Outcomes for Recipients of Liver Transplantation for Alpha-1-Antitrypsin Deficiency Related Cirrhosis

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1 LIVER TRAPLANTATION 19: , 2013 ORIGINAL ARTICLE Outcomes for Recipients of Liver Transplantation for Alpha-1-Antitrypsin Deficiency Related Cirrhosis Elizabeth J. Carey, 1 Vivek N. Iyer, 2 Darlene R. Nelson, 2 Justin H. Nguyen, 3 and Michael J. Krowka 2 1 Division of Hepatology, Mayo Clinic, Phoenix, AZ; 2 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN; and 3 Transplant Surgery, Mayo Clinic, Jacksonville, FL Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disease caused by an abnormal production of the serine protease inhibitor AAT. Liver transplantation (LT) cures cirrhosis caused by AAT deficiency and restores the normal production of AAT. There are few reports on the post-lt outcomes of patients with AAT deficiency. The aim of this study was to determine the characteristics and outcomes of patients undergoing LT for AAT deficiency at 3 large transplant centers. All patients undergoing LT at these 3 transplant centers from 1987 to 2012 for AAT deficiency (ZZ or SZ phenotype) were included. The most recent 50 patients with the MZ phenotype were also included for comparison. Data were collected retrospectively from internal databases and medical records. Seventy-three patients (50 with the ZZ phenotype and 23 with the SZ phenotype) underwent LT. The mean age was 52.8 years, and the majority of the patients (75.6%) were men. Before LT, serum AAT levels were lower for the ZZ patients versus the SZ patients (28.3 versus 58.0 mg/dl, P < 0.001). More than 40% of the SZ patients had an additional liver disease, whereas 8% in the ZZ group and 90% in the MZ group did. Before LT, there was no significant difference in pulmonary function between the ZZ and SZ groups. Seventeen patients (all with ZZ phenotype) had pulmonary function tests performed before and after LT. The forced expiratory volume in 1 second (FEV 1 ) continued to decline for the majority. The 1-, 3-, 5-, and 10-year post-lt survival rates were 86%, 83%, 80%, and 72%, respectively, for the ZZ patients and 91%, 86%, 79%, and 79%, respectively, for the SZ patients. In conclusion, survival after LT for patients with ZZ or SZ AAT deficiency is excellent. Despite the normalization of AAT levels after LT, FEV 1 continues to decline unexpectedly after LT in some ZZ and SZ patients. Liver Transpl 19: , VC 2013 AASLD. Received June 6, 2013; accepted August 27, Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disease caused by an abnormal production of the serine protease inhibitor AAT. AAT deficiency can lead to severe pulmonary and liver disease and is an accepted indication for liver transplantation (LT). Individuals with 2 copies of the M allele (MM) have a normal protein structure and function and normal serum AAT levels. The most common deficient allele is the Z allele. In the Caucasian population of the United States, the prevalence of the Z allele is 2% to 3%; 0.05% are homozygous (ZZ). 1 The S allele occurs in 2% to 4% of Caucasians but is less likely to result in clinically apparent disease. The most common abnormal phenotypes are MS, MZ, SS, SZ, and ZZ. AAT binds to and irreversibly inactivates neutrophil elastase in the lung. In addition, AAT possesses inherent anti-inflammatory properties. 2 Thus, AAT reduces lung inflammation and maintains lung integrity by balancing protease and anti-protease activity. In patients with AAT deficiency, uninhibited neutrophil elastase activity results in the destruction of alveolar elastin and eventually leads to panacinar emphysema. The pathophysiology of liver disease in patients with ZZ AAT deficiency is related to abnormal protein folding Abbreviations: AAT, alpha-1-antitrypsin; CVA, cerebrovascular accident; DLCO, diffusing capacity of the lungs for carbon monoxide; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; HCC, hepatocellular carcinoma; LT, liver transplantation;, not significant; PFT, pulmonary function test; TLC, total lung capacity; UCSF, University of California San Francisco. The authors report no grants or financial support and no conflicts of interest. Address reprint requests to Elizabeth J. Carey, M.D., Division of Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ Telephone: ; FAX: ; carey.elizabeth@mayo.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRAPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2013 American Association for the Study of Liver Diseases.

