The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Prevalence of hepatitis B and C virus infections and their related risk factors in Libya: a national seroepidemiological survey.

A high prevalence of hepatitis B (HBV) and C virus (HCV) infections has been reported among specific patient groups in Libya; a survey was thus designed to determine the extent of the problem at the national level. A multi-stage sampling design covering all administrative areas of Libya was applied, covering > 65,000 individuals of all age groups. All subjects gave a blood sample and completed a questionnaire on demographic and risk behaviour data. The prevalence of HBV surface antigen (HBsAg) and anti-HCV were 2.2% and 1.3% respectively. The prevalence of anti-HCV increased with age, rising gradually after age 30 years, in contrast to a stable prevalence of HBsAg in all age groups 10+ years. Age-adjusted risk factors for HCV infection were previous hospitalization, surgical operations, previous blood transfusions and intravenous drug use; for HBV infection only family exposure or contact with HBV case were identified.

Prevalence of hepatitis B and C virus infections and their related risk factors in Libya: a national seroepidemiological survey

A high prevalence of hepatitis B [HBV] and C virus [HCV] infections has been reported among specific patient groups in Libya; a survey was thus designed to determine the extent of the problem at the national level. A multi-stage sampling design covering all administrative areas of Libya was applied, covering > 65 000 individuals of all age groups. All subjects gave a blood sample and completed a questionnaire on demographic and risk behaviour data. The prevalence of HBV surface antigen [HBsAg] and anti-HCV were 2.2% and 1.3% respectively. The prevalence of anti-HCV increased with age, rising gradually after age 30 years, in contrast to a stable prevalence of HBsAg in all age groups 10+ years. Age-adjusted risk factors for HCV infection were previous hospitalization, surgical operations, previous blood transfusions and intravenous drug use; for HBV infection only family exposure or contact with HBV case were identified

Transverse Myelitis Associated with Anti-Ro (SSA) Autoantibodies: A Record of Two Cases.

Transverse myelitis (TM) is an inflammatory process involving a restricted area of the spinal cord. The usual dramatic presentation makes TM a medical emergency. Early detection and aggressive therapy are required in order to improve the prognosis. The association of this unique clinical phenotype and autoantibody provides circumstantial evidence that an autoimmune aetiology might be involved. We describe two cases of TM associated with anti-Ro (SSA) autoantibodies without connective tissue disease manifestations. The two patients were treated successfully with IV steroids and cyclophosphamide.

Alpha1-antitrypsin deficiency may be a risk factor for duodenal ulcer in patients with Helicobacter pylori infection.

BACKGROUND: Most individuals with Helicobacter pylori infection in Western countries have no evidence of peptic ulcer disease (PUD). We therefore assessed the PiZ deficiency variant of the major plasma protease inhibitor alpha1-antitrypsin (alpha1AT) as a risk factor for PUD in H. pylori-infected individuals. METHODS: The cohort comprised 100 patients with endoscopically or surgically proven PUD (30 patients with duodenal ulcer (DU) and 70 patients with gastric ulcer (GU)) and 162 age- and sex-matched controls with PUD-negative endoscopic findings and no history of PUD. Plasma samples were screened for alpha1AT deficiency (PiZ) with an enzyme-linked immunosorbent assay (ELISA) and phenotyped by isoelectric focusing. H. pylori infection was evaluated with an IgG ELISA technique. RESULTS: Among the 262 patients 17 (6.5%) were positive for the PiZ alpha1AT deficiency, a frequency of the same magnitude as in the Swedish general population (4.7%). Of the PiZ carriers 76% (13 of 17) had H. pylori antibodies compared with 61% (151 of 245) of the non-PiZ carriers (NS). The prevalence of DU tended to be higher in H. pylori-positive PiZ carriers than in non-PiZ carriers (15.4%, 4 of 26 versus 0 of 4). Furthermore, among patients with DU a high PiZ allele frequency (13.3%, 4 of 30) was found compared with the general population (4.7%) (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.09-8.94; P = 0.02). All DU patients carrying the PiZ allele were positive for H. pylori. In addition, four of five PiZ carriers with H. pylori infection and PUD had DU. CONCLUSIONS: The PiZ allele may be a contributing factor in the development of DU in H. pylori-positive individuals.

The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis.

Our aim was to determine the prevalence of the PiZ allele for alpha 1-antitrypsin (AAT) deficiency and some relevant antineutrophil cytoplasmic antibody (ANCA) specificities in patients with ulcerative colitis (UC), and explore a possible association between these markers. In addition, we studied the relation to disease extension and activity. Sera from 141 patients with UC (72 women) were analyzed while 50 blood donors and 54 patients with acute myocardial infarction served as controls. Serum samples were screened for PiZ with ELISA and phenotyped by isoelectric focusing. BPI-ANCA and PR3-ANCA were detected by ELISA. Results were that 8.5% (12/141) of the patients with UC were PiZ carriers, higher than expected in the general Swedish population (4.7%) (p = 0.03). There was a significant difference between PiZ-carriers and non-PiZ-carriers in the extension and severity of colitis (odds ratio = 4.1, confidence interval = 1.1, 14.9; p = 0.028, and odds ratio = 9.0, confidence interval = 1.1, 73.3; p = 0.015; respectively). BPI-ANCA and PR3-ANCA were detected in 20.5% (29/141) and 12% (17/141) (p < 0.05 compared with controls for all parameters). Occurrence of BPI-ANCA and PR3-ANCA was not related to extension or severity of colitis (p > 0.05 for both variables). We observed no association between PiZ-carrier status and occurrence of BPI-ANCA or PR3-ANCA. The increased frequency of heterozygosity for the PiZ variant of AAT deficiency among patients with UC might imply a role played by protease inhibitors for regulation of inflammation and immunologic response in UC.

The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction.

BACKGROUND/AIMS: Earlier studies have indicated an elevated risk for gallstone disease in patients with cirrhosis. This study aimed to evaluate the prevalence of gallstones in patients with chronic liver disease (CLD) with respect to sex, etiology, and severity of liver disease. METHODOLOGY: Four hundred and thirteen adults (176 women), mean age 51.2+/-14 years, with CLD, who had undergone liver biopsy during 1978-1993, and from whom sera were available, were investigated retrospectively. The results were compared with a population-based ultrasonography study of 556 healthy men and women, in their 40s and 60s. RESULTS: The prevalence of gallstones in patients with CLD did not differ from that in the control population. An increased frequency was observed in patients with CLD initially classified as cryptogenic, of whom the majority (60%) later were reclassified as chronic hepatitis C. The frequency of gallstones was also high in PiZ-heterozygotes for alpha1-antitrypsin deficiency (5/21, 24%) compared to non-PiZ-carriers (17/389, 4.8%), (p<0.001). In 67 patients with histologic evidence of cirrhosis, 30% (20/67) had gallstones (vs. 15% in the general population, p<0.01). The prevalence of gallstones increased significantly from Child's class A (16%) to C (56.2%). The difference was significant in males (18.2% vs. 62.5%, p=0.033), but not in females. Fifty percent of the patients with gallstones were symptomatic. CONCLUSIONS: Progressive liver dysfunction is a risk factor for gallstones particularly in males. HCV infection and PiZ carriership may further increase biliary lithogenesis.

Is there a relationship between abdominal aortic aneurysms and alpha1-antitrypsin deficiency (PiZ)?

OBJECTIVE: To determine if the frequency of alpha 1AT deficiency (PiZ) is increased in patients with abdominal aortic aneurysm (AAA), and, to investigate whether aneurysmal stiffness and other clinical characteristics differ in AAA patients with and without alpha 1AT deficiency. METHODS: We identified alpha 1AT-deficient individuals by a monoclonal-antibody ELISA technique, in 102 consecutive patients with AAA. Positive ELISA samples were further phenotyped by isoelectric focusing to differentiate between the heterozygosity (PiZ) and homozygosity (PiZZ) state. Aneurysmal diameter and stiffness was measured using echotracking sonography and blood pressure measurements. RESULTS: The frequency of heterozygous alpha 1AT deficiency (PiZ) in patients with AAA was similar to that in the general population (6.8% and 4.7%, respectively, p > 0.3). The frequency of popliteal and femoral aneurysm was similar in male PiZ-carriers and non-carriers with AAA, as were age at diagnosis of AAA, aneurysmal diameter, aneurysmal stiffness, and presence of factors that may be associated with AAA (i.e. smoking, hypertension, diabetes mellitus, and family history of AAA). Occurrence of ischaemic heart disease was more frequent in male non-PiZ-carriers than in male PiZ-carriers with AAA (p = 0.03). CONCLUSIONS: The frequency of alpha 1AT deficiency (PiZ) was not increased in our series of patients with AAA and patients in whom the two disorders coexisted did not appear to have different clinical characteristics except for the lower occurrence of ischaemic heart disease among the PiZ-carriers.

Alpha 1-antitrypsin deficiency and related liver disease.

Alpha1-antitrypsin (alpha1 AT) deficiency is a relatively common genetic cause of liver disease among Caucasians. It is an autosomal recessive disorder characterized by reduced serum levels of alpha1 AT, a 52-kD glycoprotein that functions as an antiprotease. The deficiency state is caused by mutations in the alpha1 AT gene on chromosome 14. Alpha1 AT shows considerable genetic variability, having more than 75 genetic variants (Pi types). The PiZ allele is the most common deficiency variant. PiZZ homozygotes have 15-20% of the normal plasma levels of alpha1 AT. The deficiency is due to lack of secretion of Z alpha1 AT from the hepatocyte, where inclusions are formed in the endoplasmic reticulum. Homozygous alpha1 AT deficiency (PiZZ) is known to predispose to emphysema and chronic liver disease. This review outlines the clinical manifestations and treatment of alpha1 AT deficiency associated liver disease, focusing on recent advances in the pathogenic mechanism of liver disease in this genetic disorder.

Alpha 1-antitrypsin deficiency.

Alpha 1-Antitrypsin deficiency (PiZ) is frequent in Caucasian populations. The predominant clinical correlates of this inborn error, i.e. chronic liver disease, emphysema, and vasculitic syndromes including their pathogenetic background are discussed in the present review.

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 alpha1-antitrypsin deficiency (PiZ homozygosity) with membranoproliferative glomerulonephritis and nephrotic syndrome, reversible after orthotopic liver transplantation.

BACKGROUND/AIMS: Nephropathy associated with alpha1-antitrypsin deficiency is assumed to be an unusual entity. We describe the case of a 23-year-old woman with severe alpha1-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 membranoproliferative glomerulonephritis. An immunofluorescence study revealed the presence of alpha1-antitrypsin (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 alpha1-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 nephropathy associated with alpha1-antitrypsin deficiency.

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 alpha 1-antitrypsin deficiency (PiZZ) as a risk factor for cirrhosis, hepatocellular carcinoma (HCC) and gallstone disease, and to analyse the respective interrelation-ships and those suggested to exist between PiZZ, alpha 1-antitrypsin and chronic hepatitis B and C. DESIGN/METHODS: This study was based on 31 autopsied adults with severe alpha 1-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% CI, 3.8-18.3; P < 0.0001), 5 cases of HCC (ORmh = 5.0; 95% CI, 1.6-15.8; P = 0.008), and 8 cases of gallstone disease (ORmh = 1.0; 95% CI, 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 anti-hepatitis 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 alpha 1-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.

Complexes between proteinase 3, alpha 1-antitrypsin and proteinase 3 anti-neutrophil cytoplasm autoantibodies: a comparison between alpha 1-antitrypsin PiZ allele carriers and non-carriers with Wegener's granulomatosis.

To test the hypothesis that anti-neutrophil cytoplasm autoantibodies (ANCAs) interfere with the functions of proteinase 3 (PR3) (the Wegener autoantigen) and alpha 1-antitrypsin (alpha 1AT), complexes of PR3/alpha 1 AT and PR3/PR3-ANCA-IgG were assayed Plasma samples were obtained from 44 patients with Wegener's granulomatosis (WG): 34 had active disease (88% ANCA positive) whereas 10 patients were in remission (20% ANCA positive). Plasma samples from 14 of the patients with active disease were also available at the time of remission. The complexes of PR3/alpha 1 AT and PR3/PR3-ANCA-IgG were detected by capture enzyme-linked immunoassays (ELISAs) alpha 1 AT deficiency was evaluated by determining PiZ alleles by ELISA. Eight (18%) of the patients were PiZ positive. The frequency of this alpha 1-antitrypsin phenotype in the Scandinavian population is 4.7% (P < 0.001). The median PR3/alpha 1AT complex level in the PiZ-positive group with active disease (n = 5) was similar to the level in the PiZ-negative group with active disease. During remission the median level for the PR3/alpha 1AT complex was significantly higher than in the acute group (P < 0.001) including both PiZ-positive and PiZ-negative patients. No difference between PiZ positivity and PiZ negativity could be found in the remission group. PR3/PR3-ANCA-IgG complexes were found in patients with acute disease as well as in patients in remission, in almost equal frequency. This complex was also present in 13/18 ANCA-negative samples from patients in remission. Finally, purified IgG fractions from WG patients were examined for their capacity to inhibit binding between PR3 and alpha 1AT. An effect on the binding between PR3 and alpha 1AT by PR3-ANCA could not be demonstrated. Thus, our results do not support the hypothesis that PR3-ANCA interferes with the binding between PR3 and alpha 1AT. However, the high prevalence of the PiZ alleles among WG patients suggests that an imbalance between proteinases and alpha 1AT may be of importance in this disease. The clinical usefulness of both the PR3/alpha 1AT and the PR3/PR3-ANCA-IgG complexes and the possible influence on ANCA detection need to be examined in prospective longitudinal studies.

Systemic necrotizing vasculitides in severe alpha1-antitrypsin deficiency.

We describe the clinical presentation and outcome in a series of eight patients with systemic necrotizing vasculitis and severe alpha1-antitrypsin (AAT) deficiency followed up at three Swedish hospitals during 1968-92. We also review six other cases reported in the literature during the same period. Diagnosis of severe AAT deficiency was based on the presence of the PiZZ phenotype, or low plasma total trypsin inhibitory capacity, or a low plasma AAT concentration (10-40% of the normal mean value) and presence of the PiSZ or PiFZ phenotype. The diagnosis of systemic vasculitis was biopsy-verified in all eight patients. Pretreatment laboratory findings, treatment protocol, and outcome were reviewed in each of the 14 patients. Of the eight patients in the Swedish series, six had systemic vasculitis of the microscopic polyangiitis form, one had Wegener's granulomatosis, and another had Henoch-Schönlein purpura. In the series as a whole (n = 14), median age at diagnosis was 48 years (range 44-84), the median number of affected organs was eight, and all 14 patients had skin involvement, and either renal or joint involvement (in most cases both); 71% (10/14) had emphysema; 57% (8/14) had hepatic abnormalities (two having cirrhosis, two fibrosis, and one multiple aneurysms in hepatic arteries); one patient who presented with acute ulcerative colitis developed manifest vasculitic syndrome three years later; and 64% (9/14) died, the major cause of death being renal failure. This syndrome, characterized by multiple organ involvement and fatal outcome, has been underdiagnosed. Physicians should be alert to the presence of the PiZ AAT deficiency gene in patients with systemic vasculitis, especially when the course is progressive or when the patient also has emphysema or cirrhosis. Awareness of those features may aid prompt recognition and enable early treatment.

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.

The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis.

We have previously demonstrated that a strong correlation exists between systemic vasculitis with proteinase 3-anti-neutrophil cytoplasm antibodies (PR3-ANCA) and heterozygosity for alpha 1-antitrypsin (alpha 1-AT) deficiency, PiZ. In the present study we characterized the PiZ-positive subgroup by laboratory findings, clinical features and outcome. The series studied consisted of 18 PiZ-positive and 81 PiZ-negative PR3-ANCA patients, comparable in sex ratio, age, C-reactive protein concentrations and renal function at diagnosis, and treatment. PiZ-positive patients had a more disseminated disease as reflected by the number of affected organs (P < 0.01). We found no group differences in relapse tendency. Overall mortality was 39% (7 of 18) in the PiZ-positive and 16% (13 of 81) in the non-PiZ group (P = 0.048). When survival analysis was restricted to 66 patients included in the study at disease onset, the group difference was significant (P = 0.016). The results suggest that the subnormal response of plasma alpha 1-AT seen in PiZ-heterozygotes enhances the risk of dissemination of the vasculitic process and the risk of a fatal outcome. We consider alpha 1-AT phenotyping to be justified in cases of PR3-ANCA-positive vasculitis. Treatments decreasing plasma alpha 1-AT (such as plasmapheresis without plasma replacement) may be deleterious.

Increased PiZ gene frequency for alpha 1 antitrypsin in patients with genetic haemochromatosis.

The putative relationship between genetic haemochromatosis and PiZ alpha 1 antitrypsin deficiency was studied using a monoclonal antibody against the PiZ variant in 67 consecutive patients with genetic haemochromatosis seen at Karolinska Hospital and Huddinge University Hospital, Stockholm over a 10 year period. Three (4.5%) of the patients with haemochromatosis were found to be PiZ homozygotes (odds ratio = 82, confidence interval = 26, 256; p < 0.0001). The prevalence of the heterozygous (PiZ) phenotype was similar to that in the general population (p = 0.937). During the ascertainment period, liver biopsy was performed in 65 (97%) of the patients; 66% (2 of 3) of the PiZ homozygotes were found to have cirrhosis compared with 10% (6/59) of the non-carriers of the PiZ variant (p = 0.039). None of the homozygous or heterozygous alpha 1 antitrypsin deficient patients had developed hepatocellular carcinoma compared with 3.4% (2 of 59) of the non-PiZ gene carriers (p = 1.0). Two of those with the homozygous phenotype had developed severe emphysema. HLA typing was performed in 18 patients, 16 (89%) of whom manifested antigens known to be linked to haemochromatosis. There were no significant differences between the PiZ gene carriers and non-carriers in mean age at onset of disease, sex distribution, or HLA type. Two of the PiZ heterozygotes had plasma alpha 1 antitrypsin concentrations below the normal range, though the group mean was lower than that of the non-PiZ carriers (p = 0.0003). The data suggest that the presence of the PiZ allele for alpha1 antitrypsin deficiency, in a double dose, is associated with genetic haemochromatosis and may contribute to the earlier onset of cirrhosis in these patients, though it does not increase the risk of hepatocellular carcinoma.