries such as Yemen. The interaction of the native Saudis with these expatriates, mostly Asians may explain the significant occurrence of HEV in the Gizan region. Similar to the epidemiological pattern in the developing countries, hepatitis A infection remains mainly a childhood disease in the Gizan region of Saudi Arabia. In the present survey it accounted for 57.3 % of all the cases in children aged less than ten years, and 26.2% in adolescents and young adults (11-20 years). Of the 91 patients with AVHA, only five (5.5%) were above 20 years of age. This is consistent with the patterns reported in other areas of high HAV endemicity ,, . The age-specific patterns of HAV infection vary according to regions and generally reflect the stage of socioeconomic development and standard of public or personal hygiene. In many countries with high socioeconomic development a dramatic decline of AVHA has been noted recently, and the disease has ceased to be a childhood infection, but that of susceptible adults and travelers , . Saudi Arabia is in a state of socioeconomic transition from developing to developed country. In such populations, epidemics of HAV infection may occur as a result of an increase in the susceptible population. Such an outbreak had been reported in a part of Saudi Arabia, recently  . A careful monitoring of the relative prevalence or incidence of AVHA in the adult patients may provide useful information on any significant change in the pattern of HAV infection in Gizan. With the availability of HAV vaccine, it is mandatory that vaccination of susceptible persons in area of high endemicity should be considered.
The parenterally-transmitted viruses of hepatitis (HBV and HCV) are of major interest and importance because of the associated high frequency of sequelae such as liver cirrhosis and hepatocellular carcinoma. The prevalence of anti-HCV among healthy Saudi Arabs is about 1-3% ,,, . Therefore, it is not surprising that only a small proportion of the cases of AVH were attributable to HCV. It is possible that more cases of acute HCV might have been detected if the acute phase sera were tested for HCV-RNA. This test is not readily available or applicable to clinical use. In our patients, repeated tests during the follow up period for any seroconversion from negative to positive anti-HCV were carried out to minimize the proportion of HCVrelated AVH cases who might have remained undiagnosed. Because of the high prevalence of hepatitis B and enterically-transmitted hepatitis viruses (HAV and HEV) in Asia and Africa, the relative prevalence of HCV as a cause of AVH is low. For example, the rates vary from 1.2% in Hong Kong, 3% in India, 9.6% in Japan and as high as 14 in Taiwan  . Similarly, a low prevalence of 2% among AVH patients was reported from Moscow  . Our findings are in agreement with these epidemiological patterns but differ from observations in areas of low endemicity for entercally transmitted viruses (such as Europe and America) where HCV accounts for 21-40% of cases of AVH , . About 19% of cases of AVH in this survey were due to HBV. It was pertinent to note that only 6.1% (8 of 131) of AVH in children (  . It was expected that such a preventive strategy would change the epidemiological profile of hepatitis infection in the population. This expectation had been confirmed by a recent survey that indicated such a decline in prevalence among Saudi children  . Improvement of socioeconomic standards and the universal immunization of children against HB combine to decrease HAV, HEV and HBV in children. Such a trend influences the etiologic profile of AVH in adults.
Experience in Taiwan indicated that the relative proportion of NANB in cases of AVH increased from 21% in 1985 to 44 % in 1991  Recent studies have shown that a significant proportion of such patients may have non A-E hepatitis , . There are very few reports that described the epidemiology of non-A-E hepatitis. It accounts for 4 % and 12%, of cases of AVH in the USA and Taiwan respectively ,. In the present study 24.4% of the patients were considered to be in this category. Infection with EB virus was excluded by ELISA in the children with non- A-E. None of the patients was immunodeficient. It has been suggested that one hepatotropic virus or more yet to be identified, may be responsible for this form of viral hepatitis. The bi-modal peak in the age distribution in our patients may provide an indirect evidence for the existence of more than one virus.
About 80% of patients with acute hepatitis E are positive for IgM anti-HEV, with levels remaining detectable for about 6-8 weeks  . Therefore, it is possible that a proportion of the children diagnosed as non A-E hepatitis might have had AVHE undetected by our assays. We believe that the absence of IgG-anti-HEV in acute phase sera and during the follow -up evaluation of the patients would make this proportion negligible. Due to non-availability of facilities we were unable to examine the role of the recently described hepatitis G virus (HGV) in our patients. However, HGV-RNA is rarely found in serum of patients with sporadic acute non A-E hepatitis but may be present in about 33% of those with acute or chronic non A-E hepatitis who had received blood transfusions. The etiological relationship of HGV to acute and chronic hepatitis is not well established. HGV-RNA has been reported in 14% of the patients with acute non A-E hepatitis and was also found in similar proportion among patients with acute hepatitis A, HBV infection (10%), HCV infection (20%) alcoholic liver disease (10%) and autoimmune chronic hepatitis (8%). The majority of those patients had history of exposure to blood or its products ,. None of our patients had any history of related blood transfusion or intravenous drug use or abuse.
Dual infections occurred in five patients (HAV and HEV in four cases and HBV and HCV in one patient). The occurrence of infections with more than one virus is well known but the clinical significance is not yet fully understood. Reports from India indicated a significant occurrence of fulminant hepatic failure in children infected simultaneously by two or more hepatotropic viruses ,. None of the five Saudi patients in this category had a fulminant course or fatal outcome.
A few limitations are inherent in a study such as ours and these should be noted in the consideration of the findings. First, it is possible that some subclinical and anicteric cases of hepatitis might have been excluded in this survey. However, this possibility was minimized by the evaluation of all patients with significant elevation of ALT or AST during the period of the study. It has been suggested that the epidemiological patterns of clinical and subclinical infections are highly unlikely to be different , . Secondly, less severe cases of hepatitis might have been treated at the level of primary health care centers without referral to the hospitals. Finally, it is possible that a proportion of the cases of non A-E might have been due to non-viral factors which we were unable to identify. Religious laws prohibit alcohol in Saudi Arabia and none of our patients admitted to prior alcohol intake. The determination of the role of toxins or local herbs in the development of non A-E hepatitis was outside the scope of the present study.
Hepatitis D may coinfect or superimpose on HBV infection and may worsen the severity of AVHB. HDV were not tested in our patients. Also, there were no facilities to test for the newly described transfusion - transmitted virus (TTV) Despite these limitations, the observations in this study provide useful information on the current pattern of AVH in the Gizan region. It indicates that HAV infection still remains a major cause of AVH especially among children and that sporadic HEV infection occurs with a significant frequency in all age groups. Ten years after the integration of HB vaccine into the EPI, the relative prevalence of acute HBV infection appears to be less than could have been otherwise expected in an area of hyperendemic HBV. HCV as a cause of acute hepatitis was less important while the proportion of non A-E may be expected to increase with the decline of the other forms of viral hepatitis. Our data may serve as a baseline against which such changes could be compared in the Gizan region of Saudi Arabia.
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