The association between serum alanine aminotransferase and hypertension: A national based cross-sectional analysis among over 21 million Chinese adults

Serum alanine aminotransferase (ALT), a sensitive and simple indicator for liver injury in clinical practice [1], was demonstrated to be closely related to obesity [2], fatty liver [3], type 2 diabetes mellitus [4], and metabolic syndrome (MetS) [5‐7] in recent decades. With the increasing prevalence of these metabolic disorders, the association between ALT and metabolic diseases has attracted considerable interest. Moreover, elevated serum ALT is a new biomarker in predicting the incidence of cardiovascular disease (CVD) and poor cardiac risk profile [8‐10]. As a risk factor of CVD, hypertension is not only an important component of MetS but also has similar risk factors related to metabolic diseases [11].

However, inconsistent results have been found in population-based studies between ALT and hypertension [12‐14]. Some studies revealed that plasma ALT was related to blood pressures (BP) [15], and the prevalence of hypertension was obviously increased with serum ALT levels [16]. Other studies did not reveal a substantial association between serum ALT and hypertension because of small sample size [13, 17] or multiple metabolic confounding risk factors in research objects [17]. Meanwhile, a gender difference was found, the association between ALT and hypertension or BP levels was only discovered among males [18]. Therefore, no convincing evidence for the association between serum ALT levels and hypertension as well as BP existed. It is essential to investigate the possible association in a large population and fill the gap of existing research. In this study, we examined the association between serum ALT and hypertension and BP among over 21 million reproductive-aged people based on the National Free Pre-pregnancy Checkups Project (NFPCP).

Overall, 24,085,722 people, including 11,986,918 women aged 20–49 years and 12,098,804 men aged 20–59 years, participated in NFPCP in 2016–2017 nationwide. Finally, 21,103,790 participants, including 10,095,225 men (47.84%) and 11,008,565 women (52.16%), were eligible for this cross-sectional study. The flowchart of participant recruitment is provided in Fig. 1.

The average age of the enrolled population was 29.55 ± 6.19 years old. Most of the participants belong to the Han ethnicity (87.98%) and came from rural areas (86.95%). The prevalence of hypertension was 4.21% (887,509 out of 21,103,790) in the total population, 2.59% (285,455 out of 11,008,565) in women, and 5.96% (602,054 out of 10,095,225) in men. Compared with normotensive participants, people with hypertension were more likely to be older; less educated; with higher salt consumption, frequent alcohol drinking, and heavy smoking; have higher BMI, ALT, and blood glucose concentrations; and suffered from diabetes and psychological stress (Table 1).

The median ALT concentration was 20.00 U/L (IQR: 15.70) among the total population and significantly higher (W = 67,846, P < 0.001) in the hypertensive group (26.00 U/L, IQR: 22.80) than in the normotensive group (20.00 U/L, IQR: 15.00). According to the standardized β value in the multivariable-adjusted logistic regression model, the specific contribution of continuous ALT to hypertension ranked fifth among 11 common cardiovascular risk factors after BMI, age, excessive salt consumption, and gender. The association between continuous ALT concentrations and hypertension odds was essentially linear (t = 176.92, P < 0.001, Fig. 2). With each increase of ALT concentration (1U/L), the odds of hypertension increased by 1% (OR = 1.01; 95% CI = 1.01–1.01) (Table 2).

Moreover, as a categorized variable, a total of 2,463,734 people had elevated ALT level (> 40 U/L), which accounted for 11.67% of all participants. The prevalence of hypertension was 3.63% (95% CI = 3.62–3.64) and 8.56% (95% CI = 8.52–8.60) in people with normal and elevated ALT levels, respectively. The multivariable-adjusted OR of hypertension was 1.55 (95% CI = 1.54–1.56) in participants with elevated ALT level compared with normal ALT level. In addition, the multivariable- adjusted ORs for hypertension were 1, 1.22 (1.21, 1.22), 1.67 (1.65, 1.68), 1.78 (1.76, 1.80), and 1.92 (1.90, 1.94) in participants with ALT levels of ≤ 20, 20.01–40, 40.01–60, 60.01–80, and > 80 U/L, respectively (t = 192.02, P _{for trend} < 0.001) (Table 2). The association between ALT levels and hypertension did not changed after adding blood glucose as covariate into the multivariable-adjusted logistic regression model among women (Table 5 of Appendix).

