Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Clin Gastroenterol Hepatol. 2018 Aug;16(8):1322-1332.e4. doi: 10.1016/j.cgh.2017.11.022. Epub 2017 Nov 16.
BACKGROUND & AIMS: Hyperbilirubinemia and hypoalbuminemia are features of hepatic dysfunction that associate with disease severity. This is because hepatic insufficiency causes hypoalbuminemia, which indirectly increases the circulating levels of free bilirubin. Circular dichroism (CD) spectroscopy can be used to quantify the molecular ellipticity (ME) of the albumin-bilirubin complex, and might associate with the severity or outcome of severe alcoholic hepatitis (SAH).
We performed a cross-sectional study of 265 patients with SAH admitted in the Department of Hepatology, Institute of Liver and Biliary Sciences in New Delhi, India from January 2014 through January 2016. Blood samples were collected and patients were followed for 12 months or death. The molar ratios of bilirubin: albumin and albumin-bilirubin complexes were determined for a discovery cohort (30 patients who survived the study period and 60 patients who did not survive) and compared with those of 60 patients with alcoholic cirrhosis and 30 healthy individuals (controls). Optical activities of albumin-bilirubin complexes in blood samples were determined by CD spectroscopy and compared among groups. Findings were validated in a separate cohort of 150 patients with SAH from the same institute. We studied the correlation between ME and albumin binding capacity (ABiC).
The molar ratio of bilirubin: albumin was higher in patients with SAH than with alcoholic cirrhosis or controls (P < .05). Patients with SAH had different CD spectra and higher ME than the other groups (P < .01); ME correlated with model for end-stage liver disease score (with and without Na) and discriminant function (r > .3; P < .01). ME values above a cut off of 1.84 mdeg predicted 3-month mortality in patients with SAH with an area under receiver operating characteristic curve of 0.87 (95% CI, 0.79-0.95), a 77% positive predictive value, and a 90% negative predictive value. The hazard ratio and concordance index of ME values for 3-month mortality in patients with SAH was 10% higher than the hazard ratio and concordance index of model for end-stage liver disease score. In patients with SAH, there was an inverse correlation between ME and ABiC (r > 0.7; P < .01). We observed a significant reduction in ABiC with increasing levels of bilirubin in vitro prepared albumin-bilirubin complex.
In a cross-sectional study of patients with SAH, we associated ME of the albumin-bilirubin complex, measured by CD spectroscopy, with outcomes of patients with SAH. Increased loading of bilirubin on albumin could explain reduced albumin function. Bilirubin removal by albumin dialysis might benefit patients with SAH.
高胆红素血症和低白蛋白血症是肝功能障碍的特征，与疾病严重程度相关。这是因为肝功能不全导致低白蛋白血症，间接增加了游离胆红素的循环水平。圆二色性（CD）光谱可用于定量白蛋白-胆红素复合物的分子椭圆率（ME），并可能与严重酒精性肝炎（SAH）的严重程度或结局相关。
我们对 2014 年 1 月至 2016 年 1 月期间在印度新德里肝脏和胆道科学研究所肝病科住院的 265 例 SAH 患者进行了一项横断面研究。采集血样并对患者进行 12 个月或死亡随访。为发现队列（30 例在研究期间存活和 60 例未存活的患者）和 60 例酒精性肝硬化患者和 30 例健康个体（对照组）确定胆红素：白蛋白和白蛋白-胆红素复合物的摩尔比。通过 CD 光谱比较各组间白蛋白-胆红素复合物的光学活性。在同一研究所的 150 例 SAH 患者的另一个队列中验证了发现。我们研究了 ME 与白蛋白结合能力（ABiC）之间的相关性。
与酒精性肝硬化或对照组相比，SAH 患者的胆红素：白蛋白摩尔比更高（P <.05）。SAH 患者的 CD 光谱不同，ME 高于其他组（P <.01）；ME 与终末期肝病模型评分（有和无 Na）和判别函数相关（r >.3；P <.01）。ME 值超过 1.84 mdeg 的截断值可预测 SAH 患者 3 个月死亡率，其受试者工作特征曲线下面积为 0.87（95%CI，0.79-0.95），阳性预测值为 77%，阴性预测值为 90%。SAH 患者 3 个月死亡率的 ME 值的危险比和一致性指数比终末期肝病模型评分的危险比和一致性指数高 10%。在 SAH 患者中，ME 与 ABiC 呈负相关（r > 0.7；P <.01）。我们观察到在体外制备的白蛋白-胆红素复合物中，随着胆红素水平的升高，ABiC 显著降低。
在对 SAH 患者的横断面研究中，我们将通过 CD 光谱测量的白蛋白-胆红素复合物的 ME 与 SAH 患者的结局相关联。胆红素对白蛋白的负荷增加可以解释白蛋白功能的降低。白蛋白透析清除胆红素可能有益于 SAH 患者。
