在慢性B肝長期世代研究下探討肥胖危險因子相關的肝纖維化和脂肪肝變性

Abstract

背景和目的 中年以後的肥胖軌跡影響慢性B型肝炎嚴重程度的相關知識仍是有限的。這一個縱式研究目的在於經由長期追蹤研究探討肥胖指標和慢性B型肝炎帶原者發展成肝纖維化和脂肪肝變性的關係。 材料和方法 研究個案包括501位參加台灣公保世代研究的慢性B型肝炎男性(中位數年紀56.0歲; 四分位數區間 52.1-61.3歲)，他們在2016至2019年間接受可信度高的肝臟纖維掃描儀。從2005至2019年檢測代謝性危險因子(包含身高體重指數[BMI]、高血糖、高三酸甘油脂、高膽固醇、高密度膽固醇過低、高血壓和腰圍 ≥ 90公分)。肝硬度測量(LSM) ≥ 7.0 kPa定義為臨床上顯著性的肝纖維化而脂肪肝變性受控衰減參數(CAP) ≥ 248 dB/m則定義為脂肪肝變性。多變項的羅吉斯迴歸來分析基礎值的代謝性危險因子和肝臟纖維掃描儀的相關因子；半母數的群組化軌跡模式用來處理分化成年以後長時間追蹤BMI和腰圍的重複測量值。 結果 108 (21.6%)位患者為臨床上顯著性的肝纖維化，而249 (49.7%)有脂肪肝變性。經由多變項因子的校正，基準值的腰圍(相對風險1.05; 95%信賴區間, 1.02 - 1.08)和血清中AST(相對風險1.04; 95%信賴區間, 1.01 - 1.06)在慢性B肝帶原者上對於臨床上顯著性的肝纖維化有正相關的風險。基準值的BMI (相對風險 1.24; 95%信賴區間, 1.06 - 1.45)、腰圍(相對風險1.07; 95%信賴區間, 1.02 - 1.12)、總膽固醇(相對風險1.01; 95%信賴區間, 1.00 - 1.02)和超音波診斷的脂肪肝(相對風險 1.87; 95%信賴區間, 1.16 - 3.02)對於脂肪肝變性有正相關性。基準值的BMI ≥ 25 kg/m2 合併血清中AST的異常( ≥ 35 IU/L)相較於基準值正常的BMI和AST族群對於顯著性的肝纖維化有加成的效果(相對風險5.33; 95%信賴區間, 2.56 - 11.11)。在縱式分析下，長時間的肥胖軌跡族群(BMI ≥ 25 kg/m2)相較於正常族群(BMI < 23 kg/m2)有較高的風險造成臨床上顯著性的肝纖維化(相對風險 2.91; 95%信賴區間, 1.58 - 5.36)和脂肪肝變性(相對風險 24.47; 95%信賴區間, 12.52 - 47.85)。相同情況下, 中央型肥胖的軌跡族群(腰圍 ≥ 90 cm)相較於正常族群(腰圍 < 90 cm)有較高的風險造成臨床上顯著性的肝纖維化(相對風險 2.41; 95%信賴區間, 1.27 - 4.58)和脂肪肝變性(相對風險 36.33; 95%信賴區間, 16.93 - 77.96)。 結論 在成年男性的慢性B肝帶原者，我們發現持續性的肥胖或是中央型肥胖會有較高的風險造成肝纖維化和脂肪肝變性。對於慢性B肝患者同時有肥胖併血清中AST的異常將會增加未來發展成臨床上顯著性肝纖維化的風險，監測肝臟疾病的惡化和即時的介入型治療是必須的。

Background Aims Little is known about the impact of trajectories of obesity during late adulthood on the severity of chronic hepatitis B (CHB). This longitudinal study aimed to assess obesity over repeated measurements during long-term follow-up and liver fibrosis and steatosis in CHB patients. Material Methods We enrolled 501 CHB males (median age 56.0 years; interquartile range 52.1-61.3 years) who were included in a Government Employees’ Central Clinics cohort and were evaluated with transient elastography between 2016 and 2019. Metabolic risk factors (including body mass index [BMI], hyperglycemia, hypertriglyceridemia, hypercholesterolemia, low HDL-cholesterol, hypertension and waist circumference ≥ 90cm) were examined between 2005 and 2019. Liver stiffness measurement (LSM) ≥ 7.0 kPa was defined as clinical significant liver fibrosis and controlled attenuation parameter (CAP) ≥ 248 dB/m was defined as liver steatosis. Multivariate logistic regression was used to investigate the association between metabolic risk factors at baseline and indicators of transient elastography. A semi-parametric group-based trajectory modeling approach was used to identify the latent trajectory groups of repeated measurements of BMI and waist circumference during the long term follow-up period. Results One hundred and eight (21.6%) patients had clinical significant liver fibrosis and 249 (49.7%) had liver steatosis. After multivariate adjustment, waist circumference (OR 1.05; 95% CI, 1.02 to 1.08) and serum AST (OR 1.04; 95% CI, 1.01 to 1.06) at baseline showed a positive association with risk of clinical significant liver fibrosis in CHB patients. BMI (OR 1.24; 95% CI, 1.06 to 1.45), waist circumference (OR 1.07; 95% CI, 1.02 to 1.12), total cholesterol (OR 1.01; 95% CI, 1.00 to 1.02) and ultrasonographic fatty liver (OR 1.87; 95% CI, 1.16 to 3.02) at baseline were positively associated with liver steatosis. There was an additive effect of BMI ≥ 25 kg/m2 and increased serum AST activity ( ≥ 35 IU/L) at baseline with the OR of 5.33 (95% CI, 2.56 to 11.11) of significant liver fibrosis , as compared with normal BMI and AST group (BMI < 23 kg/m2, AST < 35 IU/L). In longitudinal analysis, trajectory of lasting obesity (BMI ≥ 25 kg/m2) had the highest risk of clinical significant liver fibrosis (OR 2.91; 95% CI, 1.58 to 5.36) and steatosis (OR 24.47; 95% CI, 12.52 to 47.85), as compared with trajectory of stable normal BMI (BMI < 23 kg/m2). Similarly, trajectory of central-obesity (waist circumference ≥ 90 cm) had the highest risk of clinical significant liver fibrosis (OR 2.41; 95% CI, 1.27 to 4.58) and steatosis (OR 36.33; 95% CI, 16.93 to 77.96), as compared with low-stable group (waist circumference < 90 cm). Conclusions In a study of men with CHB, we found that persistence of obesity or central-obesity, was positively associated with liver fibrosis and steatosis. For CHB patients with both obesity and elevated AST activity who are at increased risk of developing clinical significant liver fibrosis, monitoring hepatic disease progression with timely intervention should be considered.