ALT concentration is linearly associated with SBP (t = 149.46, P < 0.001) and DBP (t = 163.35, P < 0.001). The mean values of SBP and DBP after age- sex-adjusted least-squares estimation remarkably rose with increasing ALT levels (Table 3). The average SBP and DBP rose by 1.19 and 0.88 mmHg respectively in people with elevated ALT level compared with normal ALT after multivariable adjustment (Table 3). Furthermore, SBP and DBP rose by 1.83 and 1.20 mmHg in each 20 U/L increments in ALT concentration in Group II (Table 6 of Appendix). Similar trends were also shown in hypertensive and normotensive populations.

Subgroup analyses showed that the odds for hypertension were increased along with categorized ALT levels across all subgroups (P _{for trend} < 0.001, Fig. 3). Besides, the strength of association was modified by BMI, alcohol drinking, cigarette smoking and HBsAg status (χ² = 52,228, 100,730, 105,347, and 131,220, respectively. P _{Cochran-Mantel–Haenszel} < 0.001). People with elevated ALT level accompanied by higher BMI (≥ 24 kg/m²), alcohol drinking or cigarette smoking had positive additive interactions (RERI > 0, S > 1) and significantly increased their odds for hypertension (Table 4). People who have positive HBsAg status had negative additive interactions (RERI < 0, S < 1) in the association between ALT levels and hypertension, although the odds for hypertension was also increased 0.22 times (OR:1.22, 95% CI = 1.20–1.24) (Table 4). Additionally, the association between ALT and hypertension did not substantially change by using multiple sensitivity analyses (Tables 7 and 8 of Appendix).

To our knowledge, our study is the first to examine the association between ALT and hypertension as well as BP in reproductive-aged adults excluding any medication, with a large sample size of more than 21 million people. Our study adds new information to the public that liver health may be associated with BP.

Conventional risk factors were all found to be related to hypertension in this study. The attributable contribution of continuous ALT elevation toward hypertension was just below BMI, age, excessive salt consumption and gender in multivariable-adjusted logistic model, which suggested that elevated ALT might be a risk factor for hypertension. The odds for hypertension was increased by 55% among people with elevated ALT compared with those who have normal ALT. This finding was similar with previous evidence that elevated ALT increased the risks for hypertension [25], MetS [7] and CVD [26].

Our results revealed a linear and strong association not only between ALT levels and hypertension odds but also between ALT levels and SBP or DBP. Besides, the positive trend between ALT levels and BP in the hypertensive and normotensive subgroups suggested that the association between serum ALT and BP was coherent and that the SBP and DBP were increasing along with serum ALT elevating whether in hypertensive or normotensive populations. These findings resulted from the hypothesis that serum ALT concentration may associate with blood pressures in the light of evidence that serum ALT was demonstrated to be associated with MetS [5‐7]. Reliable prospective cohort studies are warranted to confirm this possible relationship observed in our study and further disclose the causal relationship between serum ALT concentrations elevation and hypertension.

Although some previous studies only reported a remarkable association between ALT and hypertension in people with certain demographic characteristics [17, 27], we found a similar association in subgroups, including BMI, HBsAg, sociodemographic characteristics (age, gender, and area) and health-related behaviors (alcohol drinking and cigarette smoking). Furthermore, interaction effects were also found between serum ALT levels and some conventional hypertensive risk factors. People with elevated ALT accompanied by BMI ≥ 24 kg/m², alcohol consumption or cigarette smoking significantly increased their odds for hypertension than those with only elevated ALT level. Few existing studies have reported the interaction effects of related confounding risk factors toward the association between ALT and hypertension. A previous study has reported that the association between ALT and hypertensive risks is only found in people with central obesity [5]; excessive alcohol is a crucial cause of ALT elevation [28], rather than short-term or light alcohol consumption [29]; moreover, the additional effects between cigarette smoking and elevated serum ALT with respect to hypertension have not been discussed. In this study, we found that overweight or obesity, alcohol drinking, and cigarette smoking can further increase the odds for hypertension among people with elevated ALT levels. More studies are needed to confirm these findings and people with serum ALT elevation should pay attention to higher BMI levels, alcohol drinking and cigarette smoking. Interestingly, the odds for hypertension was higher in the negative HBsAg group than in the positive HBsAg group within elevated ALT in our analyses, which was consistent with findings that HBsAg-positive population has a lower odds for hypertension compared with those with a negative status [30].

A growing body of evidence strongly suggested that serum ALT concentration, the most appropriable predictor of liver fat accumulation [31] and metabolic derangement [32], is related to the pathophysiologic features of increasing BP. Aminotransferases are ubiquitous enzymes that catalyze the reversible transfer of amino groups from amino acids to α-keto acids and play a vital role in amino acid metabolism [33]. Elevated serum ALT levels are independently associated with a higher prevalence of dyslipidemia [34]; increasing levels of serum triglyceride contents [35]; and higher low-density lipoprotein cholesterol, non-high-density lipoprotein (HDL) cholesterol, and lower HDL cholesterol [36]. Moreover, serum ALT is closely related to glucose tolerance, insulin resistance and other conventional risk factors of metabolic diseases [6]. Higher ALT levels are also substantially correlated with excessive inflammation and oxidative stress [37]. In addition, elevated ALT concentration is positively associated with faster heart rate [6], higher risk of carotid atherosclerosis [38], increased arterial stiffness [39] and can behave as a surrogate marker of left ventricular hypertrophy and carotid artery changes [40]. All these features mentioned above contribute to the development of hypertension. Prospective studies still need to verify the pathophysiologic mechanisms between serum ALT and hypertension.

To date, our study is the largest nationwide epidemiological study that investigated the association between serum ALT without limitation of the clinical reference range and the odds of hypertension in over 21 million people. The large sample size can ensure sufficient statistical power of all analyses. Possible confounding effects regarding sociodemographic characteristics, lifestyle behaviors, psychological stresses, and history of diseases were considered in statistical analyses. Strict inclusion and exclusion criteria were adopted, in which people who were taking medicines were excluded to avoid the adverse influence of medications on ALT and blood pressures. In addition, we conducted several sensitivity analyses to verify the robustness of the observed association. Above all, the participants recruited in NFPCP have specific demographic characteristics, such as having an explicit wish to conceive, being younger, and more concerned about healthy lifestyles than the general population. The specified younger and healthier participants enabled us to explore the natural association between ALT and hypertension, in which ALT and BP were not influenced by medication-, age-, and behavior-related changes.

However, several limitations also existed. First, a cross-sectional design would not draw a causal relationship between serum ALT and hypertension. Prospective studies based on large-scale populations are needed to verify the authenticity of the observed association between serum ALT and BPs as well as the odds for hypertension. Second, not all the reproductive-aged people who planned to conceive in 2016–2017 had participated in the NFPCP in China, and most of the included participants were from rural areas (86.95%). Thus, the hypertension prevalence in our study may have been underestimated. Third, a misclassification bias of hypertension could be introduced because only one single seated BP was measured after resting for 10 min, despite the fact that the participants were informed to not drink caffeinated beverages, have a good sleep and keep a light diet 3 days before the examination. Fourth, ALT concentration may also be affected by many lifestyle behaviors a few days before examination, such as sleeping, diet and drinking status. Fifth, many questions were self-reported according to the structured questionnaire, including life behaviors and history of disease, which may introduce recall bias. Sixth, no other liver enzyme was available in NFPCP laboratory tests to support the observed association between ALT and hypertension. Finally, our research is mainly carried out in people who are relatively young and take participate in NFPCP. The findings of this research may be helpful for promoting the health of expectant parents but may not be applicable to other populations with older age.

Findings from this study showed a strong, independent, and linear association between elevated serum ALT and hypertension, which indicated that abnormal liver metabolism marked elevated serum ALT may correlate with the odds for hypertension. Future prospective cohort studies are warranted to confirm the possible relationship between ALT concentrations and hypertension and further disclose the underlying mechanisms.