A significant association between genetic hemochromato-A1ATD, liver disease 33 (82.5%) 7 (17.5%) 0 (0%) 40 sis (GH) and a 1 -antitrypsin deficiency (A1ATD) has been A1ATD, no liver reported by Rabinovitz et al. 1 in patients with severe liver disease 32 (82.1%) 7 (17.9%) 0 (0%) 39 disease. It has been suggested that there is an additive effect Controls 159 (86.9%) 22 (12.0%) 2 (1.1%) 183 of hepatic iron storage and hepatocyte damage from the ab-Published data 5 326 (88.6%) 40 (10.9%) 2 (0.5%) 368
normally folded PiZ or PiS protein. There could also be some interaction of the mutant A1ATD gene and the hemochromatosis gene by a previously undescribed mechanism, involving a third gene, resulting in liver disease even before hematolog-There is no difference between the hemochromatosis muical evidence of iron accumulation. 1 However, Fargion et al. 2 tation frequency in those A1ATD patients with liver disease reported no relationship between these conditions identi-(17.5%) and without liver disease (17.9%). It is of interest fying GH by hematological indices and liver biopsy in pathat the frequency of heterozygotes in patients with A1ATD tients with and without cirrhosis.
(17.7%) is higher than in individuals without A1ATD. How-Ninety percent of patients from Britain with GH are homoever, this difference does not reach statistical significance (% zygous for the C282Y (845G r A) mutation in the hemochrodifference: 5.5%; 95% confidence interval: 7.2%-18.2%). Our matosis (HLA-H) gene. Homozygosity for GH is estimated control heterozygote frequency is higher than that published at up to 5 per 1,000 in Europe, 3 with a carrier frequency of for the U.K. British population and represents local popula-10% to 17%. tion variation. To investigate the possibility of an interaction between the These results show that possession of the hemochromatotwo conditions resulting in chronic liver disease, we used sis mutation is not a risk factor for liver disease in A1ATD. molecular biological techniques to study 79 A1ATD patients in the United Kingdom with the PiZZ or PiSZ mutations Acknowledgment: Supported by grant 179, The Children's confirmed by isoelectric focusing. Forty patients were reappeal, Sheffield, UK (to M.J.S.). The authors thank Dr. S. ferred in childhood because of liver disease, and were found Povey for donation of DNA from A1ATD patients and Dr. D. to have fibrosis or cirrhosis on liver biopsy. Thirty-nine indi-Curtis for her assistance with development of the molecular viduals had no evidence of liver disease into adult life, 21 biology techniques. were clinically normal, and 18 had emphysema.
We used the polymerase chain reaction (PCR) and restric-MARK J. SHARRARD, M.R.C.P. tion fragment length polymorphism to investigate these pa-MIRANDA DURKIE, B.SC. tients for the C282Y mutation. A modified PCR was devel-M. STUART TANNER, F.R.C.P. oped from the method of Feder et al., 4 using the novel Department of Paediatrics forward primer 5 GGA TAA CCT TGG CTG TAC C and University of Sheffield the published reverse primer 5 CTC AGG CAC TCC TCT Children's Hospital, Western Bank CAA CC; an annealing temperature of 60ЊC was used. The Sheffield, UK PCR product was of 165 base pairs (bp) with a mutationspecific cut site for RsaI and an internal control site. Products