AIM: To determine the prevalence and causes of persistently elevated alanine aminotransferase (ALT) levels among the general population in northern Iran.

METHODS: A total of 2292 (1376 female, aged 18-75 year), were selected by systematic clustered random sampling from the cities and villages of Gonbad and Kalaleh in Golestan Province and invited to participate in the study. A comprehensive history regarding alcohol drinking and medication was taken. Body mass index (BMI), viral markers and ALT levels were measured. If ALT level was ≥ 40 U/L, it was rechecked twice within 6 mo. Those with ≥ 2 times elevation of ALT were considered as having persistently elevated ALT level. Non-alcoholic fatty liver disease (NAFLD) was diagnosed based on evidence of fatty liver upon sonography and excluding other etiology.

RESULTS: A total of 2049 (1351 female) patients participated in the study, 162 (7.9%) had elevated ALT level at the first measurement. Persistently elevated ALT level was detected in 64 (3.1%) participants, with 51 (79.6%) with no obvious etiology, six (9.3%) with Hepatitis B, four (6.2%) with Hepatitis C virus (HCV) infection and three (4.6%) with alcoholic hepatitis. The prevalence of NAFLD and alcoholic hepatitis was 2.04% (42 patients) and 0.1% (three), respectively. There was correlation between NAFLD and male gender, overweight, diabetes and living in an urban area [odds ratio = 3.03 (95% CI: 1.6-5.72), 4.21 (95% CI: 1.83-9.68), 2.86 (95% CI: 1.05-7.79) and 2.04 (95% CI: 1.00-4.16) respectively].

CONCLUSION: NAFLD is the most common cause of persistently elevated serum ALT level among the general population of Iran.

End-stage liver disease is among the top ten common causes of morbidity and mortality in adults older than 15 years, worldwide[1]. The World Health Organization (WHO) estimates that in 2002, cirrhosis caused 382 000 deaths worldwide[1]. According to the 2002 mortality report of the Ministry of Health of Iran, chronic liver diseases accounted for 1% of mortality of inhabitants aged > 15 years across the whole country[2]. Liver cirrhosis was the third and first leading cause of mortality and hospitalization, respectively, in an Iranian gastrointestinal and hepatology ward[3]. Recognition of the relative contribution of various etiologies to a disease burden is important for setting public health priorities and prevention guidelines. Iran, a Middle East developing country, has an average prevalence of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection, 3%-5% and 0.5% respectively[4–9]. HBV has been reported as the most common cause of chronic liver disease in the last decade in Iran[1011]. The etiology of chronic liver disease changes by health concerns, national prevention programs, and people’s lifestyle. The prevalence of HBV infection among healthy Iranian blood donors has declined; this may be due to better donor selection programs and an increasing number of repeat donors[12]. Rapidly increasing metabolic syndrome manifestations, including non-alcoholic fatty liver disease (NAFLD), are reported in Iran[13]. Information regarding the causes of chronic liver disease in the general population is rare in Middle-east countries. Alanine aminotransferase (ALT) is a sensitive indicator of liver cell injury and has been used to identify patients with liver disease for almost 50 years[14]. Currently, determination of serum ALT level constitutes the most frequently applied test for the identification of patients suffering from liver disease. The aim of this study was to determine the causes of chronic liver disease in the general population in Iran, using ALT as a surrogate marker of liver disease.

Our study was carried out according to the ethical standards for human experimentation and was approved by the ethics committee of the Digestive Disease Research Center, Tehran University of Medical Sciences. After explaining the aim of the study and the possible need for further blood tests and follow up, written informed consent was obtained.

A total of 2049 participants (1351 females and 1073 urban) were included in the study. Relative frequency of the participants according to demographic characteristics, laboratory tests, BMI and sex is shown in Table 1.

A total of 162 participants (7.9%) had elevated serum ALT level at the first measurement. Among the 147 of 162 participants who were invited for further evaluation, 64 were considered to have persistently elevated ALT level. In this group 51 (79.6%) had no obvious etiology, six (9.3%) had Hepatitis B, four (6.2%) had Hepatitis C, and three (4.6%) had alcoholic hepatitis. Drug history was unremarkable. Liver sonography was performed for 51 participants with persistently elevated ALT level with no obvious cause, in which 42 (2.04%) showed fatty liver and were presumed to have NAFLD. Demographic characteristics, laboratory test results, and sonography findings in participants with persistently elevated ALT level and fatty liver are shown in Table 2.

The mean BMI of NAFLD participants was 30.47 ± 5.07 kg/m² compared with 26.04 ± 5.02 kg/m² of those without NAFLD (P = 0.001). In participants with NAFLD, there were 34 who were overweight and obese, and seven who were normal weight (P = 0.001). In this study, 34/1095 (3.1%) of the overweight and 22/435 (5%) of the obese participants had NAFLD.

The mean BMI in urban participants (26.52 ± 5.32 kg/m²) was greater than that in their rural counterparts (25.69 ± 4.74 kg/m²) (P = 0.035). The prevalence of overweight and obese participants was greater in urban (626) than rural (469) participants (P = 0.001). NAFLD was more common in urban (31) than rural (11) participants, and also in men (24) than in women (18) (P = 0.005 and 0.001, respectively). There was a correlation between NAFLD and male gender, overweight and obese, diabetes and living in an urban area [odds ratio = 3.03 (95% CI: 1.6-5.72), 4.21 (95% CI: 1.83-9.68), 2.86 (95% CI: 1.05-7.79) and 2.04 (95% CI: 1.00-4.16), respectively].