2 LIVER TRAPLANTATION, Vol. 19, No. 12, 2013 CAREY ET AL and polymerization of the ZZ protein. This results in an accumulation of insoluble aggregates in the hepatocyte endoplasmic reticulum, which leads to cell death, fibrosis, and ultimately cirrhosis. Approximately 50% of ZZ homozygotes have evidence of ongoing inflammatory activity in the liver, and 2% to 43% develop cirrhosis. 3,4 The potential pathogenicity of 1 copy of the S or Z allele remains controversial, although it may contribute to cirrhosis and the need for LT. 5 In adults, severe serum AAT deficiency (due to the ZZ or SZ phenotype) accounts for approximately 1% of patients undergoing LT. 6 Although AAT deficiency is a widely accepted indication for LT in adults, there is little information in the literature regarding the hepatic and pulmonary features of these patients before and after LT. We sought to characterize LT recipients with ZZ or SZ AAT deficiency at 3 large transplant centers in the United States. PATIENTS AND METHODS Patients Data from all patients who underwent LT at 3 Mayo Clinic transplant centers (Rochester, MN; Scottsdale, AZ; and Jacksonville, FL) from 1987 to 2012 were reviewed. Dual-organ (lung-liver) transplant recipients were excluded from the analysis. All ZZ and SZ patients were included; the most recent 50 MZ patients were also included for comparison. Because patients with the MS phenotype rarely have a serum AAT deficiency, none were included. Data were collected retrospectively from internal databases and medical records. This protocol received a priori approval from the Mayo Clinic Institutional Review Board. Diagnosis of AAT Deficiency-Related Cirrhosis At the time of the transplant evaluation, a comprehensive workup for causes of chronic liver disease was performed for all patients, and it included AAT serum levels and phenotyping (before 2008) and genotyping (beginning in 2008). The diagnosis of AAT deficiency was based on the presence of an abnormal phenotype/ genotype (SZ or ZZ) in conjunction with a low serum AAT level (normal level mg/dl at Mayo laboratories). Blood work was correlated with histological findings from pre-lt liver biopsy samples and explants. Other liver diseases for which patients were tested included (1) hepatitis B virus (hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and hepatitis B DNA), (2) hepatitis C virus (hepatitis C antibody and RNA), (3) autoimmune hepatitis (anti-nuclear antibody and smooth muscle antibody), (4) primary biliary cirrhosis (anti-mitochondrial antibody), (5) iron overload (ferritin, serum iron, and transferrin saturation), (6) Wilson s disease (ceruloplasmin), (7) primary sclerosing cholangitis (dedicated hepatobiliary imaging with ultrasound, computed tomography, or magnetic resonance), (8) alcohol abuse (history), and (9) nonalcoholic steatohepatitis (history and assessment of risk factors). Pretransplant histology, when it was available, was also reviewed for compatibility with primary and secondary liver disease. Additional demographic information that was collected included the patient s age, sex, and comorbid medical conditions; the presence of hepatocellular carcinoma (HCC); pulmonary function tests (PFTs) before and after transplantation; histological findings at explant; and survival. Liver explants were examined with standard light microscopy for the characteristic intracytoplasmic, periodic acid Schiff positive, diastase-resistant globules. Standard PFTs were performed for patients at the time of their evaluation for LT on the basis of clinical symptoms or a history of smoking. PFTs included an assessment of the total lung capacity (TLC), residual volume, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), and diffusing capacity of the lungs for carbon monoxide (DLCO). These tests were performed according to applicable American Thoracic Society standards and were reported both in appropriate units and as predicted percentages of normal values based on standard equations incorporating age, height, race, and sex. 7 Seventeen patients, all with ZZ phenotype, had PFTs performed both before