Stoller James K, Hupertz Vera, Aboussouan Loutfi S
Respiratory and Education Institutes, Cleveland Clinic, Cleveland, Ohio
Pediatric Gastroenterology, Pediatric Institute, Cleveland Clinic, Cleveland, Ohio
Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD.
DIAGNOSIS/TESTING: The diagnosis of AATD relies on demonstration of low serum concentration of alpha-1 antitrypsin (AAT) and either identification of biallelic pathogenic variants in or detection of a functionally deficient AAT protein variant by protease inhibitor (PI) typing. Note: The unconventional nomenclature of alleles is based on electrophoretic protein variants that were identified long before the gene ( was known. Alleles were named with the prefix PI* (protease inhibitor*) serving as an alias for the gene. Using this nomenclature, the most common (normal) allele is PIM and the most common pathogenic allele is PIZ.
COPD is treated with standard therapy. Augmentation therapy with periodic intravenous infusion of pooled human serum alpha-1 antitrypsin (AAT) is used in individuals who have established emphysema. Lung transplantation may be an appropriate option for individuals with end-stage lung disease. Liver transplantation is the definitive treatment for severe disease (will restore AAT levels). Dapsone or doxycycline therapy is used for panniculitis; if refractory to this, high-dose intravenous AAT augmentation therapy is indicated. Every six to 12 months: pulmonary function tests including spirometry with bronchodilators and diffusing capacity measurements; liver function tests, platelet count and liver ultrasound, elastography (e.g., FibroScan), magnetic resonance imaging. Smoking (both active and passive); occupational exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes; excessive use of alcohol. Evaluation of parents, older and younger sibs, and offspring of an individual with severe AATD in order to identify as early as possible those relatives who would benefit from institution of treatment and preventive measures.
AATD is inherited in an autosomal codominant manner. If both parents are heterozygous for one pathogenic variant (e.g., PIMZ), each sib of an affected individual has a 25% chance of being affected (PIZZ), a 50% chance of being heterozygous (PIMZ), and a 25% chance of inheriting neither of the pathogenic variants (PIMM). In the less frequent instance in which one parent is homozygous (PIZZ) and one parent is heterozygous (PIMZ), the risk to each sib of being homozygous (PI*ZZ) is 50%. Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be obligate heterozygotes for a pathogenic variant. (Risk of lung disease may be increased in heterozygous individuals depending on their environmental exposures such as smoking.) Heterozygote testing for at-risk family members and prenatal and preimplantation genetic testing are possible once the pathogenic variants have been identified in the family.
α-1抗胰蛋白酶缺乏症（AATD）在从婴儿期到成年期的个体中可表现为肝功能障碍，在30岁以上的个体中可表现为慢性阻塞性肺疾病（肺气肿和/或支气管扩张）。AATD患者发生脂膜炎（游走性、炎症性、触痛性皮肤结节，可在腿部和下腹部发生溃疡）和C-ANCA阳性血管炎（肉芽肿性多血管炎）的风险也会增加。表型表达在家族内部和家族之间存在差异。在成年人中，吸烟是加速慢性阻塞性肺疾病（COPD）发展的主要因素；不吸烟者可能有正常寿命，但也可能发生肺部和/或肝脏疾病。虽然有报道，但AATD患儿的肺气肿极为罕见。AATD相关肝病仅在一小部分受影响儿童中出现，表现为新生儿胆汁淤积。肝病的发病率随年龄增长而增加。成年人的肝病（表现为肝硬化和纤维化）可能在没有新生儿或儿童肝病病史的情况下发生。AATD患者发生肝细胞癌（HCC）的风险增加。
诊断/检测：AATD的诊断依赖于血清α-1抗胰蛋白酶（AAT）浓度降低的证明，以及通过蛋白酶抑制剂（PI）分型鉴定双等位基因致病变异或检测功能缺陷的AAT蛋白变体。注意：等位基因的非常规命名基于早在该基因被发现之前就已鉴定出的电泳蛋白变体。等位基因以前缀PI*（蛋白酶抑制剂*）命名，作为该基因的别名。使用这种命名法，最常见（正常）的等位基因为PIM，最常见的致病等位基因为PIZ。
COPD采用标准疗法治疗。对于已确诊肺气肿的个体，采用定期静脉输注混合人血清α-1抗胰蛋白酶（AAT）的增强疗法。肺移植可能是终末期肺病患者的合适选择。肝移植是重症疾病的确定性治疗方法（可恢复AAT水平）。氨苯砜或强力霉素疗法用于脂膜炎；如果对此治疗无效，则需进行高剂量静脉AAT增强疗法。每6至12个月：进行肺功能测试，包括使用支气管扩张剂的肺活量测定和弥散功能测量；肝功能测试、血小板计数、肝脏超声、弹性成像（如FibroScan）、磁共振成像。避免吸烟（包括主动和被动吸烟）；避免职业性接触农业中使用的环境污染物、矿物粉尘、气体和烟雾；避免过量饮酒。对严重AATD患者的父母、年长和年幼的兄弟姐妹以及后代进行评估，以便尽早识别那些将从治疗和预防措施中受益的亲属。
AATD以常染色体共显性方式遗传。如果父母双方均为一种致病变异的杂合子（例如PIMZ），受影响个体的每个兄弟姐妹有25%的机会受影响（PIZZ），50%的机会为杂合子（PIMZ），25%的机会既不继承致病变异（PIMM）。在较罕见的情况下，一方父母为纯合子（PIZZ），另一方父母为杂合子（PIMZ），每个兄弟姐妹为纯合子（PI*ZZ）的风险为50%。除非患有AATD的个体与受影响个体或杂合子生育子女，否则其后代将必然是致病变异的杂合子。（杂合子个体患肺病的风险可能因环境暴露如吸烟而增加。）一旦在家族中鉴定出致病变异，就可以对有风险的家庭成员进行杂合子检测以及产前和植入前基因检测。
