The new england journal of medicine Review Article Dan L. Longo, M.D., Editor Alpha1-Antitrypsin Deficiency Pavel Strnad, M.D., Noel G. McElvaney, D.Sc., and David A. Lomas, Sc.D.​​ lpha1-antitrypsin (AAT) deficiency is one of the most common From the Department of Internal Med­ genetic diseases. Most persons carry two copies of the wild-type M allele icine III, University Hospital RWTH of SERPINA1, which encodes AAT, and have normal circulating levels of the (Rheinisch–Westfälisch Technische Hoch­ A schule) Aachen, Aachen, Germany (P.S.); protein. Ninety-five percent of severe cases of AAT deficiency result from the homo- the Irish Centre for Genetic Lung Dis­ zygous substitution of a single amino acid, Glu342Lys (the Z allele), which is present ease, Royal College of Surgeons in Ire­ in 1 in 25 persons of European descent (1 in 2000 persons of European descent land, Beaumont Hospital, Dublin (N.G.M.); and UCL Respiratory, Division of Medi­ are homozygotes). Mild AAT deficiency typically results from a different amino cine, Rayne Institute, University College acid replacement, Glu264Val (the S allele), which is found in 1 in 4 persons in the London, London (D.A.L.). Address re­ Iberian peninsula. However, many other alleles have been described that have vari- print requests to Dr. Lomas at UCL Re­ spiratory, Rayne Institute, University Col­ able effects, such as a lack of protein production (null alleles), production of mis- lege London, London WC1E 6JF, United folded protein, or no effect on the level or function of circulating AAT (Table 1). Kingdom, or at d . lomas@ ucl . ac . uk. AAT is synthesized in the liver and secreted into the circulation, where its pri- N Engl J Med 2020;382:1443-55. mary role is to protect lung tissue against attack by the enzyme neutrophil elas- DOI: 10.1056/NEJMra1910234 tase. Point mutations can lead to retention of AAT in the liver, causing liver disease Copyright © 2020 Massachusetts Medical Society. through a toxic “gain of function,” whereas the lack of an important circulating proteinase inhibitor predisposes homozygotes with severe deficiency to early-onset emphysema (“loss of function”). The high frequency of genetic variants suggests that AAT mutations confer a selective advantage, perhaps by amplifying the in- flammatory response to invasive respiratory and gastrointestinal infection.2 We review the current understanding of the pathophysiology of AAT deficiency and discuss how this knowledge has led to new therapeutic strategies. Pathophysiology and Clinical Features of Liver Disease AAT is synthesized within hepatocytes, intestinal and pulmonary alveolar cells, neutrophils, macrophages, and the cornea. The liver produces approximately 34 mg of AAT per kilogram of body weight per day, leading to a plasma level of 0.9 to 1.75 mg per milliliter, with a half-life of 3 to 5 days. AAT levels can rise by 100% in persons with a normal proteinase inhibitor (PI) genotype (MM) during the acute-phase response, but the increase is markedly attenuated in persons with severe deficiency alleles. AAT is synthesized within the endoplasmic reticulum and secreted through the Golgi apparatus. Severe deficiency alleles — such as the com- mon Z (Glu342Lys) allele and the rare Siiyama (Ser53Phe), Mmalton (∆Phe52), and King’s (His334Asp) alleles — do not affect synthesis but cause approximately 70% of the mutant AAT to be degraded in the endoplasmic reticulum within hepatocytes,3 15% to be secreted, and 15% to form ordered polymers.4,5 These polymers are partially degraded by autophagy6,7 and a small amount is secreted,8,9 but a propor- tion persists within the endoplasmic reticulum as inclusions that are positive on periodic acid–Schiff staining and resistant to diastase; such inclusions are the n engl j med 382;15 nejm.org April 9, 2020 1443 1444 Table 1. Key Alleles Associated with Alpha1-Antitrypsin (AAT) Deficiency.* Mutation Variant† and rs Number‡ Molecular Basis of Disease Clinical Features Epidemiology Deficiency alleles F Arg223Cys Reduced association rate constant with Coinheritance with the Z deficiency allele Case report neutrophil elastase; slow formation may confer a predisposition to em­ of polymers physema I Arg39Cys Protein misfolding; can form hetero­ No clear disease association Disease reported only in compound heterozy­ rs28931570 polymers; reduced serum protein gotes The new england journal england new Iners Gly349Arg Type II mutant (i.e., normal secretion Not known Case report n engljmed382;15 but functionally deficient) King’s Hisp334Asp Rapid polymerization in hepatocyte Neonatal jaundice; presumed high risk of Case report endoplasmic reticulum; delayed emphysema in homozygote or com­ secretion pound Z heterozygote Mmalton Δ52Phe (M2 variant) Intracellular degradation