and at various times after transplantation as part of routine clinical testing at the discretion of the attending physician. Immunosuppression A standardized immunosuppression protocol was followed at the 3 centers. From 1985 to 1994, immunosuppression consisted of cyclosporine and prednisone with or without azathioprine. In 1994, tacrolimus replaced cyclosporine; prednisone and azathioprine were continued. In 1999, mycophenolate mofetil replaced azathioprine, and the duration of prednisone was changed from lifelong to the first 4 months after LT only. In 2011, the duration of mycophenolate mofetil was reduced to the first 4 months after LT, or it was used when it was clinically indicated for a history of rejection or chronic kidney disease. Cyclosporine and tacrolimus doses were adjusted to achieve the desired serum levels, which varied according to clinical factors (underlying disease, kidney function, a history of rejection, and time from transplantation). Rapamycin was used in rare cases of calcineurin inhibitor toxicity or intolerance. Acute cellular rejection was treated with 1 g of intravenous methylprednisolone on 3 alternating days. Statistical Analysis Descriptive analyses were performed with means, standard deviations, and frequency counts. The Student t test was used for continuous variables; categorical variables were assessed with the chi-square test and Fisher s exact test. Survival after LT was evaluated with Kaplan-Meier analysis. Time zero was defined as the date of LT, and patients were followed

3 1372 CAREY ET AL. LIVER TRAPLANTATION, December 2013 TABLE 1. Demographics of LT Recipients With AAT Deficiency MZ Group Characteristic (n 5 50) Age at LT (years)* (30-70) SZ Group (n 5 23) ZZ Group (n 5 50) All Groups (n 5 123) P Value (28-69) (1-69) (1-70) 0.12 for MZ vs SZ SZ < for MZ vs ZZ 0.09 for SZ vs ZZ Male sex [n (%)] 37 (74.0) 18 (78.3) 38 (76.0) 93 (75.6) AAT level before LT (mg/dl)* (47-175) (27-102) (11-46) (11-175) <0.001 for all comparisons Calculated MELD score at transplant* (12-36) (7-40) (6-40) (6-40) Coexisting liver disease [n (%)] 45 (90.0) 10 (43.5) 4 (8.0) 59 (48.0) < for all comparisons HCC in explant [n (%)] 10 (20.0) 5 (21.7) 7 (14.0) 22 (17.9) 0.53 for SZ vs ZZ 0.67 for MZ vs SZ *The data are reported as means and standard deviations with ranges in parentheses. Co-existing liver disease in the SZ group included hepatitis C virus (n 5 5), alcoholic liver disease (n 5 3), hereditary hemochromatosis (n 5 1), or primary sclerosing cholangitis (n 5 1). The ZZ group included biliary cirrhosis (n 5 1), primary sclerosing cholangitis (n 5 1), hereditary hemochromatosis (n 5 1), or alcoholic liver disease (n 5 1). The ZZ group included 1 case of incidental cholangiocarcinoma. until death, loss to follow-up, or the end of the study period. P < 0.05 was considered significant for all data. Data were analyzed with JMP 9 (SAS, Cary, NC). RESULTS Patient Demographics A total of 5246 liver transplants were performed at the 3 centers during the study period, including 73 patients with AAT deficiency (1.4%): 50 had the ZZ phenotype, and 23 had the SZ phenotype. The most recent 50 MZ patients were also included for comparison. Seventy percent of the MZ patients did not have a serum AAT deficiency. The mean age at LT was 52.8 years, and the majority (75.6%) were men. Patients with ZZ AAT deficiency underwent LT at a younger age than MZ patients (P < 0.001). More than 97% of the patients were adults. Before transplantation, the serum AAT levels were lower for the ZZ group versus the SZ group (28.3 versus 58.0 mg/dl, P < 0.001). In the SZ group, 43.4% had an additional coexisting liver disease, whereas 8% in the ZZ group and 90% in the MZ group did. No patient received AAT augmentation therapy either before or after LT (Table 1). The overall prevalence of HCC was 17.9%, and it was similar among the 3 groups. In the MZ group, 10 patients (20%) had HCC: 8 were within the Milan criteria, and 2 were outside the University of California San Francisco (UCSF) criteria (according to explant findings). The SZ group had 5 cases of HCC (21.7%): 