Summary Background Alpha‐1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. Aims To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review. Methods A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle‐Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported. Results Thirty‐five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5‐year survival reported as over 90% in children and over 80% in adults. Discussion The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.

ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Alkyl iodides (RI) react with [Rh(C0)2121-to give acyl species [Rh(CO)(COR)I31-(R = Et, "Pr, 'Pr) and with [Ir(C0)2121-to give aZkyZ complexes [RIr(C0)2121-(R = Et, "Pr, iPr, "Bu, n-C5H11, n-CsH13). The reactions are analogous to the known reactions of Me1 with [Rh(C0)212]-and [Ir(C0)2121-. The products are characterized spectroscopically and by an X-ray crystal structure determination for Ph4As[(n-C~H13)Ir(CO)213] which showed a fac,cis eometry for the anion. [Crystal structure data: monoclinic, a = 9.408(7) A, b = 19.470(16) f, c = 19.529(12) A, / 3 = 94.99(5)", 2 = 4, space group P21/n (a nonstandard setting of P21/c Cih, No. 14); 2446 independent reflections (of 5197 measured) for which IFl/O(IFl> > 4.0; R = 0.0966 (R, = 0.0921, 238 parameters)]. Kinetic data for the reactions of [Rh(C0)2121-with EtI, "PrI, and 'PrI and for [Ir(C0)212]-with MeI, EtI, and "PrI show that oxidative addition of RI to [M(C0)2121-is first-order in both reactants. For M = Rh, reactions showed clean second-order kinetics below 80 "C, though some decomposition occurred at higher temperatures. For M = Ir, clean second-order kinetics were observed with MeI, but reactions with Et1 and "PrI showed a more complex kinetic behavior. A competing radical pathway is suggested, which can be quenched by added duroquinone. Second-order rate constants, k2, evaluated over the temperature ranges 70-80 "C (M = Rh) and 35-50 "C (M = Ir) gave the following activation parameters: (M = Rh) H / k J mol-l = 5 0 ( f l ) (R = Me), 56(f10) (R = Et), 51(f10) (R = "Pr), 61(f15) (R = iPr); M*/J mol-l K-l = -165(f4) (R = Me), -195(f25) (R = Et), -215(f25) (R = "Pr), -180(f30) (R = 'Pr); (M = Ir) H / k J mol-l = 5 4 ( f l ) (R = Me), 66(f5) (R = Et), 66(f3) (R = "Pr); AS*/J mol-l K-l -113(f4) (R = Me), -123(f15) (R = Et), -1 3 2 ( f l l ) (R = "Pr). Comparisons are made between the reactions of methyl iodide and the higher alkyl iodides with both [Rh(C0)2121-(relative rates: Me, 1000,Et, 3; =Pr, 1.7) and [Ir(C0)212]-(relative rates: Me, 1000; Et, 2.3; "Pr, 0.75). The similarity to reactivity trends for organic nucleophiles suggests an sN2 mechanism, but with a competing radical pathway for iridium. Relative rates for the two nucleophiles, k 1 4 k~h ca.150 (R = Me), 220 (R = Et), and 140 (R = nPr), are estimated. Alkyl isomerization (is0 -n) is observed for both [Rh(CO)(COPr)I31-and [PrIr(C0)21& and displacement of propene from [Rh(CO)(COPr)I31-by added ethene gives [Rh(CO)(COEt)I31-reversibly. A mechanism involving hydridoalkene intermediates is proposed. The data are consistent with the carbonylation of the higher alcohols (ROH) proceeding via rate determining oxidative addition of RI to [Rh(C0)2121-, rather than by a route involving a rhodium hydride addition to an olefin derived from the ROH.

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