A lpha 1-antitrypsin (AAT) deficiency is an autosomal. Factors Associated With Advanced Liver Disease in Adults With Alpha 1 -Antitrypsin Deficiency

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Factors Associated With Advanced Liver Disease in Adults With Alpha 1 -Antitrypsin Deficiency CHRISTOPHER L. BOWLUS,* IRA WILLNER, MARK A. ZERN,* ADRIAN REUBEN, PHILIP CHEN,* BRIAN HOLLADAY, LIANQI XIE, ROBERT F. WOOLSON, and CHARLIE STRANGE *Division of Gastroenterology, University of California at Davis, Sacramento, California; Division of Gastroenterology, Department of Biostatistics, and Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina Background & Aims: Alpha 1 -antitrypsin deficiency (AAT) is an autosomal recessive disease that affects 1 in 2500 persons and might lead to cirrhosis. Our study aim was to characterize the liver disease in AAT and identify factors associated with advanced liver disease. Methods: A cohort of the Alpha-1 Foundation Registry who reported liver disease was surveyed with a liver disease questionnaire to obtain information related to liver disease, liver transplantation, and AAT phenotype. Results: One hundred sixty-five of the 2175 participants in the registry reported a history of jaundice or liver disease, and 139 (84.2%) completed the questionnaire. Of these, 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% did not know their phenotype. Analysis of 104 participants with a known age of diagnosis included 30 participants diagnosed with liver disease before 18 years, of whom 15 had advanced liver disease defined as liver transplantation or listed for liver transplantation. No differences in age, age at diagnosis, gender, race, phenotype, or infant jaundice were identified. Seventy-four participants were diagnosed after age 18 years, of whom 25 had advanced liver disease. In this group, advanced liver disease was associated with male gender (P.006) and a greater mean body mass index (P.01), but not with race, Pi phenotype, infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequently reported in the nontransplant group (34.7% vs 8.0%, P.01), and the mean daily alcohol use was significantly greater in this group (P.04). Conclusions: Our results suggest that male gender and obesity but not alcohol or viral hepatitis predispose to advanced liver disease in adults with AAT. A lpha 1-antitrypsin (AAT) deficiency is an autosomal recessive disorder that affects 1 in 2500 persons worldwide and can result in both lung and liver injury. 1 Individuals with the PiZZ phenotype possess less than 10% of normal serum levels of AAT and are at risk of hepatitis as neonates and cirrhosis as adults. Conflicting results have been reported on whether PiMZ individuals are at an increased risk of developing liver disease Neonatal hepatitis with cholestatic jaundice occurs in approximately 10% of infants with AAT deficiency, but it generally resolves without liver transplantation However, AAT deficiency still remains the most common metabolic liver disease requiring liver transplantation in children. In adults it is an uncommon cause of liver cirrhosis, but its true prevalence within the AATdeficient population has not been established. Prevalence rates ranging from have been reported Since 1998, the Alpha-1 Foundation Registry has enrolled persons with AAT deficiency or the carrier state to facilitate studies that otherwise would be difficult to accomplish because of the low prevalence of this disorder. 25 This database provides a unique opportunity to study the liver disease associated with AAT deficiency. To determine the prevalence of liver disease in this population and the risk factors associated with advanced liver disease particularly in adults, we performed a liver disease focused survey of the Alpha-1 Foundation Registry. Methods Study Design One hundred sixty-five participants in the Alpha-1 Foundation Registry who reported jaundice or liver disease were mailed questionnaires that queried for demographic data, history of jaundice, hepatitis virus exposure, alcohol use, diabetes, high cholesterol, liver biopsy, and final diagnosis. Parents completed questionnaires for minor children. Telephone interviews were performed to clarify responses and capture data from some of the questionnaire nonresponders. The Registry requires signed consent, and all data obtained for this study were participant reported. Approval of the study was obtained by the Institutional Review Board at all sites involved. Abbreviations used in this paper: AAT, alpha 1 -antitrypsin deficiency; BMI, body mass index; CAGE, cut down, annoyed by criticism, guilty