4 were within the Milan criteria, and 1 was within the UCSF criteria. In the ZZ group, there were 7 cases of HCC (14%): 4 were within the Milan criteria, and 3 were within the UCSF criteria. PFTs PFTs were obtained at a mean of 10.2 months before LT (Table 2). Pre-LT PFTs showed a mild impairment in overall lung function for the SZ and ZZ patients. The ZZ group had slightly lower FEV 1 and DLCO values and higher TLC values, but these differences were not statistically significant. Seventeen ZZ patients had paired PFTs before and after LT (Table 3). The only statistically significant difference after transplantation was a decrease in the FEV 1 /FVC ratio. FEV 1 declined in 11 of the 17 patients (65%; Fig. 1), whereas 6 of the 17 patients (35%) showed an improvement in FEV 1 after LT. There was no obvious relationship between the current smoking status and the change in FEV 1 over time (Table 4). Ascites was present in 12 patients (71%), and 1 patient also had a pleural effusion. No patient received intravenous AAT protein replacement therapy either before or after LT. Survival The overall patient survival rates at 1, 3, 5, and 10 years were 90%, 88%, 85%, and 78%, respectively. The survival rates were 94%, 92%, 92%, and 86%, respectively, for the MZ group; 91%, 86%, 79%, and 79%, respectively, for the SZ group; and 86%, 83%, 80%, and 72%, respectively, for the ZZ group [P 5 not significant ()]. Twenty-three patients died during the follow-up period (Table 5). Only 1 patient in the ZZ and SZ groups died of pulmonary complications: a 61-yearold woman with ZZ AAT deficiency related emphysema, small cell lung cancer treated with radiation, and subsequent radiation pneumonitis died 9.3 years

4 LIVER TRAPLANTATION, Vol. 19, No. 12, 2013 CAREY ET AL TABLE 2. Pretransplant PFTs MZ Group (n 5 50) SZ Group (n 5 18) ZZ Group (n 5 40) All Groups (n 5 108) P Value TLC (L) ( ) TLC (% predicted) (44 113) FVC (L) ( ) FVC (% predicted) (37 113) FEV 1 (L) ( ) FEV 1 (% predicted) (35 115) FEV 1 /FVC ( ) DLCO (ml/minute/mm Hg) ( ) DLCO (% predicted) (36 120) Time from PFT to LT (months) (1 48) ( ) (49 129) ( ) (42 113) ( ) (43 119) ( ) ( ) (35 107) (1 78) ( ) (46 138) ( ) (42 164) ( ) (35 146) ( ) ( ) (26 104) (0 75) ( ) (44 138) ( ) (37 164) ( ) (35 146) ( ) ( ) (26 120) (0 78) 0.01 for MZ vs ZZ 0.02 for MZ vs ZZ 0.04 for MZ vs ZZ NOTE: All data are reported as means and standard deviations with ranges in parentheses. TABLE 3. Pre- and Post-LT PFTs for 17 Patients With ZZ AAT Deficiency Before LT After LT P Value TLC (L) ( ) ( ) 0.39 TLC (% predicted) (59 138) (82 142) 0.07 FVC (L) ( ) ( ) 0.68 FVC (% predicted) (44 164) (48 145) 0.77 FEV 1 (L) ( ) ( ) 0.77 FEV 1 (% predicted) (35 146) (26 146) 0.90 FEV 1 /FVC ( ) ( ) 0.01 DLCO (ml/minute/mm Hg) ( ) ( ) 0.13 DLCO (% predicted) (48 104) (46 119) 0.81 Time from LT to PFT (months) (5 133) NOTE: All data are reported as means and standard deviations with ranges in parentheses. after LT. Two MZ patients with a history of smoking developed lung cancer after LT. No patients required retransplantation. DISCUSSION This retrospective analysis provides detailed transplant information and follow-up for one of the largest series of patients undergoing LT for AAT deficiency. Additionally, we report the largest series of ZZ and SZ patients who underwent PFTs before and after LT. Only 1 of the 3 centers included in this study has a pediatric LT program, so adult patients predominated in this series. AAT deficiency can lead to cirrhosis and emphysema and is an established indication for LT. In a group of patients with ZZ AAT deficiency and established pulmonary disease, 17.5% had evidence of advanced fibrosis in the liver. 8 The diagnosis of AAT deficiency currently is not an indication for MELD exception points for higher LT priority. In the United States, survival after LT for AAT deficiency is comparable to survival after LT for other indications. 6 Despite the excellent outcomes after LT, there is a paucity of detailed information on this group; specifically, little is known about the effect of LT on the progression of lung disease.