The prevalence of once-only elevated ALT levels, after excluding individuals with viral hepatitis, alcohol and drug etiology, was 2.1%, which was nearly half of the previously reported prevalence of 5.7% in healthy blood donors in Iran[7]. This may have been due to the greater prevalence of overweight and obese participants and male predominance (70.9% and 74.7%, respectively) in the previous study compared with the present study (54.8% and 34%, respectively). It has already been shown that serum ALT level is associated with male gender and obesity[17–19]. This value is near the prevalence reported in the Third National Health and Nutrition study in the United States (2.8%)[18].

The prevalence of persistently elevated serum ALT levels (3.1%) in our study is comparable with that in previous studies from Western countries and the study of healthy blood donors in Iran[720]. The prevalence of HBsAg positivity was 5% in the present study, which is comparable to previous studies in the general population of Hamadan (2.49%), Nahavand (2.3%) and Golestan (9.7%)[4–6]. There are no published data about HCV prevalence in the general population in Iran for comparison. According to previous studies performed in healthy blood donors in Tehran, the prevalence of HBsAg positivity has declined sharply during the past 20 years, which is mainly due to better donor selection and an increasing number of repeat donors[12].

NAFLD is a diagnosis of exclusion when clinical and laboratory examination fail to reveal a cause of liver disease. It is suggested when an imaging study shows fatty liver. Liver sonography is non-invasive, safe, widely available and highly sensitive for the detection of fatty liver. In one study that compared the sensitivity of MRI, CT and liver sonography to detect fatty liver, sonography and CT had sensitivity of 100% and 93%, respectively, in detecting fatty changes that involved > 33% of the liver, with a positive predictive value of 62% and 76%, respectively[21]. We did not perform liver biopsy for diagnosis of NAFLD, and we used criteria similar to those of previous epidemiological studies of NAFLD[1822]. Large epidemiological studies on the prevalence of NAFLD in the general population are lacking, but prevalence of 2.8%-24% has been reported[182324]. In the present study, the prevalence of NAFLD was 2.04%, which is comparable to that reported previously in healthy blood donors (2.35%) and autopsies (2.1%) in Iran[725]. Although the participation rate in men was less than in women, mainly due to work constraints in men, NAFLD was three times more prevalent in men, which accords with previous studies in Asia, including the study of healthy blood donors in Iran[72627]. Previously, it was thought NAFLD is more prevalent in women, but recent data suggest there is no significant difference between the sexes. Women are overrepresented in studies of NAFLD, but it is unclear if gender is an independent risk factor for the disease[22]. The frequency of overweight (54.9%) and obesity (21.9%) in the present study was close to the frequencies reported previously in northern Iran, which showed 62.2% were overweight and 28% were obese[28]. The frequency of NAFLD reaches 80% in obese persons; NASH is reported in 9%-30% of obese adults[2930]. In the present study, 34/1095 (3.1%) overweight and 22/435 (5%) obese participants had NAFLD. There is a correlation between BMI and steatosis in several studies[22]. We showed that overweight and obesity were associated with a 4.21-fold increased risk in NAFLD participants, and mean BMI was also greater in NAFLD than non-NAFLD participants.

This study showed that living in an urban area is associated with a 2.04-fold increase in NAFLD, and this may be due to daily physical activity, lifestyle and greater prevalence of overweight and obesity in urban participants. NAFLD is associated with type 2 diabetes mellitus and glucose intolerance with or without superimposed obesity. Type 2 diabetes has been described in 20%-75% of NAFLD patients, and may increase the risk of NAFLD more than two-fold compared with that in non-diabetics. In the present study, prevalence of diabetes was 11.9% in NAFLD, and diabetes was associated with a 2.86-fold increase in NAFLD compared with non-diabetics[30]. NAFLD is now recognized as the hepatic manifestation of the metabolic syndrome, which includes hyperlipidemia, hypertension, glucose intolerance and obesity. The risk and severity of NAFLD increase with the number of components of the metabolic syndrome[31]. According to previous studies in the general population of Iran, metabolic syndrome has a prevalence of 33%, which is more common than the rate of 22% reported by the Third National Health and Nutrition Examination Survey for the USA[1332]. We did not test for uncommon liver diseases such as Wilson’s disease, α1-antitrypsin deficiency, primary biliary cirrhosis and primary sclerosing cholangitis, which can also be responsible for elevated ALT levels; as they are too infrequent to have had a major impact on our results. There are two studies that show that self-reported use of alcohol and opium are reliable and valid in this population[2733].

NAFLD was the most common cause of persistently elevated serum ALT levels in our study. The importance of NAFLD and ALT elevation is their impact on mortality as a component of the metabolic syndrome. NAFLD is not a western disease, and is the most frequent cause of persistently elevated serum ALT level in the Asia-Pacific region[26]. Identifying its risk factors and therapeutic strategies to control this public health problem seems reasonable.