Abstract
Background:
To investigate the association between air pollution and abnormal alanine aminotransferase levels in patients with chronic hepatitis B treated with nucleotide/nucleoside analogs (NAs).
Methods:
This cross-sectional study enrolled 1275 patients with chronic hepatitis B treated with nucleotide/NAs from 2019 to 2022 in Kaohsiung and analyzed the incidence and risk factors for abnormal alanine aminotransferase levels. Daily air pollutant concentrations were estimated for the year before enrollment.
Results:
Abnormal alanine aminotransferase levels were observed in 1127 patients (88.4%) before treatment with nucleotide/NAs. Logistic regression analysis revealed that the strongest factor associated with abnormal alanine aminotransferase levels was the level of hepatitis B virus DNA (odds ratio/CI: 1.40/1.25-1.57; p < 0.001), followed by concentration of particulate matter ≤2.5 µm in diameter (1.05/1.02-1.08; p < 0.001) and liver cirrhosis (0.27/0.17-0.42; p < 0.001). Among patients without cirrhosis, logistic regression analysis revealed that the strongest factors associated with abnormal alanine aminotransferase levels were the level of hepatitis B virus DNA (odds ratio/CI: 1.52/1.28-1.82; p < 0.001) and concentration of particulate matter ≤2.5 µm in diameter (1.06/1.101-1.11; p = 0.01). Among patients with cirrhosis, logistic regression analysis revealed that the strongest factor associated with abnormal alanine aminotransferase levels was hepatitis B virus DNA level (odds ratio/CI: 1.28/1.12-1.48; p = 0.001).
Conclusion:
Higher concentrations of particulate matter ≤2.5 µm in diameter caused elevated baseline alanine aminotransferase levels in patients with chronic hepatitis B receiving nucleotide/NA therapy. The impact of particulate matter ≤2.5 µm in diameter on abnormal alanine aminotransferase levels was particularly pronounced in patients without cirrhosis.
Keywords: Air pollution, alanine aminotransferase, Hepatitis B virus, Nucleotide/nucleoside analogs, Particulate matter
Lay summary: In the study, patients with chronic hepatitis B (CHB) preparing to receive NAs (nucleotide/nucleoside analogs) were found to have abnormal alanine aminotransferase (ALT) levels in 88.4% of cases before starting treatment. The study also showed that abnormal ALT levels were linked to both HBV DNA levels and PM2.5 (fine particulate matter) concentrations, after adjusting for other influencing factors. Specifically, when PM2.5 concentrations exceeded 40 µg/m3, the risk of abnormal ALT levels doubled. Additionally, patients exposed to the highest levels of PM2.5 over the course of a year were three times more likely to have abnormal ALT levels compared to those exposed to the lowest levels. This effect was particularly pronounced in patients without cirrhosis.
1. INTRODUCTION
Hepatitis B virus (HBV) infection is endemic in Taiwan and its prevalence has decreased since the introduction of the HBV vaccine.1 Chronic hepatitis B (CHB) causes liver inflammation.1,2 The risk factors for CHB-related liver inflammation include HBV DNA levels, liver fibrosis, fatty liver diseases, and metabolic derangement.3 Antiviral treatments such as nucleotide/nucleoside analogs (NAs) can improve hepatic inflammation and fibrosis.4,5
Air pollution causes hepatic inflammation that can progress to chronic liver disease.6 Air pollution impedes the normalization of liver function in patients with CHB treated with NAs.7 Air pollution is not only associated with advanced liver fibrosis in patients with chronic liver disease8 but also with liver cancer.9,10 A previous study demonstrated that air pollution and seropositivity for hepatitis B surface antigen (HBsAg) were associated with the occurrence of hepatocellular carcinoma (HCC) and had synergistic effects after adjusting for confounding factors.11 However, no study has reported an association between baseline alanine aminotransferase (ALT) levels and air pollution in patients with CHB treated with NAs.
Therefore, we aimed to investigate the association between air pollution and pretreatment ALT levels in CHB patients treated with NAs using a well-characterized cohort.
