Many biochemical tests detecting the presence of liver disease are not liver-specific and may be abnormal in nonhepatic conditions. The asialoglycoprotein receptor (ASGPR) is a hepatocyte-specific receptor for Gal/GalNAc-terminated glycopeptide or glycoprotein. The number of these receptors decreases in patients with chronic liver diseases. Here, we aimed to evaluate the use of ¹¹¹In-hexavalent lactoside, a known ASGPR imaging biomarker, as a more sensitive probe to detect small changes in liver reserve in animal models of chronic liver injury. Thioacetamide (TAA) treatment via intraperitoneal injection every 2 days in BALB/c mice continued for 1, 2, 3, or 4 months. The liver fibrosis stages were determined by Sirius Red staining and were based on the METAVIR classification method. Serum transaminase enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)), alkaline phosphatase, albumin, and bilirubin were measured using a FUJI FDC3500 i/s analyzer. The ASGPR staining was performed by immunohistocytochemical stain. The percentages of fibrosis and ASGPR were calculated using ImageJ software after collagen staining and anti-ASGPR staining, respectively. A nanoSPECT/CT was used for molecular imaging and liver uptake measurement. We observed fibrosis grades of F0–F1 in mice treated with TAA for 1 month, F2 in mice treated for 2 months, F3–F4 in mice treated for 3 months, and F4 in mice treated for 4 months. The levels of ALT and albumin were not significantly different in the TAA groups from those in the controls. Although the average levels of AST, alkaline phosphatase, and bilirubin in the TAA groups were different from those in the control group, there was little difference between TAA groups. More sensitive distinctions among TAA groups were detected in ¹¹¹In-hexavalent lactoside uptake of ASGPR, ASGPR staining, and fibrosis % than when using the conventional AST, ALT, albumin, alkaline phosphatase, and bilirubin tests. The absorption and distribution of ¹¹¹In-hexavalent lactoside were lower in the chronic hepatitis models than the normal controls. The liver reserves measured by ¹¹¹In-hexavalent lactoside uptake were 71.7 ± 7.5% and 50.9 ± 5.6% after 1 and 2 months, respectively, of TAA treatment. As an ASGPR biomarker, ¹¹¹In-hexavalent lactoside has higher sensitivity than traditional liver function tests and collagen stain to provide more objective data for evaluating compensated cirrhosis or changes in liver damage. ASGPR staining can reflect the regenerated hepatocytes, but the need for a biopsy limits its use. ¹¹¹In-hexavalent lactoside measurement is comparable with ASGPR staining, which suggests that ¹¹¹In-hexavalent lactoside measurement will be more useful as a practical, noninvasive test of chronic liver injury.

中文翻译：

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使用¹¹¹在-六价铬乳糖苷对肝储备估计在鼠害与硫代乙酰胺诱导肝纤维化

许多检测肝脏疾病存在的生化测试不是肝特异性的，并且在非肝病中可能是异常的。脱唾液酸糖蛋白受体（ASGPR）是针对Gal / GalNAc末端的糖肽或糖蛋白的肝细胞特异性受体。在患有慢性肝病的患者中，这些受体的数量减少。在这里，我们旨在评估¹¹¹的使用六价乳糖苷，一种已知的ASGPR成像生物标记物，是一种更敏感的探针，可用于检测慢性肝损伤动物模型中肝脏储备的微小变化。在BALB / c小鼠中，每2天通过腹腔注射硫代乙酰胺（TAA）治疗持续1、2、3或4个月。肝纤维化分期通过Sirius Red染色确定，并基于METAVIR分类法。使用FUJI FDC3500 i / s分析仪测量血清转氨酶（丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）），碱性磷酸酶，白蛋白和胆红素。ASGPR染色通过免疫组织化学染色进行。分别在胶原蛋白染色和抗ASGPR染色后使用ImageJ软件计算纤维化和ASGPR的百分比。nanoSPECT / CT用于分子成像和肝摄取测量。我们观察到在用TAA治疗1个月的小鼠中，F0–F1的纤维化等级，在治疗2个月的小鼠中，F2的纤维化等级，在治疗3个月的小鼠中，F3–F4的纤维化等级，以及在治疗4个月的小鼠中，F4的纤维化等级。TAA组中的ALT和白蛋白水平与对照组相比无显着差异。尽管TAA组的AST，碱性磷酸酶和胆红素的平均水平与对照组相比有所不同，但TAA组之间的差异很小。在TAA组之间发现了更敏感的区别 TAA组中的ALT和白蛋白水平与对照组相比无显着差异。尽管TAA组的AST，碱性磷酸酶和胆红素的平均水平与对照组相比有所不同，但TAA组之间的差异很小。在TAA组之间发现了更敏感的区别 TAA组中的ALT和白蛋白水平与对照组相比无显着差异。尽管TAA组的AST，碱性磷酸酶和胆红素的平均水平与对照组相比有所不同，但TAA组之间的差异很小。在TAA组之间发现了更敏感的区别¹¹¹与使用常规AST，ALT，白蛋白，碱性磷酸酶和胆红素测试相比，ASPGR，ASGPR染色和纤维化的六价乳糖苷摄入量％。在慢性肝炎模型中，¹¹¹ In-六价乳糖苷的吸收和分布低于正常对照组。TAA治疗1和2个月后，通过¹¹¹种六价乳糖苷摄取量测得的肝储备分别为71.7±7.5％和50.9±5.6％。作为ASGPR生物标志物，¹¹¹六价内乳糖苷比传统肝功能测试和胶原蛋白染色具有更高的敏感性，可为评估代偿性肝硬化或肝损害的变化提供更多客观数据。ASGPR染色可以反映再生的肝细胞，但是活检的需要限制了它的使用。¹¹¹六价乳糖苷的测定可与ASGPR染色相媲美，这表明¹¹¹六价乳糖苷的测定可作为一种实用的，无创的慢性肝损伤检测方法。