and polymer­ Well­established association with liver dis­ Most common rare deficiency allele in Sardinia; rs775982338 ization; low serum level ease and emphysema in homozygotes seen sporadically in the United Kingdom and nejm.org Canada Mmineral springs Gly67Glu Abnormal posttranslational biosyn­ Emphysema in homozygotes Unusual; described in an Afro­Caribbean person rs28931568 thesis but no polymerization; low in the United States serum level April 9,2020 Mprocida Leu41Pro Unstable protein structure leading to High risk of emphysema in homozygotes Case report of rs28931569 intracellular degradation; reduced medicine catalytic activity of circulating protein Pittsburgh Met358Arg Function altered to an antithrombin Fatal bleeding disorder Case report rs121912713 Queen’s Lys154Asn Polymer formation Compound heterozygote with Z Case report S Glu264Val Protein misfolding and reduced secre­ Emphysema seen in SZ heterozygotes Most common deficiency variant; carrier fre­ rs17580 tion; can form heteropolymers with but less severe than in ZZ; cirrhosis quency: 1 in 5 persons in southern Europe, 1 Z AAT reported in SZ heterozygotes in 30 in the United States, 1 in 23 among per­ sons of European descent in Australia, 1 in 26 among those of European descent in New Zealand; rare or nonexistent in Asia, Africa, and Aboriginal Australians Siiyama Ser53Phe Intracellular degradation and polymer­ Liver disease and emphysema in homo­ Rare, but most common deficiency allele in rs55819880 ization; low serum level zygotes Japan Mutation Variant† and rs Number‡ Molecular Basis of Disease Clinical Features Epidemiology Trento Glu75Val Nonclassical polymer formation Emphysema in compound heterozygote Case report with Z Z Glu342Lys Intracellular degradation and polymer­ In homozygotes, well­established asso­ Most common severe deficiency variant; car­ rs28929474 ization; low serum level ciation with liver disease and emphy­ rier frequency: 1 in 27 persons in northern sema; MZ heterozygotes may be more Europe, 1 in 83 in the United States, 1 in 75 susceptible to airflow obstruction and persons of European descent in Australia, 1 chronic liver disease in 46 persons of European descent in New Zealand; not seen in China, Japan, Korea, Malaysia, or northern and western Africa Null (QO) alleles QObellingham Lys217 stop codon No detectable AAT mRNA High risk of emphysema in homozygotes Case report rs199422211 and compound heterozygotes n engljmed382;15 Alpha QObolton Δ1bpPro362, causing stop Truncated protein; intracellular degra­ High risk of emphysema in homozygotes Case report codon at 373 dation and no secreted protein and compound heterozygotes 1 QOgranitefalls Δ1bpTyr160, causing stop No detectable AAT mRNA Severe emphysema reported in Z com­ Case report -Antitrypsin Deficiency codon pound heterozygote rs267606950 QOhongkong Δ2bpLeu318, causing stop Truncated protein; intracellular aggre­ High risk of emphysema in homozygotes Case reports (persons of Chinese descent) nejm.org codon at 334 gation (no polymerization), degra­ and compound heterozygotes rs1057519610 dation, and no secreted protein 1 * The information is from Lomas et al. AAT deficiency alleles with different functional effects are listed. The delta symbol denotes deletion, and mRNA messenger RNA. April 9,2020 † The single or initial letter in each name reflects the position of migration of the variant on isoelectric­focusing gels (e.g., A indicates the fastest migration, M moderate migration, and Z the slowest migration); the rest of the name represents the site of the first description (in the case of Iners, the site is unknown). Deficiency results from a range of effects on the pro­ tein: rapid polymerization of the Z, Siiyama, Mmalton, and King’s variants; slower polymer formation of S, I, and Queen’s AAT; a change in the inhibitory activity of Pittsburgh AAT; secre­ tion of an inactive protein, Iners AAT; and some of the many null variants that result in no secreted protein. ‡ The rs number is the reference SNP cluster identification number. 1445 The new england journal of medicine “Gain of function” Neonatal hepatitis or cirrhosis Proteotoxic stress ↓Circulating AAT PAS-D–positive inclusions Misfolded AAT Polymerization ↓AAT function “Loss of function” Emphysema Macrophage Neutrophil • Cysteinyl TNF cathepsins Up-regulation TNF- receptor Proteolytic • MMP 1 or 2 lung damage Activation NE NE NE NE • Lactoferrin • MMP BLT1 Neutrophil • hCAP-18 elastase LTB CXCR1 4 Inhibition NE by AAT Lactoferrin ROS Autoantibody AIRWAY TLR TACE EGFR MUCUS EPITHELIUM Panlobular Interleukin-8 emphysema CXCR1 BLOOD VESSEL histologic hallmark of the disease (Fig. 1). deficiency1 (Table 1). The rate at which most Milder deficiency alleles, such as the S (Glu- AAT mutants form polymers correlates