5 1374 CAREY ET AL. LIVER TRAPLANTATION, December 2013 In this series, AAT deficiency (ZZ and SZ phenotypes) was present in 1.4% of patients at 3 transplant centers, and this rate is similar to the national rate in the United States. 6 The age and sex characteristics of recipients with AAT deficiency are comparable to those of recipients of LT for other etiologies of liver disease. As expected, the serum levels of AAT were lower for the ZZ phenotype patients versus the SZ phenotype patients. MZ and SZ patients were also more likely to have an additional liver disease, and this is consistent with the previous finding that these phenotypes alone are not usually a cause of cirrhosis (Table 1). An appropriate return to normal was seen in the few patients whose serum AAT levels were checked after LT. However, post-lt AAT levels were not available for a large enough sample of patients for firm conclusions to be drawn. Pulmonary function before LT was mildly reduced in patients with ZZ or SZ AAT deficiency. There was no statistically significant difference in PFT parameters Figure 1. Changes in FEV 1 after LT. The black lines represent current or former smokers, and the blue lines represent never smokers. between the ZZ and SZ groups. The trajectory of pulmonary disease and pulmonary function changes after LT for AAT deficiency in adults and children remains poorly studied, and the literature in this area is sparse and conflicting. In addition, the interpretation of pulmonary function changes after LT is confounded by the resolution of ascites and/or pleural effusions, improvements in strength and debility, and, ideally, smoking cessation. Previous small series have described LT in mixed cohorts of predominantly adult MZ patients and a few ZZ or SZ patients. 9,10 Jain et al. 9 reported pulmonary outcomes for 7 LT recipients with AAT deficiency (no phenotypes were reported); only 2 had severe serum deficiencies. They found a pre-lt FEV 1 value of L (75% of the predicted normal) and no significant change after LT ( L). 9 Similarly, no changes were reported in other PFT parameters. However, 2 patients experienced dramatic changes after LT. The oldest patient, a 59-year-old never smoker, experienced a 760-mL decline (45%) in FEV 1 over the course of 42 months. The youngest patient, who was 36 years old, had a 1210-mL improvement (44%) in FEV 1 46 months after LT after the resolution of ascites and reported smoking reduction. Our series similarly shows large swings in FEV 1 after LT ranging from a 41% decline in 1 patient to a 77% improvement in another (Table 4). We were unable to correlate these changes with preexisting lung function or the presence of ascites or pleural effusion. Vennarecci et al. 10 described LT outcomes for 22 adults with AAT deficiency; 3 had the ZZ phenotype, and 1 had the SZ phenotype. Ten underwent full PFTs at a median of 28 months after LT. A post-lt FEV 1 value < 70% of the predicted value was noted for 2 patients, but no information was provided about the phenotype or pulmonary function before LT. TABLE 4. Changes in FEV 1 and Smoking History for 17 Patients With ZZ AAT Deficiency Rate of Patient Age (Years)/Sex Pre-LT FEV 1 (L) Post-LT FEV 1 (L) Time Between Tests (Years) Change (ml/year) Smoking History Ascites Pleural Effusion 41/female Never No No 46/male Never Yes No 46/male Never No No 56/male Never Yes No 58/female Never Yes No 58/male Never Yes No 65/male Never Yes No 45/male Ex Yes No 50/male Ex Yes No 50/male Ex Yes Yes 52/male Ex Yes No 54/male Ex Yes No 61/male Ex Yes No 61/male Ex No No 61/female Ex Yes No 65/male Ex No No 38/male Current No No

