Abdul-Nasser Elzouki

Strong link between the alpha1-antitrypsin PiZ allele and Wegener's granulomatosis

Abstract. Objectives. To ascertain whether a relationship exists between the PiZ alpha1‐antitrypsin (α1AT) variant and antineutrophil cytoplasm antibodies (ANCA)‐positive vasculitis in a large group of Swedish patients, and whether analysis for the presence of the PiZ variant might be useful for diagnostic or prognostic purposes.

Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?

Objectives: To assess homozygous α1-antitrypsin deficiency (PiZZ) as a risk factor for cirrhosis, hepatocellular carcinoma (HCC) and gallstone disease, and to analyse the respective interrelationships and those suggested to exist between PiZZ, α1-antitrypsin and chronic hepatitis B and C. Design/methods: This study was based on 31 autopsied adults with severe α1-antitrypsin deficiency diagnosed during the period 1963-94, in the city of Malmö, Sweden. For each autopsied PiZZ individual, four age- and sex-matched controls were selected from the same autopsy register. The autopsy rate during the study period was 57.2% of all deaths in the city and 85% of deaths at the hospital. Relative risks were estimated in terms of Mantel-Haenszel odds ratios (ORmh). Results: In the PiZZ group, we found 13 cases of cirrhosis (ORmh=8.3; 95% Cl, 3.8–18.3; P<0.0001), 5 cases of HCC (ORmh=5.0; 95% Cl, 1.6–15.8; P=0.008), and 8 cases of gallstone disease (ORmh=1 0; 95% Cl, 0.4–2.3; P=0.924), compared with 7, 4 and 29 cases, respectively, in the control group. Stratification of the data by age and sex showed the difference in relative risk of cirrhosis between the PiZZ and control groups to be significant in both sexes, but that of HCC to be significant only in the male subgroup. There was no correlation between PiZZ state and gallstone disease in either sex. All PiZZ patients with cirrhosis and HCC had had negative tests for antihepatitis B core antigen and/or hepatitis B surface antigen. Of the homozygotes with cirrhosis or HCC for whom frozen sera were available (54% (7/13) and 60% (3/5), respectively), none had antihepatitis C antibodies, as tested both with ELISA-2 and RIBA-3. The prevalence of cirrhosis was higher in the PiZZ group than in controls for all ages above 50 years (P<0.05). The occurrence of gallstone disease increased steadily with age in the two populations. Conclusions: Although males and females with severe α1-antitrypsin deficiency are not at significantly greater risk of gallstone disease, they are at greater risk of cirrhosis and HCC, the risk of HCC being more manifest in males. The risk of cirrhosis or HCC was unrelated to the presence of hepatitis B or C infection.

Serine protease inhibitors in patients with chronic viral hepatitis

BACKGROUND/AIMS This study aimed to determine whether deficiency of the major serine protease inhibitors (alpha1-antitrypsin (AAT) or alpha1-antichymotrypsin (ACT)) is associated with increased risk for chronic hepatitis B or C virus (HBV or HCV) infection. METHODS We studied 709 adults with chronic liver disease who had undergone liver biopsy during the 14-year period 1978-92. Anti-HCV testing was carried out with second-generation ELISA and immunoblot assays (RIBA 2). HBV markers were tested with commercially available radioimmunoassays. ACT and AAT concentrations in plasma were measured with electroimmunoassay and immune nephelometry. Plasma samples were screened for the AAT PiZ deficiency with ELISA technique and phenotyped by isoelectric focusing. The 229Pro-->Ala mutation for ACT deficiency was identified by PCR techniques. RESULTS Of the 709 patients, 132 (18.6%) were positive for anti-HCV according to RIBA 2. PiZ AAT deficiency was found in 44 (6.2%) of patients (one PiZZ, 38 PiMZ, and PiSZ), while subnormal ACT levels were found in 33 (4.6%) patients, frequencies that were higher than expected in the general population (p=0.0375 and p<0.0001, respectively). Of the PiZ-carriers, 8/44 (18%) were found to be anti-HCV positive according to RIBA 2, as compared to 123/662 (19%) non-PiZ-carriers (p>0.05). One of these patients had cirrhosis, four chronic active hepatitis, and three chronic persistent hepatitis. In contrast, 17/33 (51.5%) of the patients with subnormal ACT were anti-HCV positive (OR=5.2, CI=2.6-10.6; p<0.0001). No relationship was found between HBV infection and AAT deficiency or subnormal ACT levels. Only one patient with subnormal ACT levels was heterozygous for the 229Pro-->Ala mutation of ACT deficiency. There was no significant difference in the histological findings when the patients with subnormal ACT levels or PiZ allele were subgrouped according to HCV status. CONCLUSIONS There is no overrepresentation of chronic HBV or HCV in heterozygous AAT deficiency, although an association with more severe liver disease in such patients cannot be excluded. In contrast, low plasma levels of ACT that may be acquired or hereditary, due to mutations other than 229Pro-->Ala, are frequent in HCV infection.

Severe α1-antitrypsin deficiency (PiZ homozygosity) with membranoproliferative glomerulonephritis and nephrotic syndrome, reversible after orthotopic liver transplantation

Abstract Background/Aims: Nephropathy associated with α 1 -antitrypsin deficiency is assumed to be an unusual entity. We describe the case of a 23-year-old woman with severe α 1 -antitrypsin (PiZ homozygosity) deficiency who developed hepatic cirrhosis in childhood, and glomerulonephritis and nephrotic syndrome in adult life. Methods/Results: A renal biopsy was consistent with membranosproliferative glomerulophritis. An immunofluorescence study revealed the presence of α 1 -anti-trypsin (PiZ) in the subendothelial region of the glomerular basement membrane. The renal disease was reversible after orthotopic liver transplantation. Conclusions: The presence of abnormal PiZ protein in the subendothelial region of the glomerular basement membrane may suggest a possible role for this protein in the pathogenesis of glomerulonephritis. The case should add impetus to the search for α 1 -antitrypsin deficiency in any patient presenting with combined liver and renal disease, in the absence of evidence of hepato-renal syndrome, and illustrates that liver transplantation alone may reverse the neophropathy associated with α 1 -antitrypsin deficiency.

Granulomatous hepatitis induced by aspirin-kodein analgesics

Salicylate‐kodein is a widely used analgesic agent, particularly in outpatient practice. Salicylates have been incriminated in hepatic injury while kodein may induce biliary spasm. We report here a case of granulomatous hepatitis attributed to prolonged intake of this combination, which has never been reported previously to our knowledge.