synthesized in the liver and is regulated by a gene located Genetic hemochromatosis and a 1 -antitrypsin (AAT) on chromosome 14 for which several alleles have been dedeficiency are frequent in white populations. Conflictscribed. The most common allele, PiM, is associated with an ing data on the association of the two conditions and AAT concentration of 1.5 to 3.5 g/L, whereas some other alon the severity of the disease in those in whom these leles are characterized by a defect in AAT secretion and sedisorders coexist have emerged from analyses of small questration of the protein in the hepatocytes. 7 An increased numbers of patients. To determine if the frequency of risk for cirrhosis and hepatocellular carcinoma (HCC) has AAT deficiency is increased in genetic hemochromatobeen reported in subjects homozygous for the rare Z allele, 8-12 sis, we characterized this protein by isoelectric focusing whereas results are conflicting in subjects heterozygous for and DNA analysis in 115 Italian patients with the disease the Z allele and in subjects with other phenotypes. and 290 controls. The frequency of AAT deficiency in Both GH and AAT deficiency are genetically determined patients with genetic hemochromatosis was similar to autosomal recessive disorders common in white populations; that in controls (10% and 9%, respectively). The prevathe estimated prevalence of GH is 1 in 400, and that of AAT lence of cirrhosis in patients with genetic hemochromadeficiency is 1 in 1,600. 13 Thus, the two conditions could coextosis with MM phenotype was 53%, compared with 58% ist even though the gene for GH, still undetected, is located in those with non-MM phenotype; that of hepatocellular on chromosome 6 14 and that for AAT on chromosome 14 7 ; this carcinoma, occurring only in cirrhotic patients, was 22% association could account for more severe forms of GH. and 28%, respectively. In conclusion, the frequency of
In the last few years, conflicting data on the coexistence of AAT deficiency was not increased in our large series of GH and AAT deficit have been reported in small groups of Italian patients with genetic hemochromatosis. Patients patients. Eriksson et al. 15 did not find any association bein whom the two defects coexisted did not appear to tween the two conditions in 27 patients with GH, Rabinovitz have a more severe disease, but the limited number of et al. 16 observed a significant association in a selected group subjects with non-MM phenotype does not allow a conof 15 patients with GH who were candidates for liver transclusive evaluation of clinical differences between them plant, and Kaserbacher et al. 17 did not report an increased and patients with genetic hemochromatosis with MM frequency of AAT deficiency in 25 patients with GH. The phenotype. (HEPATOLOGY 1996;24:1161-1164.) purpose of this study was to define the prevalence of AAT deficiency, studied by serum and DNA analysis, in a large Genetic hemochromatosis (GH) is characterized by a progroup of Italian patients with GH and to investigate whether gressive accumulation of iron in the body, leading to severe patients with GH and AAT deficiency differ clinically. damage to different tissues. 1 Cirrhosis is the main consequence of severe iron overload in patients with GH and mark-
PATIENTS AND METHODS
edly affects their survival. 2 Despite an age-related occurrence Patients. We studied 115 of 160 unrelated consecutive patients of cirrhosis, which in turn depends on the degree of iron with GH who came to our hospital between 1985 and 1995. Because overload, 3 heterogeneity in the severity of the liver disease of technical reasons and storage problems, blood samples (which had is found even in patients of the same age. In some cases, this been drawn at the time of the ambulatory visit and stored for bio- variation can be explained by concomitant alcohol abuse or chemical tests) were available for AAT analysis for only 115 patients. infection with hepatitis C virus (HCV) or hepatitis B virus There was no difference between the subjects who were included and those who were not part of the present study in terms of sex, age, (HBV), which are synergistic with iron overload in causing and severity of disease. The diagnosis of GH in the 115 patients of liver damage. 3,4 Heterogeneity in the phenotypic presentation the present study (93 male, 22 female; aged 17-72 years, mean 48 { of the disease has also been hypothesized. 5,6 a 1 -Antitrypsin 10.5 years) was made on the basis of increased serum ferritin (350-(AAT), the principal protease inhibitor in human serum, is 8,400 ng/mL), elevated transferrin saturation (45%-98%), and the amount of iron removed by therapeutic phlebotomy to reach depletion (3-40 g), 18 in the absence of any known cause of secondary iron overload. The diagnosis was confirmed by liver biopsy in 106 pa-Abbreviations: GH, genetic hemochromatosis; HCV, hepatitis C virus; HBV, hepatitis tients. Three patients refused liver biopsy, and in 6 others biopsy B virus; AAT, a1-antitrypsin; HCC, hepatocellular carcinoma; IEF, isoelectric focusing; Ig, was contraindicated because of the risk of bleeding. Iron was depleted immunoglobulin; ELISA, enzyme-linked immunosorbent assay; RT-PCR, reverse-transcripin all 9 patients by removing ú5 g by therapeutic phlebotomy. Sixtytion polymerase chain reaction.