2. METHODS
2.1. Patients
This retrospective study consecutively enrolled patients with CHB who were treated with NAs at a medical center in Kaohsiung from 2019 to 2022. Patients were followed up from the beginning of NA treatment. Indications for NA therapy were based on the National Health Insurance Reimbursement Regulations of the Ministry of Health and Welfare in Taiwan.1,12
The inclusion criteria were as follows: (1) Liver decompensation, denoted by total bilirubin ≥2 mg/dL or prolonged prothrombin time ≥3 seconds and NAs administration for 3 years. (2) Liver cirrhosis with HBV DNA level ≥2000 IU/mL; NAs were administered lifelong. (3) Hepatitis B e-antigen (HBeAg)-positive with an HBV DNA level ≥20 000 IU/mL and ALT level ≥2 times the upper limit of normal (ULN) on two occasions 3 months apart or ALT ≥5 times the ULN. NAs therapy can be stopped after at least 1 year of consolidation therapy after HBeAg seroconversion with HBV DNA undetectable by polymerase chain reaction (PCR) and persistently normal ALT levels. (4) HBeAg-negative with HBV DNA level ≥2000 IU/mL with an ALT level ≥2 times the ULN on two occasions 3 months apart. Treatment cessation can be considered after treatment for at least 2 years, with undetectable HBV DNA documented on three separate occasions, 6 months apart. In the cohort, 423 patients (37.1%) had liver decompensation, 317 patients (24.9%) had liver cirrhosis with HBV DNA levels >2000 IU/mL, and 39.3% were HBeAg seropositive, meeting National Health Insurance (NHI) criteria.
Patients were excluded if they had any of the following conditions: co-infection with human immunodeficiency virus or hepatitis C virus (HCV), alcoholism (consuming ≥20 g of alcohol daily), ongoing interferon-based therapy, use of NAs for chemotherapy prophylaxis, and pre-existing HCC before the use of NAs.
This study was conducted in accordance with the principles of the 1975 Declaration of Helsinki, revised in 2013. This study was approved by the Ethics Committee of Kaohsiung Medical University Hospital. All patients provided informed consent before enrollment (IRB number: KMUHIRB-E(II)-20230117).
2.2. Laboratory analyses
Biochemical analyses were performed using a multichannel autoanalyzer (Hitachi Inc., Tokyo, Japan). The HBsAg levels were detected using a standard quantitative chemiluminescent microparticle immunoassay (ARCHITECT HBsAg; Abbott Diagnostics, Chicago, IL). Serum HBV DNA levels were examined using a standardized, automated, quantitative polymerase chain reaction assay (COBAS TaqMan HBV test; Roche Diagnostics, Branchburg, NJ; detection limit: 12 IU/mL).13 Abnormal ALT levels were defined as >40 IU/L. Liver cirrhosis was diagnosed based on transient elastography (FibroScan; Echosens, Paris, France; threshold: >12 kPa),14 histologic investigation; or the presence of radiological, laboratory, endoscopic, or clinical evidence of portal hypertension and/or cirrhosis. Fatty liver was diagnosed by trained physicians using abdominal ultrasonography, as previously described.15–17 The Fibrosis-4 index score was calculated using the following formula: age (years) × aspartate aminotransferase (U/L)/(platelets [109/L] × ALT1/2 [U/L]).
2.3. Air pollution exposure
Individual exposure to air pollutants, including particulate matter ≤2.5 µm in diameter (PM2.5), particulate matter ≤10 µm in diameter (PM10), NO2, and O3, was evaluated using various hybrid spatial prediction models with daily air pollutant measurements from several Taiwan Air Quality Monitoring (TAQM) stations. Briefly, the daily average PM2.5 and PM10 concentrations were measured at approximately 70 TAQM stations from 2006 to 2022. The daily average NO2 and O3 concentrations were measured at 73 TAQM stations between 2000 and 2022. Measurements of air pollutants before 2014 were used to develop prediction models for estimating individual air pollutant exposure, and data after 2014 were used to verify the reliability of the model. Other details of air pollutant assessments have been described previously.7,8,11 In the geocoding process for linking participants’ addresses to air pollutants, we first converted the participants’ addresses into longitudinal and latitudinal coordinates. Next, using QGIS (version 3.28), we performed a spatial join analysis to project each participant’s location within the corresponding township. Based on the individuals’ date of recruitment (baseline), we calculated their average exposure to air pollutants within these townships and used this as a measure of their cumulative exposure to air pollution.
