Normal Limit for Serum Alanine Aminotransferase Level and Distribution of Metabolic Factors in Old Population of Kalaleh, Iran

WC, BMI, TG and having MS modulate ALT levels in men. TG modulates ALT in women. For almost 50 years, it was accepted that UNL of ALT is about 40 U/L (3). Several studies have recently challenged the cutoff for normal ALT level (11, 12). The first Iranian study for determining UNL of ALT in adult was performed in 2002 among blood donors (10). A total of 1959 apparently healthy blood donors with the mean age of 37.4 years were recruited for the study in Tehran Blood Donation Center. UNL of ALT was calculated 40 U/L for men and 34 U/L for women among blood donors with normal weight (BMI< 25 Kg/m2). Serum ALT levels were independently associated with BMI and sex, and association of ALT was more prominent in male than female (13). The study had two limitations. The population of study was not nationally representative of Iran, and there was no laboratory data regarding associated factors with serum ALT levels.

Second Iranian study for determining UNL of ALT for adult was performed in 2006 among inhabitants in north-eastern Iran (14). Rural and urban dwellers both were included in the study. UNL of ALT was 37.5 U/L and 36 U/L in male and female respectively in normal weight participants. Male gender, high BMI and having history of diabetes mellitus were independent risk factors for ALT elevation. Same to the study in Iranian blood donors, lack of general ability and laboratory data regarding associated factors were limitations of the study.

In the current study, we recruited most healthy inhabitants in Kalaleh, Golestan, who were older than 50 years, and were candidate to recruit in a clinical trial for using medication for primary prevention of ischemic heart disease (15).

The strong points of the current study are as follows; the population had a very detailed history of any chronic diseases and relevant laboratory data. Although the current reference population for determining UNL of ALT had relevant laboratory data, but there was a limitation in age groups. So, we were not able to identify the influence of age on serum ALT level and also other factors which are probably present in younger population.

In the study of Elinav E et al. a significant association was found between age and ALT levels, made an inverted U like curve with a peak of serum ALT level at 40-55 years (16). The Mean serum ALT level was 19 ± 13 U/L in < 40 years old, 25 ± 19 U/L in 40-55 years old, 22 ± 10 U/L in 56-72 years old, 17 ± 9 U/L in 73-83 years old, and 13 ± 5 U/L in 83-100 years old (P < 0.0001) (13). In Iranian blood donors the peak of serum ALT levels was at 40 - 50 years of age too (13). We concluded that the population age was the main reason for calculating far lower level of normal ALT in our population comparing to the two previous Iranian investigations. So, it is important to consider age for interpretation of an ALT level in different ages as well as gender.

The influence of BMI on the UNL of ALT has been shown in the two previous Iranian studies (13, 14). In the current study, the effect of BMI on ALT activity was observed only in men. Leclercq I et al. studied the influence of age, BMI and sex on ALT levels among 9420 blood donors (17). Although Leclercq I et al. found a correlation between BMI and ALT level, but consistent influence of BMI on ALT level was observed only in women. In men, raising in BMI increased ALT activity only up to the fifth decade and after that no influence was seen any more (17). In Hsieh MH et al. study, 11411 Taiwanese adults were enrolled (18). Hsieh MH et al. found that WC, BMI, TG, and blood sugar are important risk factors for elevated ALT, and WC might be a better indicator of risk of abnormal liver function than BMI (18). In our study, BMI and WC were associated with higher level of ALT only in men. The association between ALT levels and WC in men was observed even in normal and near normal range of ALT levels (Table 3). The cutoff of WC that predicts metabolic syndrome in Iranian women is higher than calculated cutoff for European (7) and east-Asian women (18). The predictive cutoff of ALT for Iranian women is almost the same to the Iranian men (8- 10), and is not comparable with European or Asian countries (7, 18). Theses suggest that gender and ethnic differences in amount of visceral fat may play a role in the association between WC and ALT levels.

We found that blood pressure modulates ALT level in univariate analysis significantly; but, not in multivariate analysis that is comparable with Hsieh MH et al. study results (18). We did not find an association between elevated FBS and serum ALT levels. Saligram S et al. found that ALT level is associated with BMI, hypertriglyceridemia and low HDL but not with hemoglobin A1C and glycemic control (19). We found an association between ALT level and MS in men but not women. Most studies are reporting an association between serum ALT level and MS in various populations including elderly men (20-22).

There is no convincing data to answer whether MS or any individual component of MS is an important predictor of liver damage, indicated by an elevated ALT level in different age, sex and ethnicity. In a study from Iran, authors found high blood pressure in both genders, high WC in men and high FBS in women were independent predictors of cardiovascular disease and adding other MS parameters did not yield any improvement in model fitness for predicting cardiovascular disease (23). In our study, hypertriglyceridemia modulated ALT levels in both genders, but WC, BMI and MS were associated with ALT levels only in men .There was no association between high blood pressure and high FBS with ALT in both genders. It seems that the influence of individual parameters of MS for predicting an ALT elevation and a liver injury is different in men and women, which needs to be evaluated in a series of prospective studies. In the current study, 23% and 37.2% of men and women had MS based on the IDF definition which is comparable with the first Iranian national survey of MS which conducted in 2007 on 3024 subjects. The authors found that 37.4% of population has MS based on IDF definition. The prevalence of MS was higher in women and in the 55 -64 years old age group (8).

There is conflicting data regarding the influence of ethnicity on ALT level. Schwimmer JB et al. studied the influence of ethnicity, race and gender on ALT level in obese adolescents in a national school based survey in the USA (24).

After controlling for BMI and sex, Hispanic had significantly more ALT levels than black and white. Influence of BMI, gender and ethnicity on ALT level was studied by Bilal M et al. among students of an army medical college in Pakistan (25). The authors found that ALT levels strongly correlated with BMI and gender but not with ethnicity.

We evaluated opium usage and its duration based on a standard questionnaire and our previous study using urine codeine or morphine as the gold standard method for detecting the use of opium, showed that self-report of this variable had a sensitivity of 0.93 and a specificity of 0.89. Its reliability was also high (26). So, the recall bias even for the duration of using opium was not considerable.

In summary, our current calculated UNL of ALT (21 U/L and 19 U/L in male and female, respectively) is far lower than the upper normal limit for ALT level which had been determined by laboratory manufacture. We assumed that it is due to the age category of our population. Using current UNL of ALT increases the detection rate for serum ALT elevation from 4% to 38%, which is more expected considering the prevalence of MS and its parameters which modulate ALT level. MS and its components are very prevalent in our population. There is a lack of data regarding modulating factors of ALT levels in different ethnicity, gender and age groups. Future prospective studies for calculating UNL of ALT should take into account age, gender, ethnicity and metabolic factors.