6 LIVER TRAPLANTATION, Vol. 19, No. 12, 2013 CAREY ET AL TABLE 5. Causes of Death After LT Survival After LT Patient Age at Death (Years)/Sex Phenotype (Months) Cause of Death Death < 1 month after LT 36/male ZZ 0 Intraoperative 57/male ZZ < 1 Hepatic artery thrombosis 55/male ZZ < 1 Unknown 56/male ZZ < 1 Sepsis Death 1 6 months after LT 66/female ZZ 1 CVA 69/male SZ 1 Sepsis 34/female ZZ 2 Unknown 63/female SZ 3 Unknown 61/female MZ 3 CVA 64/male MZ 4 Unknown 56/male ZZ 5 CVA 54/male MZ 5 Renal failure Death > 6 months after LT 57/male SZ 21 Recurrent HCC 61/male MZ 26 Lung cancer (former smoker) 32/male ZZ 40 Hepatic artery thrombosis 45/male SZ 53 Unknown 50/female ZZ 60 Recurrent cholangiocarcinoma 56/male MZ 61 Recurrent HCC 65/male MZ 93 Lung cancer (former smoker) 61/female ZZ 112 Respiratory failure 66/male ZZ 113 Unknown 50/male MZ 126 Renal failure 78/female MZ 168 Multisystem organ failure In a large series reported by Kemmer et al. 6 from the United Network for Organ Sharing database, no distinction was made between AAT phenotypes within a cohort of 406 adults undergoing transplantation with AAT deficiency. Pulmonary function data were not collected as part of that database. Such inclusive groupings of AAT-deficient patients are problematic because the range of serum deficiencies and potential pulmonary implications in MZ patients are markedly different from those in ZZ or SZ patients. 2 Most MZ patients have minimal to no pulmonary function abnormalities (and minimal to no serum deficiencies), whereas ZZ and SZ patients can range from normal lung function to severe expiratory airflow obstructions due to panacinar lower lobe emphysema. Serum deficiencies are always severe in ZZ patients and moderate to severe in SZ patients. AAT is also an acute phase reactant, and one should be cautious about obtaining levels during an acute infection or illness. Consequences for pulmonary function before and after LT should be assessed by appropriate phenotyping rather than deficiency characterization. Stoller and Aboussouan 2 reviewed 7 studies (>2300 patients) and analyzed the rate of FEV 1 decline in patients presenting with primary involvement in either the liver or the lungs. They found that never smokers had an FEV 1 decline of 47 to 86 ml/year, which was similar to the decline for exsmokers, whose FEV 1 declined at 41 to 81 ml/year. 2 Current smokers experienced a faster rate of decline with reductions of 61 to 132 ml/year. The expected change in normal individuals with aging is approximately 30 ml/year; up to 60 ml/year may occur in current smokers. 11 In our series, 9 of 17 ZZ patients (53%) had an annual FEV 1 reduction > 30 ml/year after LT (Table 3). Although we did not have post-lt serum AAT levels for all of our patients, other groups have reported a return to normal serum levels after LT. 10 Those patients had FEV 1 changes similar to the changes seen in the ZZ patients despite the normalization of serum AAT levels after LT. We believe that these observations merit further study of intrapulmonary AAT neutrophil elastase interactions in ZZ and SZ recipients of LT. Notably, none of the patients in our series received augmentation therapy before or after LT. A national survey indicates that most patients with AAT lung disease receive augmentation therapy, whereas only 4% of those with liver disease receive it. 12 Survival after LT for individuals with ZZ or SZ AAT deficiency is excellent and mirrors overall survival for LT recipients. In our study, we found a 5-year survival rate of 82% (for the ZZ and SZ groups), which is similar to the 5-year survival rate of 82% reported from the

