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Alpha-1-Antitrypsin Phenotypes in Patients with Renal Arterial Fibromuscular Dysplasia

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Alpha-1-Antitrypsin Phenotypes in Patients with Renal Arterial Fibromuscular Dysplasia Journal of Human Hypertension (2000) 14, 91–94 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia A Bofinger, C Hawley, P Fisher, N Daunt, M Stowasser and R Gordon Hypertension Unit, University of Queensland Department of Medicine, Greenslopes Private Hospital, Brisbane, Queensland, Australia ␣ Fibromuscular dysplasia (FMD) is a significant cause of one (1.2%) PiSZ), suggesting that 1-AT deficiency is renal artery stenosis, especially in young females. A not a common aetiological factor in renal arterial FMD. ␣ ␣ rare association between FMD and 1-antitrypsin ( 1- However, despite FMD being three times less common ␣ AT) deficiency has been reported. We compared the 1- in males than females, and carotid artery dissection AT phenotype distribution in 83 patients with renal being a rare occurrence, a male with PiMS deficiency arterial FMD with those published for Australian popu- phenotype presented with internal carotid artery dissec- ␣ lations. 1-AT phenotyping was performed by isoelectric tion and had bilateral renal artery FMD. Further, a patient focusing between pH 4.2 and pH 4.9 on polyacrylamide with PiSZ deficiency phenotype was one of two sisters gels with PiM1M2, PiFM (non-deficiency alleles), PiMS with FMD and was more severely affected than her PiMM and PiMZ (deficiency alleles) markers. Following pheno- normal phenotype sibling. These two patients from the ␣ typing, 1-AT genotyping was performed in 10 patients present series together with nine culled from the litera- ␣ to confirm the presence of S and/or Z alleles. The ture with 1-AT deficiency phenotype and FMD suggest ␣ phenotype distribution and allele frequencies were simi- that the chance combination of 1-AT deficiency and lar to those reported for normal subjects from two Aus- FMD may predispose to severe manifestations of FMD. tralian populations (72 (86.7%) PiMM phenotype, one Journal of Human Hypertension (2000) 14, 91–94 (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and ␣ Keywords: fibromuscular dysplasia; 1-antitrypsin deficiency; renovascular hypertension; renal artery; internal carotid artery; aetiology ␣ Introduction While an association between FMD and 1-AT deficiency has been reported,3–9 we are aware of Fibromuscular dysplasia (FMD) is a non-atheroscler- only nine patients in all. Other rare associations otic, non-inflammatory vascular disease1 most com- ␣ between 1-AT deficiency and other cardiovascular monly affecting the renal, internal carotid and exter- pathology such as intracranial aneurysms,10,11 cer- nal iliac arteries. FMD is the most common cause ebral artery dissection,8,10 mesenteric artery aneur- of renovascular hypertension in patients presenting ysm rupture,12 and iliac artery dissection13 have also under 40 years of age, and affects women three times 1 been reported. more frequently than men. Although rare, arterial In the current study we tested the hypothesis that dissection is a complication of FMD, and is recog- patients with renal arterial FMD have a higher nised as a cause of stroke in the young.1 ␣ prevalence of 1-AT deficiency than the general The most abundant proteinase inhibitor in human ␣ ␣ ␣ community. We determined 1-AT phenotypes in 83 plasma is 1-antitrypsin ( 1-AT) and is thought to be patients with renal arterial FMD, and compared important in protection against proteases, parti- 2 these to published phenotype distributions in Aus- cularly neutrophil elastase. The highly polymor- 14,15 ␣ tralian populations. phic 1-AT gene identified at C14q32 has more than 70 allelic variants, most of which do not result in ␣ 2 Materials and methods decreased plasma 1-AT levels. The alleles most ␣ commonly associated with 1-AT deficiency are S One hundred and seven patients referred to a hyper- 2 ␣ and Z. Homozygotes for the Z allele have 1-AT lev- tension unit between 1970 and 1997 were diagnosed els which are only 12–18% of normal, and are at with FMD of the renal arteries. Twenty-four patients increased risk of lung and liver disease.2 The PiMZ were excluded from the present study, comprising ␣ and PiMS phenotypes have mean 1-AT levels eight who were deceased, 11 who were lost to fol- approximately 65% and 85% of normal, respect- low-up, and five from whom an appropriate blood ively.2 sample could not readily be obtained. Causes of death in the eight deceased patients were carcinoma (four patients), alcohol-related liver disease (one Correspondence: Professor Richard D Gordon, University Depart- ment of Medicine, Greenslopes Private Hospital, Newdegate patient), postoperative haemorrhage (one patient), Street, Brisbane Q 4120, Australia myocardial infarction (one patient) and unknown Received 7 June 1999; revised and accepted 1 September 1999 (one patient). Alpha-1-antitrypsin deficiency and FMD A Bofinger et al 92 The remaining 