about drinking, eye-opener drinks by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 April 2005 OBESITY, LIVER DISEASE, AND AAT DEFICIENCY 391 Responses to questions were entered by research coordinators trained in AAT deficiency and liver disease. A viral hepatitis diagnosis required previous physician-documented serologies. Alcohol use was quantified by a detailed consumption history of beer, wine, and liquor that was combined on the basis of alcohol content, size of drink, frequency of use, and years of use into a lifetime consumption of alcohol in grams. Mean daily alcohol consumption was calculated on the basis of the reported years of use. A cut down, annoyed by criticism, guilty about drinking, eye-opener drinks test (CAGE) questionnaire was recorded to identify alcohol dependency. 26 Lifetime intake that exceeded the equivalent of 80 g alcohol per day for more than 10 years or a positive response to at least 2 CAGE questions in the presence of significant alcohol intake was used to define a risk for alcohol-induced liver disease. Significant alcohol intake with 2 CAGE questions positive was defined by 100,000 lifetime g of alcohol or refusal to divulge the amount of intake. Body mass index (BMI) was calculated from current height and weight as well as weight at age 30 years. A diabetes mellitus diagnosis required a physician s diagnosis but did not require medication. Hypercholesterolemia was participant reported. Statistical Analysis Descriptive and comparative statistics were performed by using Prism 4.0 (Graphpad, San Diego, CA). Two-tailed t test and Mann-Whitney test were used to compare continuous variables, and the Fisher exact test was used to compare categorical data. A P value less than.05 was considered significant. Results Study Population At the time of study initiation, the Alpha-1 Foundation Registry was composed of 2175 participants, of whom 165 (7.6%) had reported symptoms of jaundice or liver disease. One hundred thirty-nine (84.2%) of the 165 registrants reporting a history of liver disease or jaundice in the Alpha-1 Foundation Registry agreed to participate in the study (Table 1). The mean age was years with a range from 1 75 years. The mean age at diagnosis of liver disease was years (range, 0 68 years), which was more than 10 years younger than the mean age at the time of the survey. As expected for an autosomal recessive disorder affecting primarily individuals of Northern European descent, participants were equally distributed between genders and predominantly reported their race as white (85.4%). The majority of participants reported their phenotype as PiZZ (71.3%). PiMZ was reported by 18.0% of participants, and only 5.7% did not know their phenotype. Nearly half of the participants reported neonatal jaundice. Forty-one participants (29.5%) reported being liver Table 1. Registrant Characteristics Total registry (139) PiZZ (99) Pi, % (n) ZZ 71.2 (99) MZ 18.0 (25) SZ 3.6 (5) M, M Malton 0.7 (1) MS 0.7 (1) Don t know 5.7 (8) Age distribution, % (n) 18 y 19.4 (27) 23.2 (23) 18 y 80.6 (112) 76.8 (76) Ethnicity, % (n) Asian 0.7 (1) 1.0 (1) Native American 7.9 (11) 10.1 (10) White or non-hispanic white 84.2 (117) 79.8 (79) Other or refused 7.2 (10) 9.1 (9) Male/female (% male) 70/69 (50.4) 54/45 (54.4) Viral hepatitis, % (n) 23.0 (32) 17.2 (17) Transplanted or listed for transplant, % (n) 29.5 (41) 30.3 (30) Alcohol risk, % (n) a 14.3 (16) 14.1 (10) BMI (kg/m 2 ) a Diabetes, % (n) a 14.3 (16) 9.9 (7) High cholesterol, % (n) a 17.0 (19) 15.5 (11) a Participants with liver disease diagnosed after age 18 years. transplant recipients or on a waiting list for liver transplant. Because of the known bimodal distribution of liver disease in AAT deficiency, we examined the distribution of age, age at diagnosis, and age at transplantation by AAT phenotype. For each of these variables, a bimodal distribution was observed (Figure 1). PiZZ tended to be reported more frequently in those diagnosed before age 18 years compared to those diagnosed after age 18 years (83.3% and 66.2%, P.10), and infant jaundice was significantly more frequent in those diagnosed before age 18 years compared to those diagnosed after age 18 years (86.7% and 27.0%, P.0001). Analysis of Risk Factors for Advanced Liver Disease To investigate variables associated with advanced liver disease defined as liver transplantation or listed for liver transplantation, we separated participants on the basis of an age of diagnosis less than or greater than 18 years. Thirty-five participants did not report an age of diagnosis and were excluded from further analysis. Further analysis was carried out in each age group, comparing those with advanced liver disease to those without advanced liver disease (Tables 2 and 3). Thirty participants reported that they were diagnosed before the age of 18 years, 15 of whom reported a history

3 392 BOWLUS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 Figure 1. Distributions of current age (A), age at diagnosis (B), and age at liver transplantation (C) by alpha 1 -antitrypsin phenotype in respondents reporting a history of liver disease or jaundice. of liver transplantation or being listed for liver transplantation. Those without advanced liver disease and those with advanced liver disease did not differ significantly in current age ( and years, respectively; P.06), age of diagnosis ( and years, respectively; P 1.0), or frequency of PiZZ (73.3% and 86.7%, respectively; P 1.0). Although there was a predominance of female subjects in the group diagnosed before age 18 years without advanced liver disease, no significant difference in the distribution of genders between the groups was observed (73.3% and 53.3%, respectively; P.45). A large majority in both the nonadvanced liver disease and the advanced liver disease groups reported their race as white (80.0% and 86.7%, respectively; P.8), their phenotype as PiZZ, and a history of infant jaundice (86.7% and 86.7%, respectively; P 1.0). Of the 74 participants reporting an age of diagnosis older than 18 years, 25 were liver transplant recipients or listed for liver transplantation. Of those without and with advanced liver disease, the current age ( and years, respectively; P.9), age of diagnosis ( and years, respectively; P.6), and frequency of PiZZ (67.3% and 64.0%; P.8) did not differ significantly. However, unlike the group diagnosed before the age of 18 years, those with advanced liver disease diagnosed after the age of 18 years were predominantly male (80.0%), which was significantly different compared to the slight predominance of female subjects (55.1%) in those diagnosed after 18 years without advanced liver disease (P.006). To identify co-factors that might contribute to the progression of chronic liver disease in adults with AAT deficiency, the survey included questions related to potential modifiers of liver disease including alcohol use, history of viral hepatitis, and risk factors for nonalcoholic fatty liver disease. Those with advanced liver disease did not have a significantly greater mean lifetime alcohol use or greater frequency of alcohol abuse ( kg and 14.3%, respectively) than those without advanced Table 2. Comparison of Nontransplanted and Transplanted Respondents Diagnosed Before 18 Years of Age Characteristic Nontransplant (n 15) Transplant (n 15) P value Age (y) Age at time of liver diagnosis (y) Gender, n (%).45 Female 11 (73.3) 8 (53.3) Male 4 (26.7) 7 (46.7) Race, n (%).8 White 12 (80.0) 13 (86.7) Non-white 3 (20.0) 2 (13.3) Pi,n(%) 1.0 ZZ 12 (80.0) 13 (86.7) Other 3 (20.0) 2 (13.3) Infant jaundice, n (%) 1.0 Yes 13 (86.7) 13 (86.7) No 2 (13.3) 2 (13.3) Liver biopsy, n (%).7 Yes 7 (46.7) 9 (60.0) No 8 (53.3) 6 (40.0)

4 April 2005 OBESITY, LIVER DISEASE, AND AAT DEFICIENCY 393 Table 3. Comparison of Nontransplanted and Transplanted Respondents Diagnosed After 18 Years of Age Characteristic Nontransplant (n 49) Transplant (n 25) P value Age (y) Age at time of liver diagnosis (y) Gender, n (%).006 Female 27 (55.1) 5 (20.0) Male 22 (44.9) 20 (80.0) Race, n (%).2 White 39 (79.6) 23 (92.0) Non-white 10 (20.4) 2 (8.0) Pi,n(%).8 ZZ 33 (67.3) 16 (64.0) Other 16 (32.7) 9 (36.0) Infant jaundice, n (%).4 Yes 12 (24.5) 8 (32.0) No 20 (40.8) 12 (48.0) Don t know 17 (34.7) 5 (20.0) Liver biopsy, n (%).0006 Yes 32 (66.7) 25 (100.0) No 16 (33.3) 0 (0.0) Diabetes, n (%).1 Yes 6 (12.2) 7 (28.0) No 42 (87.5) 18 (72.0) Hypercholesterolemia, n (%).5 Yes 7 (14.3) 5 (20.0) No 41 (85.4) 20 (80.0) BMI (kg/m 2 ) BMI at 30 y Current BMI Current BMI 30,n(%) 14 (28.6) 13 (52.0).07 Other causes of liver disease Viral hepatitis, n (%) 17 (34.7) 2 (8.0).01 Mean alcohol use (lifetime g alcohol) 35,510 58,501 32,587 65,021.9 Mean daily alcohol (g/d) Alcohol abuse, n (%) 7 (14.3) 3 (12.0) 1.0 Hepatitis or alcohol abuse, n (%) 19 (38.8) 4 (16.0).06 liver disease ( kg and 12.0%, respectively; P.9 and 1.0). In fact, the mean daily alcohol use in the advanced liver disease group was approximately half the use in the group without advanced liver disease ( vs g/d; P.04). In addition, the percentage reporting a history of viral hepatitis was significantly greater in those without advanced liver disease compared to those with advanced liver disease (34.7% vs 8.0%; P.01). Metabolic factors contributing to the progression of liver disease were also investigated. The percentage reporting a history of hypercholesterolemia or diabetes did not differ between the groups. However, in those with advanced liver disease, mean BMI was significantly greater ( vs ; P.01), and although not statistically significant, the percentage with a BMI greater than 30 kg/m 2 tended to be greater (52.0% vs 28.6%; P.07). To correct for the potential increase in body mass after liver transplantation, we also recorded the participants weight at 30 years of age to calculate a BMI at age 30 years. No participants diagnosed after the age of 18 years underwent transplantation before the age of 30 years. Even with this correction, the mean BMI at 30 years in those with advanced liver disease was significantly greater ( vs ; P.009). In addition, separate analysis of those reporting a PiZZ phenotype showed that the mean BMI at 30 years was significantly greater in the transplant group ( ) versus the nontransplant group ( ; P.05). In addition to the analysis discussed above, we analyzed subjects grouped by age of presentation of liver disease rather than age of diagnosis. In this analysis, a total of 139 subjects were included. We found that all univariate comparisons in both the adult and pediatric groups were consistent except for age and liver biopsy in the pediatric group. In this analysis, the mean age of the pediatric group with advanced liver disease ( years) was significantly less than in the group without advanced liver disease ( years; P.01). In addition, 72.7% of the pediatric group with advanced liver

5 394 BOWLUS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 disease reported having a liver biopsy, compared to 30.8% without advanced liver disease (P.03). Discussion AAT deficiency is a relatively rare cause of advanced liver disease in children and adults. Thus, the prevalence of liver disease and its natural history in AAT-deficient individuals have been difficult to assess. In addition, factors potentially contributing to the progression of liver disease in AAT deficiency have not been well studied. This report is the largest series of patients with liver disease associated with AAT deficiency and has identified obesity as a potential risk factor in adults with AAT deficiency. The prevalence of liver disease and advanced liver disease in our study population of 7.6% (165/2175) and 1.8% (40/2175), respectively, are lower than those reported in most other studies. These low prevalences are likely the result of enrollment bias because the current Registry followed the National Heart Lung and Blood Institute Registry. The National Heart Lung and Blood Institute Registry of Individuals Severely Deficient in Alpha-1 Antitrypsin studied progression of lung disease as the primary outcome. 25 Analysis of multiple-cause mortality data found that liver disease was included as a cause of death on 21% of death certificates listing AAT deficiency. 20 Autopsy data from Sweden found cirrhosis present in 37% of AAT cases. 22 Studies of AAT cohorts in Sweden and Canada have reported lower prevalence rates of 0.12 and 0.05, respectively. 23,24 However, in neither of these studies, nor in ours, was liver biopsy performed to assess liver disease. Thus, the prevalence of cirrhosis or advanced liver disease from these reports is likely an underestimate. As expected, we found a bimodal distribution in the presentation of liver disease in AAT deficiency. The well-characterized infant hepatitis had a mean age at diagnosis of less than 1 year. Large prospective studies in Sweden and in the United States have helped to define the natural history of AAT liver disease in infants. 17 Only 10% of AAT-deficient infants develop neonatal hepatitis with jaundice, and by 18 years of age most have normal liver test results. 18,19 Our study population represents those more severely affected, with greater than 80% diagnosed before age of 18 years reporting a history of infantile jaundice and half requiring liver transplantation. One previous study reported a female predominance in infants requiring liver transplantation. 27 Our study did not identify an association between gender or any other variable with the need for pediatric liver transplantation. In our study population, adult onset of liver disease was diagnosed at a mean age of 43 years, regardless of the need for liver transplantation. This is approximately 20 years younger than the mean age of death in individuals with AAT deficiency and cirrhosis and approximately 10 years younger than the mean age of adults clinically diagnosed with AAT deficiency. 22,23 However, it is similar to the mean age of transplantation in adult PiZZ patients. 8,28 The influence of PiMZ and PiSZ on liver disease progression has been marked by controversy. However, the frequency of PiMZ and PiSZ in populations of patients with advanced liver disease from various causes including chronic hepatitis C and cryptogenic liver disease has been reported to be greater than the general population in several studies. 4,8,9,29 A reciprocal role of viral hepatitis influencing the progression of PiZZ-associated liver disease has not been documented. Autopsy data of AAT-deficient individuals with cirrhosis do not show an increase in viral hepatitis compared to age- and sex-matched control subjects. 22 Our results support the conclusion that viral hepatitis does not significantly influence the progression of cirrhosis in AAT deficiency. Alcohol has been suggested to be an important factor in the progression in liver disease associated with AAT deficiency, but this conclusion is based on a small number of cases. 24 We took detailed histories of alcohol consumption, both current and past, to determine whether alcohol use was associated with more advanced liver disease. On the contrary, we found that current alcohol consumption in patients with advanced liver disease was significantly less than those without advanced liver disease. However, lifetime alcohol use and abuse were not different. However, we cannot rule out a possible bias as a result of liver transplantation selection. As with other liver diseases, male gender has previously been associated with cirrhosis in AAT deficiency. Male predominance has ranged from 1:2 1:6 and is 1:4 in our report. 8,22,24,28 Interestingly, in our study male predominance was only identified in the group requiring liver transplantation but not in the group with liver disease without liver transplantation. This suggests that male gender might be more important in the progression of liver disease as opposed to the establishment of liver disease in AAT deficiency. The unique finding in this report is the association between obesity and liver transplantation in AAT deficiency. Obesity has also been associated with more advanced disease in chronic hepatitis C and nonalcoholic steatohepatitis We found that the mean BMI of those requiring liver transplantation was significantly

6 April 2005 OBESITY, LIVER DISEASE, AND AAT DEFICIENCY 395 greater than of those without liver transplantation. In addition, obesity defined by a BMI 30 kg/m 2 showed a strong trend toward being more frequent in the liver transplant group. However, steroid use and other factors associated with transplantation might have significantly influenced BMI. Therefore we included a question to determine the weight at age 30 years, which is before the age that any adult participant underwent transplantation. The mean BMI at age 30 years was also significantly greater in the liver transplant group, suggesting that obesity is an important risk factor for the progression of liver disease in AAT deficiency. Although most of our findings are consistent with previous smaller studies, our results must be interpreted with caution because they might have been influenced by several biases. First, the cross-sectional design measured prevalence rather than incidence. This might have reduced the prevalence of viral hepatitis or alcohol use in the advanced liver disease group if they died at a younger age. Second, patients were self-selected as reporting having had a liver transplantation or listed for liver transplantation. However, individuals with compensated cirrhosis would be missed. Also, our definition of advanced liver disease might have missed those who were too ill or had contraindications for liver transplantation. Finally, there is a possibility of recall bias, particularly with patients reporting their weight at age 30 years. Clearly, a more detailed study of this cohort and longitudinal studies of AAT are required to confirm the findings of the present study. In summary, we have surveyed the largest cohort of patients with AAT deficiency and liver disease reported in the literature. Despite the potential biases and deficiencies inherent in a study using a questionnaire to investigate a self-selected population, our findings are in agreement with previous studies. Notably, there is a bimodal distribution in the presentation of liver disease, with the peaks in prevalence occurring in infancy and in the fifth decade. In adults with AAT deficiency, male gender and obesity appear to be risk factors for advanced liver disease. Future studies involving protocol liver biopsies are needed to confirm these findings and identify other factors associated with cirrhosis in AAT deficiency. References 1. de Serres FJ. Worldwide racial and ethnic distribution of alpha1- antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 2002;122: Bell H, Schrumpf E, Fagerhol MK. Heterozygous MZ alpha-1- antitrypsin deficiency in adults with chronic liver disease. Scand J Gastroenterol 1990;25: Carlson J, Eriksson S. Chronic cryptogenic liver disease and malignant hepatoma in intermediate alpha 1-antitrypsin deficiency identified by a Pi Z-specific monoclonal antibody. Scand J Gastroenterol 1985;20: Eigenbrodt ML, McCashland TM, Dy RM, et al. Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease. Am J Gastroenterol 1997;92: Eriksson S. Liver disease and intermediate alpha 1-antitrypsin deficiency. Acta Med Scand 1981;210: Eriksson S, Moestrup T, Hagerstrand I. Liver, lung and malignant disease in heterozygous (Pi MZ) alpha1-antitrypsin deficiency. Acta Med Scand 1975;198: Fischer HP, Ortiz-Pallardo ME, Ko Y, et al. Chronic liver disease in heterozygous alpha1-antitrypsin deficiency PiZ. J Hepatol 2000;33: Graziadei IW, Joseph JJ, Wiesner RH, et al. Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology 1998;28: Hodges JR, Millward-Sadler GH, Barbatis C, et al. Heterozygous MZ alpha 1-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis. N Engl J Med 1981; 304: Hultcrantz R, Glaumann H, Lindberg G, et al. Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases. Scand J Gastroenterol 1986; 21: Lima LC, Matte U, Leistner S, et al. Molecular analysis of the Pi*Z allele in patients with liver disease. Am J Med Genet 2001;104: Morin T, Martin JP, Feldmann G, et al. Heterozygous alpha 1-antitrypsin deficiency and cirrhosis in adults, a fortuitous association. Lancet 1975;1: Propst T, Propst A, Dietze O, et al. High prevalence of viral infection in adults with homozygous and heterozygous alpha 1-antitrypsin deficiency and chronic liver disease. Ann Intern Med 1992;117: Roberts EA, Cox DW, Medline A, et al. Occurrence of alpha-1- antitrypsin deficiency in 155 patients with alcoholic liver disease. Am J Clin Pathol 1984;82: Serfaty L, Chazouilleres O, Poujol-Robert A, et al. Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study. Hepatology 1997;26: Vecchio FM, Fabiano A, Orsini G, et al. Alpha-1-antitrypsin MZ phenotype and cryptogenic chronic liver disease in adults. Digestion 1983;27: Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294: Sveger T, Eriksson S. The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology 1995;22: Wall M, Moe E, Eisenberg J, et al. Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990; 116: Browne RJ, Mannino DM, Khoury MJ. Alpha 1-antitrypsin deficiency deaths in the United States from : an analysis using multiple-cause mortality data. Chest 1996;110: Berg NO, Eriksson S. Liver disease in adults with alpha-1-antitrypsin deficiency. N Engl J Med 1972;287: Eriksson S. Alpha 1-antitrypsin deficiency and liver cirrhosis in adults: an analysis of 35 Swedish autopsied cases. Acta Med Scand 1987;221: Larsson C. Natural history and life expectancy in severe alpha1- antitrypsin deficiency, Pi Z. Acta Med Scand 1978;204: Cox DW, Smyth S. Risk for liver disease in adults with alpha 1-antitrypsin deficiency. Am J Med 1983;74: Strange C. Alpha-1 Foundation research registry: from the past to the future. J Pediatr Gastroenterol Nutr 2002;34: Buchsbaum DG, Buchanan RG, Centor RM, et al. Screening for

7 396 BOWLUS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 alcohol abuse using CAGE scores and likelihood ratios. Ann Intern Med 1991;115: Ibarguen E, Gross CR, Savik SK, et al. Liver disease in alpha-1- antitrypsin deficiency: prognostic indicators. J Pediatr 1990; 117: Vennarecci G, Gunson BK, Ismail T, et al. Transplantation for end stage liver disease related to alpha 1 antitrypsin. Transplantation 1996;61: Kishimoto Y, Yamada S, Hirayama C. An association between alpha 1-antitrypsin phenotype and chronic liver disease. Hum Genet 1990;84: Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33: Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30: Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29: Ortiz V, Berenguer M, Rayon JM, et al. Contribution of obesity to hepatitis C-related fibrosis progression. Am J Gastroenterol 2002;97: Address requests for reprints to: Christopher L. Bowlus, MD, Division of Gastroenterology, UC Davis Medical Center, 4150 V Street, PSSB 3500, Sacramento, CA clbowlus@ucdavis.edu; fax: (916)