Teckman Jeffrey H, Blomenkamp Keith S
Department of Pediatrics, Saint Louis University School of Medicine, 1465 S. Grand Blvd., Saint Louis, MO, USA.
Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1465 S. Grand Blvd., Saint Louis, MO, USA.
Methods Mol Biol. 2017;1639:1-8. doi: 10.1007/978-1-4939-7163-3_1.
Classical alpha-1 antitrypsin (a1AT) deficiency is an autosomal recessive disease associated with an increased risk of liver disease in adults and children, and with lung disease in adults (Teckman and Jain, Curr Gastroenterol Rep 16(1):367, 2014). The vast majority of the liver disease is associated with homozygosity for the Z mutant allele, the so-called PIZZ. These homozygous individuals synthesize large quantities of a1AT mutant Z protein in the liver, but the mutant protein folds improperly during biogenesis and approximately 85% of the molecules are retained within the hepatocytes rather than appropriately secreted. The resulting low, or "deficient," serum level leaves the lungs vulnerable to inflammatory injury from uninhibited neutrophil proteases. Most of the mutant Z protein molecules retained within hepatocytes are directed into intracellular proteolysis pathways, but some molecules remain in the endoplasmic reticulum for long periods of time. Some of these molecules adopt an unusual aggregated or "polymerized" conformation (Duvoix et al., Rev Mal Respir 31(10):992-1002, 2014). It is thought that these intracellular polymers trigger a cascade of intracellular injury which can lead to end-organ liver injury including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (Lindblad et al., Hepatology 46(4):1228-1235, 2007). The hepatocytes with the largest accumulations of mutant Z polymers undergo apoptotic death and possibly other death mechanisms. This intracellular death cascade appears to involve ER stress, mitochondrial depolarization, and caspase cleavage, and is possibly linked to autophagy and redox injury. Cells with lesser burdens of mutant Z protein proliferate to maintain the liver cell mass. This chronic cycle of cell death and regeneration activates hepatic stellate cells and initiates the process of hepatic fibrosis. Cirrhosis and hepatocellular carcinoma then result in some patients. Since not all patients with the same homozygous PIZZ genotype develop end-stage disease, it is hypothesized that there is likely to be a strong influence of genetic and environmental modifiers of the injury cascade and of the fibrotic response.
经典α-1抗胰蛋白酶（a1AT）缺乏症是一种常染色体隐性疾病，与成人和儿童患肝病风险增加以及成人患肺病风险增加相关（特克曼和贾因，《当代胃肠病学报告》16(1):367，2014年）。绝大多数肝病与Z突变等位基因的纯合性有关，即所谓的PIZZ。这些纯合个体在肝脏中合成大量a1AT突变Z蛋白，但突变蛋白在生物合成过程中折叠不当，约85%的分子滞留在肝细胞内，而不是被适当分泌。由此导致的血清水平低，即“缺乏”，使肺部易受未受抑制的中性粒细胞蛋白酶引起的炎症损伤。滞留在肝细胞内的大多数突变Z蛋白分子被导向细胞内蛋白水解途径，但一些分子会在很长一段时间内留在内质网中。其中一些分子呈现出异常的聚集或“聚合”构象（迪沃克斯等人，《呼吸疾病综述》31(10):992 - 1002，2014年）。据认为，这些细胞内聚合物引发一系列细胞内损伤，可导致终末期肝脏损伤，包括慢性肝炎、肝硬化和肝细胞癌（林德布拉德等人，《肝脏病学》46(4):1228 - 1235，2007年）。突变Z聚合物积累最多的肝细胞会经历凋亡死亡，可能还有其他死亡机制。这种细胞内死亡级联反应似乎涉及内质网应激、线粒体去极化和半胱天冬酶裂解，并且可能与自噬和氧化还原损伤有关。突变Z蛋白负担较轻的细胞会增殖以维持肝细胞数量。这种细胞死亡和再生的慢性循环会激活肝星状细胞并启动肝纤维化过程。然后一些患者会发展为肝硬化和肝细胞癌。由于并非所有具有相同纯合PIZZ基因型的患者都会发展为终末期疾病，因此推测损伤级联反应和纤维化反应的遗传和环境修饰因素可能有很大影响。