83 patients were interviewed by (PiMS, PiMZ or PiSZ). Allele frequencies for M, F, one of the authors (AB). Duration of hypertension S and Z were 0.927, 0.006, 0.048 and 0.018 respect- was determined as the number of years between the ively. These are similar to those reported for Aus- first diagnosis of sustained hypertension and the tralian normals14,15 and also for several different diagnosis of FMD. Caucasian populations.2,17,18 The diagnosis of FMD was confirmed by angio- Comparison of the 10 deficiency phenotype graphic (80 patients) and/or pathologic (21 patients) patients with the 73 non-deficiency phenotype examination. All angiograms were reviewed by three patients revealed no significant differences in gen- of the authors (AB, CH, ND). Each FMD-affected der distribution, age at diagnosis of FMD, duration renal artery was classified as unifocal (focal or of hypertension, type of FMD lesion, number with tubular) or multifocal. A focal lesion was defined as bilateral FMD, nor number with unilateral renal a solitary stenosis of less than 1 cm in length, and atrophy. a tubular lesion as a smooth, concentric stenosis of However, two patients with deficiency pheno- greater than 1 cm in length. A multifocal lesion was types are of interest. A 50-year-old male with PiMS defined as two or more adjacent stenoses deficiency phenotype suffered a spontaneous dissec- (significantly more in the majority) giving the tion of the right internal carotid artery and was characteristic ‘beaded’ appearance. Lesions were found to have bilateral renal arterial FMD. The sin- classified as unilateral (right or left) or bilateral. gle patient with PiSZ phenotype in this series was ‘Unilateral renal atrophy’ was defined as a differ- one of two sisters with FMD, and presented aged 44 ence in bipolar length of greater than 2 cm between with bilateral renal artery and iliac artery multifocal the two kidneys on IVP or renal angiography. FMD, severe right renal artery stenosis and unilat- ␣ 1-AT phenotyping was performed by isoelectric eral renal atrophy. She had no clinical evidence of focusing between pH 4.2 and pH 4.9 on polyacryla- lung or liver pathology. Her sister with FMD and mide gels using PiM1M2, PiMS, PiMZ and PiFM PiMM phenotype presented at age 57 with bilateral ␣ markers. Following phenotyping, 1-AT genotyping mild renal artery FMD, no renal atrophy and iliac was performed in 10 patients, using the method of artery multifocal FMD. Anderson et al16 to confirm the presence of S and/or Z alleles. Discussion Statistical analysis was performed using Statistica software (Release 5.0, StatSoft, Inc. Tulsa, USA). In a retrospective review of 6696 autopsies perfor- Parametric data were expressed as mean (± standard med at the Mayo Clinic,3 25 patients had FMD, six ␣ deviation), and non-parametric as median (range). had 1-AT deficiency and only two (with PiZZ The t-test for independent samples was used for phenotype) had both. In one of these, the FMD affec- parametric data, the Mann–Whitney U test for non- ted the renal arteries, and, in the other, the iliac ␣ parametric data, the Fisher exact test for differences arteries. Both patients with FMD and 1-AT between proportions, and the Chi square test for dif- deficiency died of disseminated fungal infection ferences between observed and expected phenotype with mycotic aneurysms during post-transplant frequencies. A two-sided probability value of less immunosuppressive therapy. than 0.05 was considered statistically significant. A search of the literature revealed only seven ␣ additional patients with FMD and 1-AT deficiency.4–9 Only one of these was said to have Results 9 ␣ renal arterial FMD. A 15-year-old girl with 1-AT Sixty patients (54 female) had multifocal disease deficiency (PiZZ phenotype) died of a ruptured and 23 (17 female) had unifocal disease. Seventy- splenic artery aneurysm associated with medial fib- two (86.7%) of the patients were PiMM phenotype, roplasia following orthotopic liver transplantation.4 ␣ one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) A 16-year-old girl with mild 1-AT deficiency (PiMP PiMZ and one (1.2%) PiSZ (Table 1). That is, 10 phenotype) had a giant intracranial aneurysm of the (12%) of the patients had deficiency phenotypes middle cerebral artery associated with intimal 5 ␣ FMD. An 11-year-old boy with 1-AT deficiency ␣ (PiSZ phenotype) had a left middle cerebral artery Table 1 Observed and expected 1-AT phenotype distribution in 83 FMD patients occlusion and a ‘string-of-beads’ appearance in the supraclinoid portion of the left internal carotid 6 ␣ FMD patients Expected artery. Two females with 1-AT deficiency (both distributiona PiMZ phenotype) had bilateral internal carotid sten- 7 ␣ Multifocal Unifocal Total osis caused by FMD. A 59-year-old female with 1- AT deficiency (phenotype PiMS) had a dissecting Phenotype aneurysm of the right vertebral artery, a saccular MM 51 21 72 73 aneurysm of the posterior communicating artery, FM 1 0 1 0 8 b and FMD of the left vertebral artery.
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