In this study, we used township-level average air pollutant concentrations to represent an individual’s cumulative exposure. This decision was based on the consideration that people generally spend a significant amount of time engaging in activities within the townships where they reside, rather than being confined solely to their residential addresses. Therefore, the overall average concentration of air pollutants at the township level is considered a more accurate reflection of an individual’s actual exposure than estimates based strictly on household-level data. The 10-fold cross-validation R² values for the prediction models were approximately 0.87 for PM2.5, 0.85 for O3, 0.70 for NO2, and 0.89 for PM10.
2.4. Statistical analyses
Frequencies were compared between the groups using the chi-square (χ2) test with Yates’ correction or Fisher exact test. Data are presented as mean ± SD. Data were compared using analysis of variance, Student’s t test, or the nonparametric Mann–Whitney U test. A stepwise logistic regression analysis was applied to analyze the factors independently associated with abnormal ALT levels by analyzing the covariates with p values <0.1 in the univariate analysis or the factors considered to have potential and clinical relevance. Statistical analyses were performed using IBM Statistical Product and Service Solutions version 25 (IBM Corp., Armonk, NY). All statistical analyses were based on two-sided hypothesis tests, with p values <0.05 considered statistically significant.
3. RESULTS
3.1. Patient characteristics
We initially recruited 3000 patients with CHB who received NA treatment (Fig. 1). After excluding patients with pre-existing HCC (n = 370), those using NAs for chemotherapy prophylaxis (n = 811), those with anti-HCV seropositivity (n = 118), those receiving interferon-based therapy (n = 33), those with unavailable addresses (n = 271), those with alcoholism (consuming ≥20 g/d of alcohol) (n = 67), and those with unavailable ALT levels (n = 55), 1275 patients were enrolled in the final analysis.
Fig. 1.
Flowchart of patient enrollment. ALT = alanine aminotransferase; CHB = chronic hepatitis B; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; NAs = nucleoside/nucleotide analogs.
The mean age of the participants was 48.2 years, and 72.8% were male. The mean HBV DNA level was 5.9 log10 IU/mL. Patients with liver cirrhosis accounted for 28.8% (n = 367) of the study population (Table 1). The average annual air pollutant exposure levels were 40.0 µg/m3 for PM2.5, 71.1 µg/m3 for PM10, 21.5 parts per billion (ppb) for NO2, and 28.3 ppb for O3. The Pearson correlation coefficients between pollutants are provided in Supplementary Table 1, http://links.lww.com/JCMA/A311. Supplementary Table 2, http://links.lww.com/JCMA/A311, presents a basic statistical summary including the mean, SD, median, and interquartile range (minimum [Q1] and maximum [Q3]).
Table 1.
Characteristics of the 1275 chronic hepatitis B patients preparing for NAs treatment
| All patients (n = 1275) | |
|---|---|
| Age (y, mean [SD]) | 48.2 (14.0) |
| Male, n (%) | 928 (72.8) |
| Diabetes, n/N (%) | 174/1156 (15.1) |
| BMI (kg/m2, mean [SD]) | 24.6 (4.1) |
| AST (IU/L, median [IQR]) | 105.0 (229.0) |
| ALT (IU/L, median [IQR]) | 144.0 (402.2) |
| Platelet count (×103 u/L, mean [SD]) | 165.7 (74.4) |
| FIB-4 (median [IQR]) | 3.0 (4.9) |
| HBV DNA (log10 IU/mL, mean [SD]) | 5.9 (1.9) |
| HBeAg seropositivity (%) | 500/1271 (39.3) |
| Liver cirrhosis, n (%) | 367 (28.8) |
| Fatty liver, n/N (%) | 338/1057 (32.0) |
| Baseline PM2.5 (µg/m3, mean [SD]) | 40.0 (7.0) |
| Baseline PM10 (µg/m3, mean [SD]) | 71.1 (10.5) |
| Baseline ozone (ppb, mean [SD]) | 28.3 (2.8) |
| Baseline NO2 (ppb, mean [SD]) | 21.5 (5.2) |
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; FIB-4 = fibrosis-4 index; HBeAg = Hepatitis B e-antigen; HBV = hepatitis B virus; IQR = interquartile range; NAs = nucleoside/nucleotide analogs; NO2 = nitrous oxide; PM2.5 = particulate matter 2.5; PM10 = particulate matter 10.
3.2. Factors associated with abnormal ALT levels
Abnormal ALT levels before treatment were reported in 1127 (88.4%) patients. Patients with abnormal ALT levels were younger (47.4 vs 54.0 years; p < 0.001) and had higher HBV DNA levels (6.1 vs 4.6 log10 IU/mL; p < 0.001), concentrations of PM2.5 (40.3 vs 37.5 µg/m3; p < 0.001), PM10 (71.6 vs 67.1 µg/m3; p < 0.001), and NO2 (21.7 vs 20.3 ppb; p = 0.01), incidence of fatty liver (33.6% vs 17.0 %; p < 0.001), and HBeAg seropositivity (42.2% vs 17.7%; p < 0.001), and lower incidence of liver cirrhosis (25.5% vs 54.1%; p < 0.001) than those with normal ALT levels (Table 2).
Table 2.
Factors associated with the abnormal ALTa
| Abnormal ALT | Yes, n = 1127 | No, n = 148 | Univariate p value | Logistic regression analysis | ||
|---|---|---|---|---|---|---|
| OR | 95% CI | p | ||||
| Age (y, mean [SD]) | 47.4 (14.0) | 54.0 (13.2) | <0.001 | 0.99 | 0.97-1.01 | 0.44 |
| Male, n (%) | 829 (73.6) | 99 (66.9) | 0.09 | 1.39 | 0.83-2.30 | 0.21 |
| Diabetes, n/N (%) | 147/1013 (14.5) | 27/143 (18.9) | 0.17 | |||
| BMI (kg/m2, mean [SD]) | 24.6 (4.1) | 24.7 (4.0) | 0.83 | |||
| Platelet count (×103 u/L, mean [SD]) | 165.0 (69.7) | 107.7 (103.8) | 0.53 | |||
| Creatinine (mg/dL, mean [SD]) | 1.0 (1.1) | 1.2 (1.7) | 0.20 | |||
| HBV DNA (log10 IU/mL, mean [SD]) | 6.1 (1.8) | 4.6 (1.9) | <0.001 | 1.40 | 1.25-1.57 | <0.001 |
| HBeAg seropositivity, n/N (%) | 474/1124 (42.2) | 26/147 (17.7) | <0.001 | 1.50 | 0.77-2.94 | 0.23 |
| Fatty liver, n/N (%) | 320/951 (33.6) | 18/106 (17.0) | <0.001 | 1.35 | 0.73-2.47 | 0.34 |
| Liver cirrhosis, n (%) | 287 (25.5) | 80 (54.1) | <0.001 | 0.27 | 0.17-0.42 | <0.001 |
| Baseline PM2.5 (µg/m3, mean [SD]) | 40.3 (6.8) | 37.5 (7.8) | <0.001 | 1.05 | 1.02-1.08 | <0.001 |
| Baseline PM10 (µg/m3, mean [SD]) | 71.6 (10.3) | 67.1 (12.0) | <0.001 | 1.01 | 0.97-1.06 | 0.56 |
| Baseline ozone (ppb, mean [SD]) | 28.3 (2.8) | 28.6 (2.8) | 0.33 | |||
| Baseline NO2 (ppb, mean [SD]) | 21.7 (5.1) | 20.3 (5.6) | 0.01 | 1.00 | 0.95-1.06 | 0.96 |
ALT = alanine aminotransferase; BMI = body mass index; HBeAg = Hepatitis B e-antigen; HCC = hepatocellular carcinoma; HBV = hepatitis B virus; NO2 = Nitrous oxide; OR = odds ratio; PM2.5 = particulate matter 2.5; PM10 = particulate matter 10.
ALT > 40 IU/L.
Logistic regression analysis revealed that HBV DNA level was the strongest factor associated with abnormal ALT levels (odds ratio [OR]/CI: 1.40/1.25-1.57; p < 0.001), followed by PM2.5 concentration (OR/CI: 1.05/1.02-1.08; p < 0.001) and liver cirrhosis (OR/CI: 0.27/0.17-0.42; p < 0.001). The optimum cutoff value of the PM2.5 concentration associated with abnormal ALT levels was 41.6 µg/m3 (area under the receiver operating characteristic curve: 0.61; p < 0.001). Considering PM2.5 concentration >40 µg/m3 as the threshold, the logistic regression analysis revealed that the strongest factor associated with abnormal ALT levels was PM2.5 concentration >40 µg/m3 (OR/CI: 2.03/1.28-3.20; p = 0.002), followed by HBV DNA level (OR/CI: 1.40/1.25-1.58; p < 0.001) and liver cirrhosis (OR/CI: 0.27/0.17-0.42; p < 0.001).
3.3. Factors associated with abnormal ALT levels among patients without cirrhosis
We further analyzed the factors associated with abnormal ALT levels, stratified by liver cirrhosis. Among patients without cirrhosis, those with abnormal ALT levels were younger (45.5 vs 55.0 years; p < 0.001) and had higher HBV DNA levels (6.3 vs 4.4 log10 IU/mL; p < 0.001), concentrations of PM2.5 (40.6 vs 36.2 µg/m3; p < 0.001) and PM10 (72.0 vs 65.5 µg/m3; p < 0.001), and incidence of HBeAg seropositivity (48.7% vs 19.1%; p < 0.001), and lower platelet count (181.7 × 103/µL vs 220.7 × 103/µL; p = 0.01) than those with normal ALT levels (Table 3).
Table 3.
Factors associated with the abnormal ALTa in non-cirrhotic patients
| Abnormal ALT | Yes, n = 840 | No, n = 68 | Univariate p | Logistic regression analysis | ||
|---|---|---|---|---|---|---|
| OR | 95% CI | p | ||||
| Age (y, mean [SD]) | 45.0 (13.9) | 55.0 (13.7) | <0.001 | 0.97 | 0.94-1.00 | 0.05 |
| Male, n (%) | 614 (73.1) | 38 (55.9) | 0.003 | 1.27 | 0.59-2.74 | 0.54 |
| Diabetes, n/N (%) | 96/754 (12.7) | 7/66 (10.6) | 0.85 | |||
| BMI (kg/m2, mean [SD]) | 24.3 (4.1) | 23.9 (4.2) | 0.42 | |||
| Platelet count (×103 u/L, mean [SD]) | 181.7 (66.5) | 220.7 (113.0) | 0.01 | 1.00 | 0.99-1.00 | 0.05 |
| Creatinine (mg/dL, mean [SD]) | 1.0 (1.0) | 1.4 (2.1) | 0.18 | |||
| HBV DNA (log10 IU/mL, mean [SD]) | 6.3 (1.8) | 4.4 (2.2) | <0.001 | 1.52 | 1.28-1.82 | <0.001 |
| HBeAg seropositivity, n/N (%) | 409/839 (48.7) | 13/68 (19.1) | <0.001 | 0.82 | 0.29-2.33 | 0.71 |
| Fatty liver, n/N (%) | 297/726 (40.9) | 12/46 (26.1) | 0.06 | 2.02 | 0.89-4.58 | 0.09 |
| Baseline PM2.5 (µg/m3, mean [SD]) | 40.6 (6.8) | 36.2 (8.4) | <0.001 | 1.06 | 1.01-1.11 | 0.01 |
| Baseline PM10 (µg/m3, mean [SD]) | 72.0 (10.3) | 65.5 (12.7) | <0.001 | 0.98 | 0.92-1.04 | 0.45 |
| Baseline ozone (ppb, mean [SD]) | 28.2 (2.7) | 28.3 (2.8) | 0.76 | |||
| Baseline NO2 (ppb, mean [SD]) | 21.9 (5.1) | 20.7 (5.2) | 0.11 | |||
ALT = alanine aminotransferase; BMI = body mass index; HBeAg = Hepatitis B e-antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; NO2 = nitrous oxide; OR = odds ratio; PM2.5 = particulate matter 2.5; PM10 = particulate matter 10.
ALT > 40 IU/L.
Logistic regression analysis revealed that the strongest factors associated with abnormal ALT levels were HBV DNA level (OR/CI: 1.52/1.28-1.82; p < 0.001) and PM2.5 concentration (OR/CI: 1.06/1.101-1.11; p = 0.01). The use of quartiles to assess exposure to air pollutants confirmed these results, and we identified a significant trend for PM2.5 (Table 4).
Table 4.
Adjusted ORs, 95% CI, and p trend values for the association between PM2.5 and abnormal ALTa in non-cirrhotic patients, according to quartiles of the distribution
| Pollutant | Quartile | OR (95% CI) |
|---|---|---|
| PM2.5 | 1 (<34.65) | 1.00 |
| 2 (34.65-41.23) | 4.64 (1.50-14.31) | |
| 3 (41.23-45.74) | 7.19 (2.05-25.24) | |
| 4 (>45.74) | 2.93 (1.23-7.00) | |
| p trend | 0.001 |
Models adjusted for the age, sex, platelet, HBV DNA, HBeAg seropositivity, fatty liver, PM2.5, and PM10 in to multivariate analysis.
ALT = alanine aminotransferase; HBeAg = Hepatitis B e-antigen; HBV = hepatitis B virus; OR = odds ratio; PM2.5 = particulate matter 2.5.
ALT >40 IU/L.
3.4. Factors associated with abnormal ALT levels among patients with cirrhosis
Among patients with cirrhosis, those with abnormal ALT levels had higher HBV DNA levels (5.6 vs 4.8 log10 IU/mL; p < 0.001) than those with normal ALT levels. Logistic regression analysis revealed that HBV DNA level was the strongest factor associated with abnormal ALT levels (OR/CI: 1.28/1.12-1.48, p = 0.001) (Table 5).
Table 5.
Factors associated with the abnormal ALTa in cirrhotic patients
| Abnormal ALT | Yes, n = 287 | No, n = 80 | Univariate p | Logistic regression analysis | ||
|---|---|---|---|---|---|---|
| OR | 95% CI | p | ||||
| Age (y, mean [SD]) | 54.5 (11.4) | 53.2 (12.9) | 0.37 | |||
| Male, n (%) | 215 (74.9) | 61 (76.2) | 0.88 | |||
| Diabetes, n/N (%) | 51/259 (15.7) | 20/77 (26.0) | 0.27 | |||
| BMI (kg/m2, mean [SD]) | 25.4 (4.1) | 25.3 (3.7) | 0.91 | |||
| Platelet count (×103 u/L, mean [SD]) | 117.0 (54.8) | 129.4 (73.8) | 0.18 | |||
| Creatinine (mg/dL, mean [SD]) | 1.1 (1.0) | 1.1 (1.2) | 0.94 | |||
| HBV DNA (log10 IU/mL, mean [SD]) | 5.6 (1.8) | 4.8 (1.5) | <0.001 | 1.28 | 1.12-1.48 | 0.001 |
| HBeAg seropositivity, n/N (%) | 65/285 (22.8) | 13/79 (16.5) | 0.28 | |||
| Fatty liver, n/N (%) | 23/225 (10.2) | 6/60 (10.0) | 1.00 | |||
| Baseline PM2.5 (µg/m3, mean [SD]) | 39.5 (6.6) | 38.5 (7.3) | 0.26 | |||
| Baseline PM10 (µg/m3, mean [SD]) | 70.4 (10.2) | 68.3 (11.4) | 0.13 | |||
| Baseline ozone (ppb, mean [SD]) | 28.6 (2.9) | 28.7 (2.8) | 0.69 | |||
| Baseline NO2 (ppb, mean [SD]) | 21.1 (5.3) | 20.0 (5.9) | 0.13 | |||
ALT = alanine aminotransferase; BMI = body mass index; HBeAg = Hepatitis B e-antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; NO2 = nitrous oxide; OR = odds ratio; PM2.5 = particulate matter 2.5; PM10 = particulate matter 10.
ALT > 40 IU/L.
4. DISCUSSION
This study found that abnormal ALT levels were associated with HBV DNA levels and PM2.5 concentrations after adjusting for confounding factors in patients with CHB receiving NA treatment. PM2.5 concentrations >40 µg/m³ were linked to a 2-fold increased risk of abnormal ALT levels. Patients in the highest quartile of annual PM2.5 concentration exposure had a 3-fold increased risk of abnormal ALT levels compared with those in the lowest quartile. The impact of PM2.5, on abnormal ALT levels was particularly pronounced in patients without cirrhosis.
HBV infection causes hepatic inflammation, which leads to abnormal ALT levels. Factors associated with abnormal ALT levels in patients with CHB include HBV DNA levels, fatty liver disease, metabolic effects, and alcohol use.3 The use of NAs improves ALT levels,18 retards fibrosis progression, decreases the incidence of cirrhosis and HCC, and12 improves long-term survival.17 Normalized ALT levels are an important indicator of disease control during NA treatment. Previous studies have shown that NAs improve ALT levels in HBeAg-negative patients without cirrhosis with a low viral load after 1 year of therapy, after adjusting for confounding factors.7,19 Older age and prior NA therapy were positively associated with HBsAg loss, while current NA therapy was negatively associated with HBsAg loss in patients with CHB having a low viral load.20
Air pollution can trigger inflammation and oxidative damage, which can lead to chronic liver disease.6 Air pollution contributes to fatty liver disease21 and triggers impaired liver function. Air pollution impedes the normalization of ALT levels in patients with CHB treated with NAs.7 Furthermore, air pollution is associated with advanced liver fibrosis in patients with chronic liver disease.8 A dose-dependent correlation between air pollution and severity of hepatic fibrosis has been noted. Moreover, air pollution is also associated with liver cancer.9,10 A previous study demonstrated that air pollution and HBsAg seropositivity were associated with HCC occurrence and had synergistic effects after adjusting for confounding factors.11 Air pollution may accelerate the development of HCC in patients with CHB and cirrhosis receiving NA treatment.22 No previous study has reported an association between pretreatment ALT levels and air pollution in patients with CHB treated with NAs.
PM2.5 has been associated with elevated ALT levels23 and increased incidence of liver fibrosis8 and liver cancer.11,24 However, its role in patients with CHB before treatment has not yet been elucidated. In this study, we found that high concentrations of PM2.5 and high HBV DNA levels caused hepatic inflammation after adjusting for confounding factors. Indications for NA therapy in CHB are based on the clinical phase of CHB.25 However, there may be a gray zone in which the features do not correspond to any specific phase. Some hepatologists suggest NA therapy only if the HBV DNA level is >2000 IU/mL.26 PM2.5 has been associated with hepatic complications, may lower the efficacy of NA treatment in patients residing in areas with high air pollution.
This study had some limitations. First, air pollutant exposure was calculated as the mean value for 1 year before the patient was enrolled. We did not compare the effects of the different time intervals or longer observation periods. Second, we did not have comprehensive data on the socioeconomic background, smoking status, alcohol consumption, inactive carrier status, or active hepatitis. A few of the patients in this study were inactive carriers. Among patients with normal ALT, more than 50% had liver cirrhosis. The small number of patients made further analyses difficult. Third, metabolic-associated steatotic liver disease was not considered. A strength of this study is that air pollution remained an independent risk factor for abnormal ALT levels after adjusting for confounding factors. To our knowledge, this is the first report on the association between air pollution and abnormal ALT levels in patients with CHB treated with NAs.
In conclusion, high PM2.5 concentrations were associated with abnormal ALT levels in patients with CHB treated with NAs. The impact of PM2.5 on abnormal ALT levels was particularly pronounced in patients without cirrhosis. Further studies are warranted to determine long-term outcomes in these patients.
ACKNOWLEDGMENTS
This work was supported in part by grants from the National Science Council of Taiwan (NSTC 112-2923-B-037-002-MY3, NSTC 112-2314-B-037-076-MY3), Taiwan and Mongolia Joint Project (TWN-2-2022/03), and Kaohsiung Medical University (KMUH111-1R05, KMUH112-2R11, and KMUH112-2M02).
APPENDIX A. SUPPLEMENTARY DATA
Supplementary data related to this article can be found at http://links.lww.com/JCMA/A311.
Supplementary Material
Footnotes
Conflicts of interest: The author declares that he/she has no conflicts of interest related to the subject matter or materials discussed in this article.
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