7 1376 CAREY ET AL. LIVER TRAPLANTATION, December 2013 UNOS database for patients with AAT deficiency. 6 Many of the deaths were in the early posttransplant period (within 3 months), and were related to complications of LT (infection, recurrent malignancy, or hepatic artery thrombosis. However, 1 patient died from respiratory causes: a 61-year-old woman with a history of AAT deficiency related emphysema, small cell lung cancer treated with radiation, and subsequent radiation pneumonitis died 9.3 years after LT. Two MZ patients with a history of smoking developed lung cancer after LT. Although pulmonary function continues to decline in some patients after LT, progression to end-stage lung disease is rare. The retrospective nature of this study mandates caution in the interpretation of its results. The obvious limitation is that PFTs were not ordered routinely either before or after LT for all patients. It is possible that PFTs were performed only for those patients who were symptomatic or had evidence of clinical lung disease, and a selection bias may be present in these data. Although our findings may not be representative of all ZZ or SZ patients, they do highlight the need for a prospective study to better define lung function over time. Our results also highlight the importance of a consultation with a specialist in pulmonary disease for LT recipients with ZZ or SZ AAT deficiency before and after LT. Optimal medical management may include the addition of bronchodilator therapy and AAT replacement therapy in highly select patients. We currently suggest participation in a planned posttransplant bronchoscopy protocol to assess bronchoalveolar lavage fluid after transplantation for elastase activity, leukotriene B4, and interleukin-8 levels. Post-LT intravenous AAT replacement therapy is not necessary if serum levels are normal. Additional follow-up for patients who do show PFT deterioration should include AAT phenotyping and genotyping and a serum level assessment. In summary, we have described clinical characteristics and outcomes for a large series of patients undergoing LT for severe AAT deficiency (ZZ or SZ phenotype). Additionally, we have provided the largest published series of PFTs before and after LT for AAT deficiency. Excellent short- and long-term outcomes have been noted for patients undergoing LT for AAT deficiency, and progression to end-stage lung disease is rare. However, the wide variability in pulmonary function after LT remains poorly understood. Future research should more carefully address the direction and magnitude of changes in pulmonary function after LT and identify exacerbating and mitigating factors. Because there is considerable heterogeneity in the clinical manifestations of severe AAT deficiency, all ZZ and SZ patients should be screened for both lung disease and liver disease. REFERENCES 1. de Serres FJ, Blanco I, Fernandez-Bustillo E. PI S and PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis 2007;67: Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 2005;365: Clark V, Brantly M, Dhanasekaran R, Schreck P, Rouhani F, Nelson D. ALT abnormalities in adults with alpha-1 antitrypsin deficiency [abstract]. J Hepatol 2011; 54(suppl 1):S American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;168: Graziadei IW, Joseph JJ, Wiesner RH, Therneau TM, Batts KP, Porayko MK. Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology 1998;28: Kemmer N, Kaiser T, Zacharias V, Neff GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008;40: Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al.; for ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J 2005; 26: Dawwas MF, Davies SE, Griffiths WJ, Lomas DA, Alexander GJ. Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease. Am J Respir Crit Care Med 2013;187: Jain AB, Patil V, Sheikh B, Apostolakos M, Ryan C, Kashyap R, Orloff M. Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases. Exp Clin Transplant 2010;8: Vennarecci G, Gunson BK, Ismail T, H ubscher SG, Kelly DA, McMaster P, Elias E. Transplantation for end stage liver disease related to alpha 1 antitrypsin. Transplantation 1996;61: Wise RA. The value of forced expiratory volume in 1 second decline in the assessment of chronic obstructive pulmonary disease progression. Am J Med 2006;119(suppl 1): Strange C, Stoller JK, Sandhaus RA, Dickson R, Turino G. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration 2006;73: