Background

This rare inherited disorder is associated with lung and liver diseases and may be linked to several other diseases including inflammatory bowel disease. Although many patients present in childhood, later onset cases may occur. The gene locus is pleomorphic and over 75 alleles have been identified.

Outline

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
Alpha 1-antitrypsin deficiency deaths in the United States from 1979-1991. An analysis using multiple-cause mortality data. Browne RJ, Mannino DM, Khoury MJ. Air Pollution and Respiratory Health Branch, National Center for Environmental Health, Centers for Disease Control and Prevention (CDC), Atlanta, USA.	Chest 1996 Jul;110(1):78-83 Abstract quote OBJECTIVE: To describe trends of reported alpha 1-antitrypsin deficiency mortality in the United States from 1979-1991. METHODS: We analyzed death certificate reports in the multiple-cause mortality files compiled by the National Center for Health Statistics. RESULTS: Of the 26,866,600 deaths that occurred during the 13-year period, 1,930 had alpha 1-antitrypsin deficiency listed as a cause of death. Over this period, we would have expected 5,400 to 13,400 persons with this condition to die. The age-adjusted mortality rate with reported alpha 1-antitrypsin deficiency listed increased 86%, from 4.3 per 10 million in 1979 to 8.0 per 10 million in 1991. alpha 1-Antitrypsin deficiency mortality rates were higher among whites than among blacks or persons of other races. alpha 1-Antitrypsin deficiency was listed in 2.7% of all deaths with obstructive lung disease among persons aged 35-44 years old and in 1.2% of all deaths listing hepatic disease among children aged 1 to 14 years old. CONCLUSIONS: alpha 1-Antitrypsin deficiency is an important risk factor for obstructive lung disease and hepatic disease in the United States, and it was reported with increasing frequency through the study period, although it is still likely underreported.
Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. McElvaney NG, Stoller JK, Buist AS, Prakash UB, Brantly ML, Schluchter MD, Crystal RD. Pulmonary-Critical Care Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md, USA	Chest 1997 Feb;111(2):394-403 Abstract quote OBJECTIVE: alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder characterized by a high risk for the development of emphysema at an early age. In 1988, the National Heart, Lung and Blood Institute, National Institutes of Health, initiated a registry of individuals with alpha 1-AT deficiency to help define the natural history and clinical course of this disorder. This article describes demographic and clinical characteristics of subjects enrolled in the Registry at baseline. DESIGN: Prospective longitudinal natural history study. SETTING: Thirty-seven clinical centers in the United States (36 centers) and Canada (one center). PATIENTS: There were 1,129 subjects 18 years of age or older with severe deficiency of alpha 1-AT, defined as having serum alpha 1-AT levels < or = 11 mumol/L confirmed by a Central Phenotyping Laboratory, or a ZZ or ZNull genotype identified by genomic DNA analysis. RESULTS: Most enrollees were symptomatic white subjects in their fourth to sixth decade, with a ZZ phenotype, a history of having smoked cigarettes, and pulmonary function tests demonstrating a pattern consistent with emphysema. Interestingly, only a small percentage were current smokers on enrollment, suggesting that this population is amenable to smoking cessation. A subgroup of individuals in the Registry with relatively normal lung function were younger, more likely to have never smoked and more likely to have come to medical attention owing to a family history of alpha 1-AT deficiency rather than symptomatic involvement. CONCLUSIONS: These results emphasize the need for increased awareness and early detection of alpha 1-AT deficiency. In this endeavor, dissemination of the information contained in the Registry to health-care professionals and the general population, along with initiation of appropriate preventative measures before significant lung damage has occurred, could have considerable benefits for individuals with this condition.
Occupational exposure risks in individuals with PI*Z alpha(1)-antitrypsin deficiency. Mayer AS, Stoller JK, Bucher Bartelson B, James Ruttenber A, Sandhaus RA, Newman LS. Division of Environmental and Occupational Health Sciences and Pulmonary Division, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado, USA.	Am J Respir Crit Care Med 2000 Aug;162(2 Pt 1):553-8 Abstract quote We obtained questionnaire and spirometry data from 128 alpha(1)-antitrypsin (alpha(1)AT)-deficient individuals with phenotype PI*Z to examine the relationship between chronic respiratory symptoms, airflow limitation, treatment requirements, and semiquantitative estimates of occupational exposure to dust, fumes, smoke, and gas. After adjusting for age, smoking, and prior lower respiratory tract infections, increased prevalence of chronic cough (OR = 4.69, 95% CI = 1.57-13.74, p = 0.006) and having left a job due to breathlessness (OR = 2.72, 95% CI = 1.07-6.92, p = 0.036) were seen in individuals reporting high mineral dust exposure compared with those with no exposure. Subjects reporting high mineral dust exposure also had significantly lower FEV(1) (31% predicted for high exposure versus 36% for low and 40% for unexposed, p = 0.032). The excess risk of chronic cough seen with occupational fumes or smoke exposure disappeared after adjusting for mineral dust exposure, but the association with lower FEV(1)/FVC ratio persisted (p = 0.022). Personal tobacco use was a significant risk factor for most outcome measures, but no interaction with occupational exposure was seen. These results suggest that occupational inhalational exposures are independently associated with respiratory symptoms and airflow limitation in severely alpha(1)AT-deficient individuals.
GEOGRAPHY
Alpha 1-antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. Hutchison DC. Department of Respiratory Medicine, King's College School of Medicine, London, U.K.	Respir Med 1998 Mar;92(3):367-77 Abstract quote alpha 1-Antitrypsin (AT) is the principal serum inhibitor of proteolytic enzymes such as neutrophil elastase. AT can exist as over 90 different genetically determined variants known as the Pi system; the three most important variants are type M (90% of population) and types S and Z, two of the commoner abnormal variants. Homozygotes of type Z have a severe reduction in the serum AT concentration and may develop pulmonary emphysema or hepatic cirrhosis. Heterozygotes of type SZ have a less severe reduction in serum AT concentration and the association with clinical disease is less clear. The S and Z variants are found mainly among those of European stock. The gene frequency for Pi type Z is highest on the north-western seaboard of the continent and the mutation seems likely to have arisen in southern Scandinavia. The distribution of type S is quite different; the gene frequency is highest in the Iberian peninsula and the mutation is likely to have arisen in that region. A population survey for determining the number of type Z homozygotes in a given community is important for planning purposes now that AT replacement therapy is potentially available.
Molecular diagnosis of intermediate and severe alpha(1)-antitrypsin deficiency: MZ individuals with chronic obstructive pulmonary disease may have lower lung function than MM individuals. Dahl M, Nordestgaard BG, Lange P, Vestbo J, Tybjaerg-Hansen A. Department of Clinical Biochemistry, Herlev University Hospital, DK-2730 Herlev, Denmark.	Clin Chem 2001 Jan;47(1):56-62 Abstract quote BACKGROUND: We tested whether intermediate (MZ, SZ) and severe (ZZ) alpha(1)-antitrypsin deficiency affects lung function in the population at large. METHODS: We performed spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)] and genotyping of 9187 individuals from the adult general population of Copenhagen, Denmark. RESULTS: As expected, the frequencies of individuals with MM, MS, SS, MZ, SZ, and ZZ genotypes were 0.891, 0.054, 0.001, 0.052, 0.001, and 0.001, respectively. Genotype interacted with clinically established chronic obstructive pulmonary disease (COPD) on the percentage of the predicted FEV(1) (P = 0. 004): the percentage of the predicted FEV(1) was reduced in MZ compared with MM individuals among those with clinically established COPD, but not among those without COPD. Furthermore, SZ compound heterozygotes had lower FEV(1)/FVC ratios than MM individuals (P <0.05), and ZZ homozygotes had lower percentages of the predicted FEV(1) and FEV(1)/FVC ratios than MM, MS, SS, and MZ individuals (all Ps <0.01). Reduced lung function in SZ and ZZ vs MM individuals could be demonstrated in current and ex-smokers, but not in nonsmokers. Compared with MM individuals in the same groups, FEV(1) was reduced 655 mL in MZ individuals with clinically established COPD, 364 mL in SZ current smokers, and 791 mL in ZZ current smokers. CONCLUSIONS: In the population at large, MZ was associated with reduced pulmonary function in individuals with clinically established COPD, whereas SZ and ZZ were associated with reduced pulmonary function in smokers. The presence of the alpha(1)-antitrypsin MZ genotype may in certain circumstances produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Alpha1-antitrypsin Pi phenotypes S and Z in Spain: an analysis of the published surveys. Blanco I, Fernandez E. Seccion de Neumologia, Hospital Valle del Nalon, Asturias, Spain.	Respir Med 2001 Feb;95(2):109-14 Abstract quote The aim of the present study was to review published surveys on allelic frequencies S and Z in Spanish populations to evaluate the validity of the reported data. Thirty-four studies published since 1965 were retrieved by MEDLINE, Index Medicus and consultations with experts. The criteria for studies selection were (i) sample size > or = 250 individuals; (ii) alpha-1-antitrypsin phenotyping determination performed by means of crossed antigen-antibody electrophoresis or isoelectrofocusing; (iii) S and Z reported outcomes with an upper 95% CI smaller than mean + 2 SD, a lower 95% CI smaller than mean - 2 SD, and the following ratio: 100 x (95%CI upper limit - 95%CI lower limit)/allelic frequency, for both S and Z, included in the mean +/- 2 SD interval. Thirteen out of 34 surveys retrieved complied with the proposed criteria for S gene frequency analysis and 11 fulfilled the criteria for Z. The greatest frequency for S type is in the north-west of the country (149 alleles per 1000 in Galicians natives), while frequencies in the rest of the country are approximately 100 alleles per 1000. The greatest frequency for Z type has been reported in newborn infants from Valladolid (20.8) and in a randomly selected general population of Asturias (19.7). In the rest of Spain, Z frequencies range from 1.5 to 15 alleles per 1000 genes.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ANCA
alpha 1-Antitrypsin (AAT) deficiency and ANCA-positive systemic vasculitis: genetic and clinical implications. Callea F, Gregorini G, Sinico A, Gonzales G, Bossolasco M, Salvidio G, Radice A, Tira P, Candiano G, Rossi G, Petti A, Ravera G, Ghiggeri G, Gusmano R. Department of Pathology, Spedali Civili, Brescia, Italy.	Eur J Clin Invest 1997 Aug;27(8):696-702 Abstract quote A high incidence of alpha 1-antitrypsin (AAT) deficiency has been reported in patients with C-ANCA systemic vasculitis in association with antibodies against proteinase-3 (PR3). To clarify the role of AAT deficiency in the acute vasculitic process as well as in progression of the disease, we studied 84 patients with either C-ANCA or P-ANCA vasculitis with special reference to: (a) the AAT gene, (b) the phenotypic (Pi) variants and (c) the serum levels during both acute illness and remission. The PiZ gene was found in six patients (8% vs. 1.5% controls) irrespective of the type of autoantibodies (C-ANCA vs. P-ANCA). All PiZ patients displayed the ability to raise their AAT serum levels up to the normal range during acute illness. In contrast, 24 patients with the PiM phenotype presented low AAT serum levels during acute illness. In all these patients, the AAT levels returned to normal values during the remission. Low AAT levels were associated with low levels of C-reactive protein (PCR) (P < 0.001), with a less severe renal involvement or a minor risk of death, and, in one tested patient, with a novel point mutation (TCGA-->TCAA) at the enhancer-promoter region of the AAT gene. Low AAT serum levels did not correlate with either type/titre of autoantibody or distribution/severity of the vasculitis process. In the case-control study, high AAT levels emerged as a major determinant of progression towards end-stage renal failure [odds ratio 3 (95% CI 1.1-8.4)]. These results indicate: (a) a high incidence of the PiZ gene of AAT in systemic vasculitis irrespective of the type of autoantibodies; (b) a novel form of AAT deficiency associated with the normal PiM phenotype becoming manifest only during acute illness; (c) dysregulation of the acute-phase response affecting selectively AAT or both AAT and PCR; (d) correlation between low plasma levels of AAT and less severe renal involvement or risk of death.
Analysis of anti-neutrophil cytoplasmic antibodies (ANCA): frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects. Audrain MA, Sesboue R, Baranger TA, Elliott J, Testa A, Martin JP, Lockwood CM, Esnault VL. Immunology Department, Hotel Dieu, Nantes, France.	Nephrol Dial Transplant 2001 Jan;16(1):39-44 Abstract quote BACKGROUND: ANCA are autoantibodies directed against polymorphonuclear cell antigens, mainly proteinase 3 (PR3) and myeloperoxidase (MPO), which are implicated in the pathogenesis of small-vessel necrotizing vasculitis. Alpha1-antitrypsin is the main inhibitor of neutral serine proteinase [i.e. human leukocyte elastase (HLE) and PR3] present in PMN alpha-granules (alphaGr). An association first reported by us between PR3 ANCA and the deficient PiZZ phenotype in ANCA-positive systemic vasculitis, now widely confirmed by others, led us to study the incidence and specificity of ANCA among PiZZ subjects. METHODS: We tested a population of 191 PiZZ (273 sera) for ANCA activity versus 272 PiMM matched control subjects using alphaGr or antigen-specific ELISA [PR3, HLE, MPO, lactoferin (LF) and bactericidal/ permeability increasing protein (BPI)]. RESULTS: The incidence of antibodies directed against alphaGr and HLE but not PR3, MPO, LF or BPI was increased in the PiZZ as compared to the PiMM group (Fisher probability respectively P < 0.0001 and P < 0.05). CONCLUSIONS: ANCA not directed against classical antigens (MPO and PR3) may be found in PiZZ patients. However, these patients do not develop systemic vasculitis features. Therefore, alpha1-antitrypsin deficiency is not sufficient to induce ANCA positive vasculitides, and may only act as a second hit amplifying factor.
ANEURYSM, ABDOMINAL AORTIC
Abdominal aortic aneurysms and alpha 1-antitrypsin deficiency. Elzouki AN, Eriksson S. Department of Medicine, University of Lund, Malmo General Hospital, Sweden.	J Intern Med 1994 Nov;236(5):587-91 Abstract quote The incidence of abdominal aortic aneurysms (AAAs) has been reported to be increased in heterozygous (PiMZ) and homozygous (PiZZ) alpha 1-antitrypsin (alpha 1 AT) deficiency. We report a further case of AAA in a PiSZ alpha 1AT-deficient female with primary biliary cirrhosis (PBC). Moreover, to assess the risk of AAA in patients with PiZZ alpha 1AT deficiency, we conducted a retrospective study based on 30 consecutive autopsied adult cases of severe alpha 1AT deficiency identified during the period 1963-1993 in the city of Malmo, Sweden, during which autopsies were performed in 49,548, or 58.4%, of all residents in the city who died. From the homozygote frequency in the general population, 50 of these would be expected to have alpha 1AT deficiency. The disease had been diagnosed in 35, and autopsies had been performed in 30 adults. Each autopsied case was matched with four controls selected from the same autopsy register, and the Mantel-Haenszel odds ratio (ORmh) was calculated. We found one case of AAA amongst the 30 PiZZ individuals autopsied, and one case amongst 120 autopsied controls (ORmh = 2.65, 95% confidence limits, 0.47-15.0; P = 0.273). We found no significant evidence of the relationship between AAA and the PiZZ polymorphism, although previously reported by others. At least in severe alpha 1AT deficiency, any coexistence of the PiZZ phenotype and AAA would seem to be fortuitous.
ANEURYSM, INTRACRANIAL
Alpha-1-antitrypsin phenotypes among patients with intracranial aneurysms. Schievink WI, Katzmann JA, Piepgras DG, Schaid DJ. Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA.	J Neurosurg 1996 May;84(5):781-4 Abstract quote A deficiency of alpha 1-antitrypsin has been implicated in the development of arterial aneurysms, including intracranial aneurysms. The authors determined the prevalence of alpha 1-antitrypsin deficiency of different phenotypes in 100 consecutive patients with intracranial aneurysms and compared the distribution of alpha 1-antitrypsin phenotypes to that in the general population (904 people). The study population consisted of 44 men and 56 women with a mean age of 52 years (range 15-81 years). The heterozygous alpha 1-antitrypsin deficiency states (PiMS and PiMZ) were more common in patients (16%) than in the general population (7%), providing an odds ratio of 2.56 (95% confidence interval (CI) 1.32-4.75; p = 0.005). In addition, one patient (1%) was homozygous for the deficient allele (PiZZ) compared to an expected number of 0.015, providing an odds ratio of 67.0 (95% CI 2.0-363.3; p = 0.015). These findings lead the authors to suggest that the heterozygous and homozygous alpha 1-antitrypsin deficiency states are genetic risk factors for the development of intracranial aneurysms.
ANEURYSM, SPLENIC ARTERY
Alpha-1 antitrypsin deficiency and splenic artery aneurysm rupture: an association? Gaglio PJ, Regenstein F, Slakey D, Cheng S, Takiff H, Rinker R, Dick D, Thung SN. Division of Transplantation, Tulane University School of Medicine, New Orleans, Louisiana, USA.	Am J Gastroenterol 2000 Jun;95(6):1531-4 Abstract quote OBJECTIVE: Theoretically, patients with alpha 1-antitrypsin deficiency may be vulnerable to the development of splenic artery aneurysms. alpha-1 antitrypsin deficiency can induce cirrhosis with portal hypertension, and resulting protease-antiprotease imbalances may exaggerate arterial wall weakness due to proteolysis of arterial structural proteins. A splenic artery aneurysm rupture 7 days after liver transplantation provoked a reassessment of the incidence of this phenomenon in a liver transplant population. METHODS: Case records from three institutions and the results of a survey sent to 126 liver transplantation programs in the United Network for Organ Sharing database were reviewed. The incidence of splenic artery aneurysm rupture in the peritransplantation period, etiology of liver disease associated with this phenomenon, and recommendations regarding management of splenic artery aneurysms was assessed. RESULTS: Twenty-one cases of splenic artery aneurysm rupture were identified. alpha-1 antitrypsin deficiency was the most common cause of cirrhosis in the majority of identified patients who presented with splenic artery aneurysm rupture, which was associated with a mortality rate of 57%. Respondents to the survey indicated that a preoperative evaluation was warranted if a splenic artery aneurysm was suspected; however, no consensus regarding management exists. CONCLUSIONS: The presence and risk of rupture of splenic artery aneurysms may be greater in patients with alpha-1 antitrypsin deficiency. If identified before rupture, an aggressive approach to diagnosing and treating these aneurysms should be initiated. At present, no consensus exists regarding the management of splenic artery aneurysms.
INFLAMMATORY BOWEL DISEASE
The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis. Elzouki AN, Eriksson S, Lofberg R, Nassberger L, Wieslander J, Lindgren S. Department of Medicine, University Hospital, Malmo, Sweden.	Inflamm Bowel Dis 1999 Nov;5(4):246-52 Abstract quote 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.
Alpha1-antitrypsin deficiency and inflammatory bowel diseases. Yang P, Tremaine WJ, Meyer RL, Prakash UB. Department of Health Sciences Research, Mayo Clinic Rochester, MN 55905, USA.	Mayo Clin Proc 2000 May;75(5):450-5 Abstract quote OBJECTIVE: To evaluate a possible etiologic role of alpha1-antitrypsin deficiency (alpha1AD), most frequently caused by a Z allele mutation, in ulcerative colitis (UC) and Crohn disease (CD). PATIENTS AND METHODS: This retrospective study included 10 patients diagnosed with and/or treated for inflammatory bowel disease (IBD) between 1976 and 1997 and identified from the Mayo Clinic Medical Index System. All 10 patients had either alpha1AD and CD or alpha1AD and UC. The alpha1-antitrypsin (alpha1AT) types and levels were determined with isoelectric focusing testing. The allele types, representing genotypes, were designated PiZZ (or ZZ) for homozygotes and PiMZ (or MZ) for heterozygotes. RESULTS: Seven patients had UC: 4 were genotype ZZ and 3 MZ. Four of these 7 patients had emphysema, 2 had asthma, and 1 had chronic bronchitis. Five were cigarette smokers, but only 1 had smoked coincident with activity of her UC. Two of the UC patients never smoked, and 1 of these 2 had asthma. Three of the 10 patients had CD, 2 genotype ZZ and 1 MZ. Two of the 3 patients were long-term cigarette smokers, and both had emphysema. Nine of the 10 patients with UC and alpha1AD required surgery. CONCLUSIONS: The need for surgery in patients with UC and alpha1-AD may point to a unique phenotypic subgroup of patients with alpha1AD and severe UC. Further studies are required to substantiate the etiologic role of alpha1AD in IBD. Our observations, if confirmed by future studies, suggest that in patients with both IBD and chronic obstructive pulmonary disease, alpha1AD testing should be considered.
MISMATCH REPAIR GENE DEFECTS
Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers. Yang P, Cunningham JM, Halling KC, Lesnick TG, Burgart LJ, Wiegert EM, Christensen ER, Lindor NM, Katzmann JA, Thibodeau SN. Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Department of Medical Genetics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.	Mol Genet Metab 2000 Dec;71(4):639-45 Abstract quote Microsatellite instability (MSI) is a genomic alteration observed in 15-30% of colorectal cancer (CRC). Two MSI phenotypes have been defined for CRC: MSI-H is characterized by MSI at > or =30% of the examined loci and MSI-L by MSI at 1-30% of the loci. An absence of MSI at any examined loci has been defined as a microsatellite stable (MSS) phenotype. Current data suggest the majority of MSI tumors are the result of defective DNA mismatch repair (MMR). In this study, we have determined the alpha(1)-antitrypsin deficiency carrier (alpha(1)ATD-ht) status of 161 CRC patients whose MSI phenotype and protein expression states had previously been determined. Cases were selected to enrich a larger number of MSI-H cases. Among 51 CRC patients with MSI-H tumors, the alpha(1)ATD-ht rate was 21.6%; among 110 patients with MSI-L/MSS tumors, the rate was 9.1% (MSI-H vs MSI-L/MSS, P = 0.02); and among the 191 population-based controls the alpha(1)ATD-ht rate was 9.4% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among alpha(1)ATD-ht was 3.1 after adjusting for age, gender, and smoking history. The risk of having MSI-H CRC among current and past smokers was 6.6 and 2.7, respectively. Patients who were alpha(1)ATD-ht and smoked had a 20-fold increased risk of developing an MSI-H CRC compared to nonsmokers who were homozygous normal at the alpha(1)ATD locus. Our findings suggest an etiologic link between alpha(1)ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and alpha(1)ATD allele in the development of MSI-H CRC.
PANCREATITIS, CHRONIC
Alpha 1-antitrypsin deficiency and chronic pancreatitis. Rabassa AA, Schwartz MR, Ertan A. Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.	Dig Dis Sci 1995 Sep;40(9):1997-2001 Abstract quote Alpha 1-antitrypsin deficiency is a genetic disorder commonly associated with pulmonary and hepatic injury. Low serum levels of this glycoprotein result in an imbalance between circulating protease and protease inhibitors, which is thought to play a role in the development of emphysema. In recent studies, a protease-to-protease inhibitor imbalance in patients with alpha 1-antitrypsin deficiency was thought to be a mechanism contributing to the development of chronic pancreatitis. The heterozygous phenotype and low levels of this glycoprotein have been reported to occur more frequently in patients with chronic pancreatitis than in healthy controls. We report a patient with Pi-SS phenotype alpha 1-antitrypsin deficiency and chronic pancreatitis complicated by recurrent pancreatic pseudocysts and chronic abdominal pain. Our case supports the association between chronic pancreatitis and alpha 1-antitrypsin deficiency. Furthermore, this case provides support for the use of pancreatic stent drainage in the management of intractable abdominal pain in patients with chronic pancreatitis and a dominant stricture.

 

PATHOGENESIS	CHARACTERIZATION
GENERAL
Conformational changes in serpins and the mechanism of alpha 1-antitrypsin deficiency. Carrell RW, Whisstock J, Lomas DA. Department of Haematology, University of Cambridge, United Kingdom.	Am J Respir Crit Care Med 1994 Dec;150(6 Pt 2):S171-5 Abstract quote alpha 1-Antitrypsin is a member of the serine proteinase inhibitor, serpin, family of protease inhibitors, which have their reactive centers situated on a mobile peptide loop. This reactive loop can adopt varied conformations and perturbations of molecular structure to allow the pathological linking of the loop of one molecule to a beta-pleated sheet of another. This linkage has been shown to be the cause of the polymerization and aggregation within the hepatocyte of the common Z mutant of antitrypsin. The occurrence of loop-sheet polymerization has been confirmed with other deficiency variants of antitrypsin that accumulate in the liver (Mmalton, Siiyama) and also shown to occur in pathological mutants of C1-inhibitor and antithrombin. Deductive evidence indicates that the loop is inserted into the A-sheet of the next molecule, but recent structural findings raise the possibility of insertion into the C-sheet. This detail of loop-sheet polymerization is important for the design of strategies to interfere with insertion and hence lesson the accumulation of Z antitrypsin that is responsible for associated liver damage.
Mutations which impede loop/sheet polymerization enhance the secretion of human alpha 1-antitrypsin deficiency variants. Sidhar SK, Lomas DA, Carrell RW, Foreman RC. Department of Physiology and Pharmacology, University of Southampton, United Kingdom.	J Biol Chem 1995 Apr 14;270(15):8393-6 Abstract quote alpha 1-Antitrypsin plasma deficiency variants which form hepatic inclusion bodies within the endoplasmic pathway include the common Z variant (Glu342-->Lys) and the rarer alpha 1-antitrypsin Siiyama (Ser53-->Phe). It has been proposed that retention of both abnormal proteins is accompanied by a common mechanism of loop-sheet polymerization with the insertion of the reactive center loop of one molecule into a beta-pleated sheet of another. We have compared the biosynthesis, glycosylation, and secretion of normal, Z and Siiyama variants of alpha 1-antitrypsin using Xenopus oocytes. Siiyama and Z alpha 1-antitrypsin both duplicated the secretory defect seen in hepatocytes that results in decreased plasma alpha 1-antitrypsin levels. Digestion with endoglycosidase H localized both variants to a pre-Golgi compartment. The mutation Phe51-->Leu abolished completely the intracellular blockage of Siiyama alpha 1-antitrypsin and reduced significantly the retention of Z alpha 1-antitrypsin. The secretory properties of M and Z alpha 1-antitrypsin variants containing amino acid substitutions designed to decrease loop mobility and sheet insertion were investigated. A reduction in intracellular levels of Z alpha 1-antitrypsin was achieved with the replacement of P11/12 alanines by valines. Thus a decrease in Z and Siiyama alpha 1-antitrypsin retention was observed with mutations which either closed the A sheet or decreased loop mobility at the loop hinge region.
CIGARETTE SMOKING
Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency. Hill AT, Bayley DL, Campbell EJ, Hill SL, Stockley RA. Dept of Medicine, Queen Elizabeth Hospital, Birmingham, UK.	Eur Respir J 2000 May;15(5):886-90 Abstract quote Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor alpha1-antitrypsin (alpha1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe alpha1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin-8 (IL-8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, alpha1AT and secretory leukoprotease inhibitor (SLPI). Finally serum alpha1AT was measured to determine the degree of protein leakage (sputum sol serum alpha1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL-8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with alpha1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti-proteinase screen with both reduced sputum alpha1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin-8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with alpha1-antitrypsin deficiency had greater inflammation suggesting that alpha1-antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.
CIRRHOSIS
A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Wu Y, Whitman I, Molmenti E, Moore K, Hippenmeyer P, Perlmutter DH. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.	Proc Natl Acad Sci U S A 1994 Sep 13;91(19):9014-8 Abstract quote Liver injury in PiZZ alpha 1-antitrypsin (alpha 1-AT) deficiency probably results from toxic effects of the abnormal alpha 1-AT molecule accumulating within the ER of liver cells. However, only 12-15% of individuals with this same genotype develops liver disease. Therefore, we predicted that other genetic traits that determine the net intracellular accumulation of the mutant alpha 1-AT molecule would also determine susceptibility to liver disease. To address this prediction, we transduced skin fibroblasts from PiZZ individuals with liver disease or without liver disease with amphotropic recombinant retroviral particles designed for constitutive expression of the mutant alpha 1-AT Z gene. Human skin fibroblasts do not express the endogenous alpha 1-AT gene but presumably express other genes involved in postsynthetic processing of secretory proteins. The results show that expression of human alpha 1-AT gene was conferred on each fibroblast cell line. Compared to the same cell line transduced with the wild-type alpha 1-AT M gene, there was selective intracellular accumulation of the mutant alpha 1-AT Z protein in each case. However, there was a marked delay in degradation of the mutant alpha 1-AT Z protein after it accumulated in the fibroblasts from ZZ individuals with liver disease ("susceptible hosts") as compared to those without liver disease ("protected hosts"). Appropriate disease controls showed that the lag in degradation in susceptible hosts is specific for the combination of PiZZ phenotype and liver disease. Biochemical characteristics of alpha 1-AT Z degradation in the protected hosts were found to be similar to those of a common ER degradation pathway previously described in model experimental cell systems for T-cell receptor alpha subunits and asialoglycoprotein receptor subunits, therefore, raising the possibility that the lag in degradation in the susceptible host is a defect in this common ER degradation pathway. Thus, these data provide evidence that other genetic traits that affect the fate of the abnormal alpha 1-AT Z molecule, at least in part, determine susceptibility to liver disease. These data also validate a system for elucidating the biochemical/genetic characteristics of these traits and for examining the relevance to human disease of pathways for protein degradation in the ER.
Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. Mahadeva R, Chang WS, Dafforn TR, Oakley DJ, Foreman RC, Calvin J, Wight DG, Lomas DA. Respiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom	J Clin Invest 1999 Apr;103(7):999-1006 Abstract quote The association between Z alpha1-antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z alpha1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S alpha1-antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z alpha1-antitrypsin and another conformationally unstable variant (I alpha1-antitrypsin; 39Arg-->Cys) identified in a 34-year-old man with cirrhosis related to alpha1-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z alpha1-antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT. King MA, Stone JA, Diaz PT, Mueller CF, Becker WJ, Gadek JE. Department of Radiology, Ohio State University Hospitals, Columbus 43210, USA.	Radiology 1996 Apr;199(1):137-41 Abstract quote PURPOSE: To assess bronchiectasis depicted with computed tomography (CT) in patients with alpha 1-antitrypsin deficiency and to examine associated clinical correlates. MATERIALS AND METHODS: CT scans in 14 patients with alpha 1-antitrypsin deficiency were evaluated by two thoracic radiologists for the presence and extent of bronchiectasis and emphysema. The findings were correlated with numeric infection scores on the basis of symptoms of sputum production and respiratory infection and with a history of conditions that may predispose to development of bronchiectasis. RESULTS: Six (43%) of 14 patients had CT evidence of bronchiectasis. Patients with bronchiectasis had significantly higher infection scores than did patients without bronchiectasis (P < .005). Two patients had diffuse cystic bronchiectasis, and neither reported a history of illness that may have predisposed them to this condition. CONCLUSION: Bronchiectasis may be more common in patients with alpha 1-antitrypsin deficiency than has been previously recognized. The diagnosis of alpha 1-antitrypsin deficiency should be considered in patients with emphysema and diffuse cystic bronchiectasis.
Repeatability of lung density measurements with low-dose computed tomography in subjects with alpha-1-antitrypsin deficiency-associated emphysema. Stolk J, Dirksen A, van der Lugt AA, Hutsebaut J, Mathieu J, de Ree J, Reiber JH, Stoel BC. Department of Pulmonology (C3-P), Leiden University Medical Center, Leiden, the Netherlands	Invest Radiol 2001 Nov;36(11):648-51 Abstract quote RATIONALE AND OBJECTIVES: Multislice computed tomography (MSCT) of the lungs provides a new opportunity for longitudinal assessment of lung densities because of shorter scan duration. The aim of the present study was to assess the intraindividual variation of lung densities measured by MSCT of patients with emphysema. METHODS: Ten patients with emphysema participated in a study in which MSCT was obtained on two occasions, approximately 2 weeks apart. Scanning parameters were 140 kV, 20 mAs, 4 x 2.5-mm collimation, and effective slice thickness of 2.5 mm. Lung density was measured as the 15th percentile point and the relative area below -910 Hounsfield units (HU) by using Pulmo-LKEB software. RESULTS: The mean difference of the 15th percentile point was -1.29 +/- 3.2 HU, and that for the relative area below the -910-HU parameter was -1.02% +/- 3.09%. Intraclass coefficients of variation were 0.96 (0.86-0.99) and 0.94 (0.8-0.98), respectively (95% confidence interval). CONCLUSIONS: Lung density parameters of emphysema derived by MSCT provide an opportunity for analysis of the treatment effects of new drugs on the progression of emphysema.
LABORATORY MARKERS
SCREENING
Simple method for alpha1-antitrypsin deficiency screening by use of dried blood spot specimens. Costa X, Jardi R, Rodriguez F, Miravitlles M, Cotrina M, Gonzalez C, Pascual C, Vidal R. Dept of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona, Spain.	Eur Respir J 2000 Jun;15(6):1111-5 Abstract quote The use of dried blood spot (DBS) specimens in quantitative alpha1-antitrypsin (alpha1-AT) detection or genetic analysis is limited because protein levels in the samples are low and they contain components that can interfere with polymerase chain reaction amplification. A methodological adaptation was developed to overcome these drawbacks which is discussed here. The study population consisted of 200 healthy volunteers and 300 patients with chronic obstructive pulmonary disease (COPD). DBS specimens were tested for alpha1-AT concentration using a modified nephelometric assay and phenotyped with an isoelectric focusing method. Genetic diagnosis was established by deoxyribonucleic acid sequencing using a simple purification procedure to remove contaminants. The nephelometric method showed a detection limit of 0.284 mg x dL(-1), corresponding to a serum concentration of 13 mg x dL(-1). The correlation coefficient between alpha1-AT concentrations in DBS versus serum samples was R2=0.8674 (p<0.0001). All 200 healthy individuals had DBS alpha1-AT concentrations >1.9 mg x dL(-1), corresponding to 114 mg x dL(-1) in serum samples. One hundred and twenty-five COPD patients (42%) showed alpha1-AT values <1.8 mg x dL(-1). Twenty patients with the PIZ phenotype had alpha1-AT values lower than 0.64 mg x dL(-1). On the basis of genotyping, one COPD patient was classified as heterozygous (PIMM(heerlen)). Selective elution of contaminants resulted in optimal alpha(1)1-antitrypsin genotyping. Because of its sensitivity and excellent correlation with the standard method, the dried blood spot quantitative assay is a reliable tool for routine measurement of alpha1-antitrypsin.
Pilot detection study of alpha(1) antitrypsin deficiency in a targeted population. Fleming LE, Oquendo S, Bean JA, Tamer R, Finn S, Wanner A. Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami, Florida 33136, USA.	Am J Med Genet 2001 Sep 15;103(1):69-74 Abstract quote Screenings for the genetic disorder alpha(1) antitrypsin deficiency (AAT Deficiency) have been one of two models: large screenings of general populations and small targeted detection programs in high-risk groups. The most appropriate screening and detection methodologies in terms of target populations, subject participation and yield of positive tests, however, have not been well defined. The major objective of this pilot study was to evaluate the effectiveness in terms of participation of two different AAT Deficiency detection programs using a self-administered fingerstick blood test. Individuals ages 30-60 under the care of a pulmonary physician and with a diagnosis of emphysema, COPD, chronic bronchitis, or bronchiectasis were the targeted population. Participants were offered AAT Deficiency testing in the pulmonary physician's office compared with testing offered through mail. Participation (i.e., frequency of subject participation in the detection program) of two different AAT Deficiency detection programs. Non-participation was due to fear of self-administered testing and research studies; women were more likely to participate than men. Eligible subjects were significantly more likely to participate when offered testing by their pulmonary physician in-office (83%) than mail-only (42%) (P < 0.02). Although self-administered genetic testing is available, highest participation in AAT Deficiency detection program was found when offered directly by the physician. This finding may have implications for screening and detection of other genetic diseases. Future studies need to evaluate the yield (i.e., frequency of positive tests) of these detection methodologies in highly targeted populations.
LINKAGE ANALYSIS
Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease. De Tommaso AM, Rossi CL, Escanhoela CA, Serra HG, Bertuzzo CS, Hessel G. Departments of Pediatrics, Medical Genetics, Anatomical Pathology and Clinical Pathology, Faculty of Medical Sciences (FCM), State University of Campinas-UNICAMP, Caixa Postal 6111-13083-970-Campinas, SP, Brazil.	Arq Gastroenterol 2001 Jan-Mar;38(1):63-8 Abstract quote BACKGROUND: Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. OBJECTIVE: The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. PATIENTS AND METHODS: Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq-1 (Z allele). RESULTS: Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. CONCLUSION: These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.
Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases. Silverman EK, Mosley J, Rao DC, Palmer LJ, Province M, Elston RC, Weiss ST, Campbell EJ. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Mass., USA.	Hum Hered 2001;52(4):223-32 Abstract quote Objectives: Severe alpha 1-antitrypsin (A1AT) deficiency is the one proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Familial aggregation has been demonstrated for COPD among individuals who do not have A1AT deficiency, but linkage analysis of COPD has not been reported. To investigate the optimal phenotype definitions and analytical methods for the linkage analysis of COPD, we examined a set of 28 A1AT- deficient families containing 155 individuals. We have used the protease inhibitor (PI) type as a genetic marker rather than a disease gene, and we have performed linkage analysis between PI type and serum A1AT level and spirometry-related phenotypes. Methods: Linkage analysis was performed on the quantitative phenotypes forced expiratory volume at 1 s (FEV(1) as % predicted), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC as % predicted), and serum A1AT level using the variance component approach in SOLAR, the generalized estimating equation approach in RELPAL, and the model-based classical lod score method in LINKAGE. Linkage analysis with qualitative A1AT and spirometry phenotypes was performed using a model-based method (LINKAGE) and a model-free method (GENEHUNTER). Adjustments for smoking effects were investigated under each method. Results: All of the methods demonstrated linkage of PI type to serum A1AT level. Interestingly, however, the other quantitative phenotypes provided only weak evidence for linkage of PI type to lung disease. Better evidence for linkage of lung disease to PI type was found using a moderate or a mild threshold for the definition of airflow obstruction. Conclusions: For linkage analysis of spirometry phenotypes in A1AT deficiency, qualitative phenotypes provided stronger evidence for linkage than quantitative phenotypes. Possible contributors to the stronger evidence for linkage to qualitative spirometry phenotypes include the ascertainment scheme and the nonnormality of the pulmonary function data in PI Z subjects. This study provides guidelines for studies of the genetics of COPD unrelated to A1AT deficiency.
POLYMERASE CHAIN REACTION
Rapid and simple diagnosis of the two common alpha 1-proteinase inhibitor deficiency alleles Pi*Z and Pi*S by DNA analysis. Braun A, Meyer P, Cleve H, Roscher AA. Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universitat Munchen, Abteilung fur Klinishce Chemie und Biochemie, Germany.	Eur J Clin Chem Clin Biochem 1996 Sep;34(9):761-4 Abstract quote We describe a simple DNA-based method to assign the two common alpha 1-proteinase inhibitor (alpha 1-antitrypsin) deficiency alleles in the Pi-system (Pi*Z and Pi*S). Two sets of mutated primers are used in the polymerase chain reaction (PCR), followed by a restriction enzyme digest of the products. The mutated forward primers create a Taq I site only if the wildtype alleles (mostly M or subtypes) are present and not in the presence of the Pi*Z or Pi*S alleles. The reverse primers are mutated for an invariant Taq I site which serves as an internal control site in order to assure the completion of the restriction enzyme digest. The digested PCR products can be clearly resolved by 2.5% MetaPhore-agarose gel electrophoresis. This simple PCR probing of the most common alpha 1-antiproteinase deficiency alleles can be routinely applied either to samples showing quantitatively decreased alpha 1-antiproteinase values in serum or to blood spots of Guthrie cards used for mass screening purposes. In addition, this method may provide the opportunity for a simple, rapid, and reliable prenatal diagnosis of alpha 1-antiproteinase deficiency in special cases.
Rapid analysis of alpha1-antitrypsin PiZ genotype by a real-time PCR approach. Ortiz-Pallardo ME, Zhou H, Fischer HP, Neuhaus T, Sachinidis A, Vetter H, Bruning T, Ko Y. Medizinische Universitats-Poliklinik Bonn, Germany.	J Mol Med 2000;78(4):212-6 Abstract quote alpha1-Antitrypsin (AAT) deficiency is a common inherited cause of emphysema and cirrhotic liver disease. Current laboratory diagnosis of Pi (proteinase inhibitor) status by protein analysis depends on the availability of blood samples and has a limited accuracy. Single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing can be performed from blood cells or from tissue samples, but it is a time-consuming procedure not suitable for screening purposes. We used a Light-Cycler assisted PCR approach to identify the PiZ mutation and to determine hetero- and homozygous carrier status from whole blood and from paraffin-embedded archival tissue specimens. The results were compared to those obtained by standard PCR amplification followed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR identified heterozygous PiZ mutations in 16 samples, a homozygous PiZ status in three cases, and wild-type PiM in five control samples. In all cases the results were confirmed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR has a high detection rate for the PiZ mutation. It can be performed from blood or from fixed archival tissues, requires only small amounts of DNA, and allows a rapid diagnosis on a high output level.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
LIVER AND LUNG DISEASE
Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ). von Schonfeld J, Breuer N, Zotz R, Liedmann H, Wencker M, Beste M, Konietzko N, Goebell H. Department of Gastroenterology, University Clinic, Essen, Germany.	Digestion 1996;57(3):165-9 Abstract quote Alpha 1-Antitrypsin deficiency predisposes to pulmonary emphysema, liver cirrhosis and hepatocellular carcinoma. Anecdotal evidence and a large autopsy study suggest that severe lung and liver disease rarely coexist in the same subject, but this has not been studied in patients. Therefore we investigated 27 patients with severe alpha 1-deficiency (Pi ZZ) and pulmonary emphysema for signs of liver disease and impaired hepatic function. A subgroup of 7 patients underwent quantitative liver function tests. On physical examination or ultrasonography, cirrhosis or tumor was not suspected in any patient. Conventional liver function tests were completely normal in 17 patients. Elevated serum activities of gamma-glutamyltranspeptidase and/or aminotransferases were seen in 10 patients. In some, the elevation was only marginal and in none more than twice normal. The serum bilirubin concentration and activity of alkaline phosphatase were increased in 1 patient. Serum protein, albumin, fibrinogen, antithrombin III, alpha 1-fetoprotein concentrations, serum activities of cholinesterase and glutamate dehydrogenase, activated partial thromboplastin time and prothrombin time were normal in all patients. The indocyanine green half-life was abnormal only in 1 of 6 patients, suggesting that hepatic blood flow was not impaired in the study group. However, the lidocaine half-life and galactose elimination capacity, parameters of hepatic metabolization, were impaired in 4 and 6 of 7 patients, respectively. We conclude that liver disease or impaired liver function is not a clinically relevant problem in most patients with pulmonary emphysema due to alpha 1-antitrypsin deficiency. But results of quantitative liver function tests, although performed in only a small group of patients, suggest that hepatic metabolization might be impaired even in those patients who present with pulmonary disease.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
KIDNEY
Alpha-1-Antitrypsin Deficiency and Nephropathy. Montanelli A, Mainardi E, Pini L, Corda L, Grassi V. Department of Clinical Pathology, Ospedale Maggiore of Crema, Italy.	Nephron 2002 Jan;90(1):114-115 Abstract quote Glomerulonephritis occurring in association with alpha(1)-antitrypsin deficiency has been sporadically reported in the literature but it is assumed to be a rare and poorly investigated disease. The complete pathologic pattern of glomerular lesions has not yet been established. The aim of our work was to investigate the correlation between the extent of antiprotease deficiency and the expression of nephropathy evaluated in two groups of patients (47 heterozygotic subjects with the PiMZ phenotype and 12 homozygotic subjects with the PiZZ phenotype) by a noninvasive approach with urinalyses and proteinuria measurement. No statistical differences between proteinuria in the two groups were observed suggesting that nephropathy is not a direct and single expression of the protein deficiency.
LIVER
Liver cell dysplasia in alpha-1-antitrypsin deficiency. Cohen C, Derose PB. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.	Mod Pathol 1994 Jan;7(1):31-6 Abstract quote Large cell liver cell dysplasia (LCD), a suggested preneoplastic change progressing to hepatocellular carcinoma, has been reported associated with alpha-1-antitrypsin deficiency which in some countries has an increased frequency of hepatocellular carcinoma. We examined the nonneoplastic liver from 13 alpha-1-antitrypsin deficiency patients for LCD and, using a labeled streptavidin-biotin technique, for immunohistochemical markers: AAT (1/200), hepatitis B surface (HBsAg, prediluted) and core (HBcAg, 1/400) antigens, and monoclonal (1/20) and polyclonal (1/40) mutant p53, a tumor suppressor gene. There were eight males and five females ranging from 2 mo to 76 yr (mean 40 yr). Nine livers showed cirrhosis, one chronic persistent hepatitis, one portal fibrosis, and two cholestatic hepatitis (in the two infants). The nine cases with LCD included five males and four females of mean age 46 yr (range, 17-71), eight with cirrhosis and one with portal fibrosis. Only one liver with LCD and cirrhosis had HBcAg in cirrhotic and dysplastic cells. No patient had developed hepatocellular carcinoma. All 13 livers were immunonegative for HBsAg and mutant p53, and immunopositive for AAT present in normal, cirrhotic, and dysplastic liver cells. Thus, LCD was identified in 82% of adult alpha-1-antitrypsin deficiency livers (69% including infantile patients), 89% with cirrhosis, and none with malignancy. HB expression was rarely present; serology for HB and/or hepatitis C was positive in 46% adults. Immunoreactive AAT was present in dysplastic cells. p53 gene mutations do not appear to have a role in the pathogenesis of LCD in alpha-1-antitrypsin deficiency.
Objective ranking of fibrosis in standard histologic sections of human neonatal liver: applicability to alpha1-antitrypsin deficiency. Moustafellos E, Illueca M, Remotti HE, Auld PA, Hanauske-Abel HM. Department of Pediatrics, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York 10021, USA.	J Pediatr Gastroenterol Nutr 2000 May;30(5):503-8 Abstract quote BACKGROUND: The etiologic heterogeneity of fibrotic liver disease has resulted in the formulation of diverse, often disease-specific, classification systems for biopsy assessment, based on tissue morphology and staining. Their qualitative nature and observer dependency remain a concern, and no classification exists for several significant conditions--for example, alpha1-antitrypsin deficiency (alpha1-ATD). The authors propose a disease- and morphology-independent numeric ranking system to objectively quantify fibrosis in a standard histologic section, based on its content of protein amino acids. This PNC system is applied to two cases of alpha1-ATD liver fibrosis. METHODS: High-performance liquid chromatography separation of the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-labeled acid hydrolysate of an individual needle biopsy section, followed by the calculation of specific amino acid ratios to eliminate confounding variables. RESULTS: As required by the PNC system, three numeric values were identified per tissue section, one increasing (P quotient), one decreasing (N quotient), one constant (C quotient) as fibrosis progresses, assessed by calibration against Knodell-staged samples. Generated for the alpha1-ATD sections, these three coordinates numerically referenced the degree of fibrosis in a manner that in each case was consistent with the histologic evaluation, the laboratory values, and the clinical course. CONCLUSIONS: Numeric, objective referencing of the degree of fibrosis in routine liver biopsy sections, based on the PNC system, is technically possible.
Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. Volpert D, Molleston JP, Perlmutter DH. Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, Missouri 63110, USA.	J Pediatr Gastroenterol Nutr 2000 Sep;31(3):258-63 Abstract quote BACKGROUND: A prospective nationwide screening study initiated more than 20 years ago in Sweden has shown that clinically significant liver disease develops in only 10% to 15% of alpha1-antitrypsin (AT)-deficient children. This study provides information about 85% to 90% of those children, many of whom had elevated serum transaminases in infancy but have no evidence of liver injury by age 18 years. However, there is relatively limited information about the course of alpha1-AT-deficient children who have cirrhosis or portal hypertension. Based on several anecdotal experiences, we have been impressed by the relatively slow progression and stable course of the liver disease in some of these children. METHODS: We reviewed the course of patients with homozygous PIZZ alpha1-antitrypsin deficiency seen at this institution since establishing a patient database 16 years ago. RESULTS: Of 44 patients with alpha1-AT deficiency, 17 had cirrhosis, portal hypertension, or both. Nine of the 17 patients with cirrhosis or portal hypertension had a prolonged, relatively uneventful course for at least 4 years after the diagnosis of cirrhosis or portal hypertension. Two of these patients eventually underwent liver transplantation, but seven are leading relatively healthy lives for up to 23 years while carrying a diagnosis of severe alpha1-AT deficiency-associated liver disease. Patients with the prolonged stable course could be distinguished from those with a rapidly progressive course on the basis of overall life functioning but not on the basis of any other more conventional clinical or biochemical criteria. CONCLUSIONS: These data provide further evidence for the variable severity of liver disease associated with alpha1-AT deficiency and indicate that some patients have chronic, slowly progressing or nonprogressing cirrhosis.
Chronic liver disease in heterozygous alpha1-antitrypsin deficiency PiZ. Fischer HP, Ortiz-Pallardo ME, Ko Y, Esch C, Zhou H. Department of Pathology, University of Bonn, Germany.	J Hepatol 2000 Dec;33(6):883-92 Abstract quote BACKGROUND/AIMS: The contribution of the heterozygous state PiZ of alpha1-antitrypsin deficiency (AATD) to the pathogenesis of chronic liver disease is debated. We analyzed whether patients with this genetic defect carrying a single PiZ gene are at increased risk for developing chronic liver disease. METHODS: 1847 consecutive biopsy cases and 1030 autopsy cases of Caucasian adults were screened immunohistochemically for PiZ deposits. The zygosity status was analyzed by single-strand conformational polymorphism (SSCP) and by sequencing DNA extracted from paraffin-embedded tissue. RESULTS: All analyzed biopsy cases were heterozygous for the PiZ mutation. The biopsy group revealed a significantly higher rate of PiZ-positive cases (3.4%) than the autopsy group (1.8%) (p=0.019). PiZ deposits ranged from scarce granules to extensive globular inclusions as in homozygous AATD of PiZ type. The extent of PiZ deposits correlated well with the inflammatory activity and stage of fibrosis. Cirrhotic livers contained globular PiZ deposits significantly more often than the biopsies with minor fibrosis. PiZ-positive biopsies from patients without concurrent liver disease (n= 26) revealed only minor fibrosis in the age group between 20 and 39 years, but significantly more severe fibrosis and significantly more PiZ deposits in the older age groups. Biopsies with concurrent liver disease (n=28) presented with significantly more severe inflammation and fibrosis, and more PiZ deposits than the cases without concurrent liver disease. CONCLUSIONS: Patients with heterozygous AATD of PiZ type bear an increased risk for chronic liver disease. If at all, this genetic defect will become clinically relevant only in middle-aged or old adults. It rarely causes liver cirrhosis even without concurrent liver disease. It can aggravate or can be aggravated by advanced coexistent chronic liver diseases. PiZ immunohistochemistry is an easy, highly specific method to detect this metabolic defect on liver biopsies.
SKIN
A subtle clue to the histopathologic diagnosis of early alpha 1-antitrypsin deficiency panniculitis. Geller JD, Su WP. Department of Dermatology, Mayo Clinic, Rochester, MN 55905.	J Am Acad Dermatol 1994 Aug;31(2 Pt 1):241-5 Abstract quote An excisional biopsy specimen of a lesion of several days' duration in an 18-year-old woman revealed moderate splaying of neutrophils between collagen bundles throughout the reticular dermis and incipient necrosis of the dermis and subcutaneous fat. Mild infiltration of neutrophils and macrophages was seen in the septal and lobular panniculus. A biopsy performed on one of the patient's more chronic lesions demonstrated dermal necrosis, degeneration and fibrosis of septa, acute lobular panniculitis with a large number of neutrophils, and foci of subcutaneous fat necrosis with islands of sparing. Splaying of neutrophils between the collagen bundles in the reticular dermis appears to be the earliest histopathologic finding of alpha 1-antitrypsin deficiency panniculitis.
Panniculitis revealing qualitative alpha 1 antitrypsine deficiency (MS variant). Loche F, Tremeau-Martinage C, Laplanche G, Massip P, Bazex J. Department of Dermatology, Purpan Hospital, place du Docteur-Baylac 31059 Toulouse Cedex, France.	Eur J Dermatol 1999 Oct-Nov;9(7):565-7 Abstract quote A 16-year-old girl presented painful, red, nodular lesions on the abdomen. A cutaneous biopsy showed inflammatory cell infiltrate and fibrosis in the dermis and in the septa with isolated adipocyte lobules. alpha1-antitrypsin level was found to be normal but M1S phenotype of alpha1-antitrypsin was determined by isoelectric focusing in polyacrylamide gel. alpha1-antitrypsin level was normal for her family but M2S phenotype was found in her father. Alpha 1-antitrypsin (alpha1 AT) deficiency is a common hereditary disorder of Caucasians. The locus is pleiomorphic and 75 alleles have been identified. Numerous pathological mutations can be classified by the mechanisms which cause the deficiency. The major clinical importance of this deficiency is emphysema and liver disease. Panniculitis is rarely reported and seems to occur principally for the ZZ or MZ phenotype and for low levels of alpha1 AT. MS phenotype has been more rarely reported and triggering agents such as trauma and infections must be present. However, normal levels of alpha1 AT in the serum have previously been reported as in our case, and we suggest the study of alpha1 AT phenotype even if the plasma level is normal.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS	PAS with diastase resistant globules within the hepatocytes
IMMUNOPEROXIDASE

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Neonatal causes of hepatitis
Emphysema

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases. Seersholm N, Kok-Jensen A, Dirksen A. Department of Pulmonology, Bispebjerg Hospital, Copenhagen, Denmark.	Thorax 1994 Jul;49(7):695-8 Abstract quote BACKGROUND--Previous estimates of the survival times of patients with alpha 1-antitrypsin deficiency have been based on selected patients. METHODS--The survival times of 397 patients with severe alpha 1-antitrypsin deficiency identified by pulmonary impairment (index cases) or through family studies (non-index cases) were compared. RESULTS--The overall median survival time was 54.5 years with no significant difference between men and women. Survival for index cases was less than for the non-index cases regardless of smoking history (49.4 years and 69.3 years respectively). When index and non-index cases were analysed separately there was no difference between the survival of smokers and never smokers in the index group. In the non-index group smokers had a shorter survival time than never smokers. The survival time of never smokers was similar to that of the normal Danish population. CONCLUSIONS--The prognosis of severe alpha 1-antitrypsin deficiency is better than previously assumed and, although smoking is a major risk factor, the development of emphysema in patients with severe alpha 1-antitrypsin deficiency is multifactorial.
Prognosis and life expectancy on alpha-1-antitrypsin deficiency and chronic liver disease. Propst A, Propst T, Ofner D, Feichtinger H, Judmaier G, Vogel W. Dept. of Internal Medicine, Innsbruck University, Austria	Scand J Gastroenterol 1995 Nov;30(11):1108-12 Abstract quote BACKGROUND: Alpha-1-antitrypsin deficiency is a common autosomal recessive disorder associated with early development of emphysema, liver cirrhosis, and hepatocellular carcinoma. The aim of the present study was to define prognosis and life expectancy in patients with alpha 1-antitrypsin deficiency with and without chronic liver disease. METHODS: After a follow-up of 15 years the estimated life table analysis of mortality of 160 patients with alpha 1-antitrypsin deficiency was retrospectively calculated. The survival time was estimated using the Kaplan-Meier survival curves and was compared with the life expectancy of the age- and sex-matched population of west Austria. RESULTS: Fifty-four patients with alpha 1-antitrypsin patients had evidence of chronic liver disease; of these, 78% showed positive viral markers. Of the 106 patients with alpha 1-antitrypsin deficiency without chronic liver disease none had evidence of additional viral infection. Life expectancy in patients with alpha-1 antitrypsin deficiency and chronic liver disease was significantly lower than in patients with alpha 1-antitrypsin deficiency without chronic liver disease (p = 0.001). No difference in life expectancy in alpha 1-antitrypsin deficiency without chronic liver disease was found in comparison with that of the normal population. CONCLUSIONS: We suggest that in alpha 1-antitrypsin deficiency-associated chronic liver disease it is the high coinfection rather than the inborn error of metabolism itself that is responsible for a deterioration of life expectancy or for the poor prognosis of the disease.
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? Elzouki AN, Eriksson S. Department of Medicine, Lund University, University Hospital, Malmo, Sweden.	Eur J Gastroenterol Hepatol 1996 Oct;8(10):989-94 Abstract quote 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 Malmo, 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.
Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group.	Am J Respir Crit Care Med 1998 Jul;158(1):49-59 Abstract quote Subjects >= 18 yr of age with serum alpha1-antitrypsin (alpha1-AT) levels <= 11 microM or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1, 048 subjects who had been contacted >= 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0. 43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV1 measurements >= 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups (p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.
Alpha1-antitrypsin deficiency allele carriers among lung cancer patients. Yang P, Wentzlaff KA, Katzmann JA, Marks RS, Allen MS, Lesnick TG, Lindor NM, Myers JL, Wiegert E, Midthun DE, Thibodeau SN, Krowka MJ. Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.	Cancer Epidemiol Biomarkers Prev 1999 May;8(5):461-5 Abstract quote Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD with LC, few studies examined the association of alpha1AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with >70 variants reported. There are at least 10 alleles associated with deficiency in alpha1-antitrypsin. Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). alpha1AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, P < or = 0.01, respectively). Our preliminary findings suggest that individuals who carry an alpha1AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.
Is heterozygous alpha-1-antitrypsin deficiency type PIZ a risk factor for primary liver carcinoma? Zhou H, Ortiz-Pallardo ME, Ko Y, Fischer HP. Department of Pathology, University of Bonn, Germany.	Cancer 2000 Jun 15;88(12):2668-76 Abstract quote BACKGROUND: It is well known that homozygotes with alpha-1-antitrypsin deficiency type PiZ are associated with an increased risk of chronic liver disease and liver carcinoma. The aim of this study was to determine whether heterozygous PiZ status is a risk factor for liver carcinoma development. METHODS: Three hundred seventeen consecutive primary liver carcinomas and the tumor-bearing liver tissue (tumor series) from adult patients were screened immunohistochemically for hepatocellular PiZ deposits. Liver specimens from 1663 consecutive adult patients (biopsy series) and liver tissue from 1030 consecutive adult autopsies (autopsy series) served as controls. The zygosity status of alpha-1-antitrypsin was verified by analysis of single strand conformational polymorphism and by sequencing DNA extracted from paraffin embedded tissue. RESULTS: The PiZ frequency in the tumor series (5.99%) was significantly higher than in the biopsy series (3.43%) or the autopsy series (1.84%). Cholangiocarcinomas and/or combined hepatocholangiocarcinomas were seen significantly more frequently in PiZ-associated liver carcinomas (57.9%) than in non-PiZ-associated carcinomas (27.2%). Cirrhosis was found in only 3 of the 19 PiZ-associated carcinomas. The remaining 16 livers showed varying stages of fibrosis or normal tissue. All nine cases with PiZ-associated liver carcinoma suitable for genetic analysis showed heterozygous PiZ mutations. CONCLUSIONS: Heterozygotes of type PiZ are associated with an increased risk of primary liver carcinoma. PiZ-associated carcinoma may develop in noncirrhotic liver tissue and without concurrent liver disease, and is frequently characterized by cholangiocellular differentiation. The site specific antibody ATZ11 is a reliable morphologic tool for detecting PiZ individuals.
Longitudinal Changes in Physiological, Radiological, and Health Status Measurements in alpha(1)-Antitrypsin Deficiency and Factors Associated with Decline. Dowson LJ, Guest PJ, Stockley RA. Lung Investigation Unit, Nuffield House, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham, United Kingdom.	Am J Respir Crit Care Med 2001 Nov 15;164(10):1805-1809 Abstract quote The FEV(1) declines rapidly in alpha(1)-antitrypsin deficiency (alpha(1)-ATD) but less is known about other measures of disease severity and the factors, other than smoking, that are associated with progression of emphysema. The natural history of alpha(1)-ATD was studied prospectively in 43 patients with the PiZ phenotype and emphysema at a single center over 2 yr. The mean +/- SE change in FEV(1) was -67 +/- 14 ml/yr, accompanied by a reduction in transfer factor (mean change in diffusing capacity of the lung for CO [DL(CO)] -1.07 +/- 0.21 ml/min/mm Hg/yr; p < 0.001) and lung density in the upper zones as assessed by quantitative high-resolution computed tomography (HRCT) (mean change in voxel index 2.8 +/- 0.6%/yr; p < 0.001). The decline in FEV(1) related to baseline FEV(1) (r = -0.56, p < 0.001), bronchodilator reversibility (r = 0.52, p < 0.001), and (for patients with FEV(1) > 35% predicted) exacerbation frequency (r = -0.38, p = 0.02). There was also a decline in the St. George's Respiratory Questionnaire (SGRQ) Activity score (mean change -4.3 +/- 1.2 units/yr, p < 0.001) that correlated with FEV(1) decline (r = 0.45, p = 0.002). Progression of emphysema in alpha(1)-ATD is dependent on baseline physiology and exacerbation frequency and may be detected by several different measurements of which HRCT density mask analysis and DL(CO) appear most sensitive.
TREATMENT
LIVER TRANSPLANTATION
Liver transplantation for end-stage liver disease associated with alpha-1-antitrypsin deficiency in children: pretransplant natural history, timing and results of transplantation. Filipponi F, Soubrane O, Labrousse F, Devictor D, Bernard O, Valayer J, Houssin D. Clinique Chirurgicale, Hopital Cochin, Paris, France.	Hepatol 1994 Jan;20(1):72-8 Abstract quote Alpha-1-antitrypsin deficiency is an inborn metabolism error which can cause emphysema and liver disease. As regards the pathophysiology of liver disease, this deficiency is poorly understood, and it is also not known why only a small proportion of Pi ZZ individuals progress towards cirrhosis and liver failure. Since there is no specific therapy for end-stage liver disease associated with alpha-1-antitrypsin deficiency, patients are considered candidates for liver transplantation. In this paper, the natural history of 16 children who underwent liver transplantation is reviewed. Fourteen patients had neonatal cholestasis as a first symptom of the disease and hepatosplenomegaly was present in all children by the age of 12 months. In 11 children, jaundice recurred, always with liver function deterioration. Two patients had a histological paucity of interlobular bile ducts and required early transplantation due to rapid progression of liver failure. At the time of pretransplant assessment, all the patients in this study had portal hypertension and seven of them had experienced at least one episode of gastrointestinal bleeding. One child had moderate intrapulmonary shunts with hypoxemia, but the others had normal spirometry and blood gases. There was no other extrahepatic complication of alpha-1-antitrypsin deficiency. Eighteen orthotopic liver transplantations were performed in 16 patients. One patient died 8 days after retransplantation due to graft necrosis. \Fifteen patients (94%) were alive after a median follow-up of 22 months with an excellent quality of life, normal serum alpha-1-antitrypsin levels and without evidence of liver disease recurrence or pulmonary complications.
Liver transplantation for alpha-1-antitrypsin deficiency in children. Prachalias AA, Kalife M, Francavilla R, Muiesan P, Dhawan A, Baker A, Hadzic D, Mieli-Vergani G, Rela M, Heaton ND. Liver Transplant Surgical Service, King's College Hospital, Denmark Hill, London, UK.	Transpl Int 2000;13(3):207-10 Abstract quote Alpha-1-antitrypsin (a1-AT) deficiency is an inborn error of metabolism, which can cause liver disease. The condition is one of the most common genetic disorders in the Caucasian population. Here we review our experience with 21 children suffering from end-stage liver disease due to a1-AT deficiency. All children are PIZZ homozygotes. Nineteen of them initially presented with neonatal jaundice and two with hepatosplenomegaly in childhood. Twenty-five liver transplantations were performed. All children are currently alive at a median followup of 40 months. Liver replacement provides the only definite treatment for children with end-stage liver disease associated with a1-AT deficiency. Excellent results can be achieved by reducing waiting time for transplantation and by early referral to a liver transplant centre.
ALPHA-1-ANTITRYPSIN SUPPLEMENTATION
A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DC, Ulrik CS, Skovgaard LT, Kok-Jensen A, Rudolphus A, Seersholm N, Vrooman HA, Reiber JH, Hansen NC, Heckscher T, Viskum K, Stolk J. Department of Respiratory Medicine, The Rigshospital, Copenhagen, Denmark.	Am J Respir Crit Care Med 1999 Nov;160(5 Pt 1):1468-72 Abstract quote We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.
Short-term supplementation therapy does not affect elastin degradation in severe alpha(1)-antitrypsin deficiency. The American-Italian AATD Study Group. Gottlieb DJ, Luisetti M, Stone PJ, Allegra L, Cantey-Kiser JM, Grassi C, Snider GL. Department of Medicine, Boston University School of Medicine, MA 02118-2394, USA.	Am J Respir Crit Care Med 2000 Dec;162(6):2069-72 Abstract quote We evaluated the ability of intravenous supplementation therapy with alpha(1)-antitrypsin (AAT) to reduce the rate of urinary excretion of desmosine (DES), a specific marker of elastin degradation, in eight men and four women with emphysema due to severe, congenital deficiency of AAT (range 17-69 mg/dl). Nine were former cigarette smokers, two were current smokers, and one reported never smoking; their mean age was 54 (SD 12) yr and their mean FEV(1) was 41 (18%) of predicted. Urinary DES was measured by isotope dilution and HPLC. Prior to the start of AAT supplementation, mean DES excretion was 13.0 (5.0) microg/g creatinine, 73% higher than in healthy nonsmokers. During 8 wk of supplementation therapy, mean urinary DES excretion was 13.0 (5.9) microg/g creatinine, unchanged from the baseline period (p = 0.85 by repeated measures ANOVA). We conclude that baseline levels of elastin degradation in emphysematous patients with severe AAT deficiency were abnormally high and that 8 wk of AAT supplementation therapy did not appreciably reduce the rate of elastin degradation. These findings raise the possibilities that protective levels of AAT in the lungs are insufficient or that elastin degradation in the lungs of these subjects is not dependent upon neutrophil elastase at this time.
Alpha1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Abboud RT, Ford GT, Chapman KR Stnadards Committee of the Canadian Thoracic Society. University of British Columbia, Vancouver, Canada.	Can Respir J 2001 Mar-Apr;8(2):81-8 Abstract quote OBJECTIVE: To prepare new guidelines for the Canadian Thoracic Society (CTS) regarding severe alpha1-antitrypsin (AAT) deficiency and AAT replacement therapy. MATERIALS AND METHODS: Previously published guidelines and the medical literature about AAT deficiency and AAT replacement were reviewed. The prepared statement was reviewed and approved by the CTS Standards and Executive Committees. RESULTS: Three studies evaluated AAT replacement. The National Heart, Lung and Blood Institute's AAT Registry was a nonrandomized comparison of patients receiving and not receiving AAT replacement, and evaluated the decline in forced expiratory volume in 1 s (FEV1) in 927 subjects. The rate of FEV1 decline was significantly less in those receiving AAT treatment (66 +/- SE 5 mL/year versus 93 +/- SE 11 mL/year; P=0.03) only in the subgroup with FEV1 35% to 49% predicted. In another study comparing 198 German patients receiving weekly AAT infusions and 97 untreated Danish patients, the mean annual decline in FEV1 was significantly less in treated patients only in the subgroup with FEV1 31% to 65% predicted (62 mL versus 83 mL, P=0.04). Neither of these studies was a randomized, controlled study and, thus, cannot be taken as proof of efficacy. A randomized, double-blind, placebo controlled trial of monthly replacement therapy over three years in 56 exsmokers with severe AAT deficiency and moderate emphysema showed a trend (P=0.07) favouring slower progression of emphysema by computed tomography scan in the group receiving AAT replacement. CONCLUSIONS: AAT replacement therapy has not been proven definitively to be clinically effective in reducing the progression of disease in AAT-deficient patients, but there is a possible benefit to selected patients. A placebo controlled, randomized clinical trial of AAT replacement therapy is required. The authors recommend reserving AAT replacement therapy for AAT-deficient patients with impaired FEV1 of 35% to 50% predicted who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1, and participation of all AAT-deficient subjects in the Canadian AAT Registry.
ALPHA-PROTEASE INHIBITOR SUPPLEMENTATION
Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Wencker M, Fuhrmann B, Banik N, Konietzko N; Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen. Ruhrlandklinik, Department of Pneumology, University Hospital, Essen, Germany.	Chest 2001 Mar;119(3):737-44 Abstract quote BACKGROUND: The efficacy of IV augmentation therapy with human alpha(1)-protease inhibitor (alpha(1)-Pi) in patients with severe alpha(1)-Pi deficiency is still under debate. STUDY OBJECTIVES: To evaluate the progression of emphysema in patients with alpha(1)-Pi deficiency before and during a period in which they received treatment with alpha(1)-Pi. DESIGN: Multicenter, retrospective cohort study. SETTING: Outpatient clinics of 26 university clinics and pulmonary hospitals. PATIENTS: Ninety-six patients with severe alpha(1)-Pi deficiency receiving weekly augmentation therapy with human alpha(1)-Pi, 60 mg/kg of body weight, had a minimum of two lung function measurements before and two lung function measurements after augmentation therapy was started. Lung function data were followed up for a minimum of 12 months both before and during treatment (mean, 47.5 months and 50.2 months, respectively). MEASUREMENTS AND RESULTS: Patients were grouped according to the severity of their lung function impairment. The change in FEV(1) was compared during nontreatment and treatment periods. In the whole group, the decline in FEV(1) was significantly lower during the treatment period (49.2 mL/yr vs 34.2 mL/yr, p = 0.019). In patients with FEV(1) > 65%, IV alpha(1)-Pi treatment reduced the decline in FEV(1) by 73.6 mL/yr (p = 0.045). Seven individuals had a rapid decline of FEV(1) before treatment, and the loss in FEV(1) could be reduced from 256 mL/yr to 53 mL/yr (p = 0.001). CONCLUSION: Some patients with severe alpha(1)-Pi deficiency and well-preserved lung function show a rapid decline in FEV(1). These patients profit from weekly IV therapy with human alpha(1)-Pi and have less rapid decline if treated. Early detection of patients at risk and early start of augmentation therapy may prevent accelerated loss of lung tissue.
GENE THERAPY
Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy. Brigham KL, Lane KB, Meyrick B, Stecenko AA, Strack S, Cannon DR, Caudill M, Canonico AE. Center for Lung Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.	Hum Gene Ther 2000 May 1;11(7):1023-32 Abstract quote We sought to determine whether a normal alpha1-antitrypsin (AAT) gene could be expressed in respiratory epithelium and whether local expression would have antiinflammatory effects. In an unblinded study, we delivered a normal AAT gene in a plasmid-cationic liposome complex to one nostril of each of five subjects with AAT deficiency; the other, untreated nostril served as a control. AAT protein concentration in nasal lavage fluid (NALF) increased in the transfected nostril (TN), but not in the control nostril (CN), of every subject, peaking on day 5 at levels about one-third normal (baseline CN, 4.1 +/- 1.2 microg/mg of protein; baseline TN, 4.3 +/- 1.3; day 5 CN, 4.0 +/- 0.5 [p = NS versus baseline]; day 5 TN, 9.0 +/- 1.7 [p < 0.5 versus baseline]); isoelectric focusing identified the transgene-generated protein (M) in the only two patients in whom the measurement was possible. The reverse transcriptase-polymerase chain reaction (RT-PCR), performed on NALF from TN and CN of four of the five subjects, was positive for transgene message in TN in all cases and negative in NALF from CN except for one time point in one subject. Interleukin 8 (IL-8) concentrations in NALF were elevated at baseline (normal [N = 10] = 2.5 +/- 0.5 ng/mg of protein; baseline TN = 5.5 +/- 0.8, p < 0.05 versus normal) and decreased after AAT transfection (TN = 2.9 +/- 0.6, p < 0.05 versus baseline) but not in the control nostril (CN = 6.5 +/- 2.2, p = NS versus baseline). NALF samples taken from four of the patients while receiving intravenous AAT protein showed normal concentrations of AAT, but IL-8 concentrations (10.5 +/- 4.2 ng/mg of protein, p = NS versus baseline) were not decreased from baseline. We conclude that plasmid-cationic liposome delivery of a normal AAT gene to the respiratory epithelium of deficient patients produces potentially therapeutic local AAT concentrations and that AAT gene therapy, unlike AAT protein therapy, is antiinflammatory.
PBA
Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Burrows JA, Willis LK, Perlmutter DH. Departments of Pediatrics, Washington University School of Medicine, Division of Gastroenterology and Nutrition, Children's Hospital, St. Louis, MO 63110, USA.	Proc Natl Acad Sci U S A 2000 Feb 15;97(4):1796-801 Abstract quote In alpha1-AT deficiency, a misfolded but functionally active mutant alpha1-ATZ (alpha1-ATZ) molecule is retained in the endoplasmic reticulum of liver cells rather than secreted into the blood and body fluids. Emphysema is thought to be caused by the lack of circulating alpha1-AT to inhibit neutrophil elastase in the lung. Liver injury is thought to be caused by the hepatotoxic effects of the retained alpha1-ATZ. In this study, we show that several "chemical chaperones," which have been shown to reverse the cellular mislocalization or misfolding of other mutant plasma membrane, nuclear, and cytoplasmic proteins, mediate increased secretion of alpha1-ATZ. In particular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active alpha1-ATZ in a model cell culture system. Moreover, oral administration of PBA was well tolerated by PiZ mice (transgenic for the human alpha1-ATZ gene) and consistently mediated an increase in blood levels of human alpha1-AT reaching 20-50% of the levels present in PiM mice and normal humans. Because clinical studies have suggested that only partial correction is needed for prevention of both liver and lung injury in alpha1-AT deficiency and PBA has been used safely in humans, it constitutes an excellent candidate for chemoprophylaxis of target organ injury in alpha1-AT deficiency.
PANNICULITIS TREATMENT
Panniculitis associated with severe alpha 1-antitrypsin deficiency. Treatment and review of the literature. Smith KC, Pittelkow MR, Su WP. Department of Dermatology, Mayo Clinic, Rochester, MN 55905.	Arch Dermatol 1987 Dec;123(12):1655-61 Abstract quote Panniculitis associated with homozygous severe alpha 1-antitrypsin deficiency was documented in three women hospitalized for painful cutaneous and subcutaneous ulcerations (severe panniculitis with spontaneous ulceration and drainage of clear or serosanguineous fluid). None had a history of trauma or infection. One patient responded rapidly and completely to treatment with dapsone. One patient, who had more extensive disease, failed to respond to prednisone plus dapsone; infusions of alpha 1-proteinase inhibitor concentrate led to resolution of her panniculitis. One patient who had severe and extensive panniculitis and pleural effusions failed to respond to corticosteroids but did well when both dapsone and infusions of alpha 1-proteinase inhibitor concentrate were added to her treatment program.
alpha 1-antitrypsin deficiency-associated panniculitis: resolution with intravenous alpha 1-antitrypsin administration and liver transplantation. O'Riordan K, Blei A, Rao MS, Abecassis M. Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.	Transplantation 1997 Feb 15;63(3):480-2 Abstract quote Panniculitis is a rare complication of alpha 1-antitrypsin (A1AT) deficiency that is characterized by acute inflammatory infiltrate and fat necrosis. Different treatment strategies are used to provide symptomatic relief. Here we describe two patients with homozygous A1AT deficiency who developed panniculitis and were successfully treated with A1AT replacement. The patient who received a liver transplant experienced complete resolution of the skin lesions. The patient who received A1AT intravenously showed complete response, but the skin lesions recurred when the levels of A1AT fell below 50 mg/100 ml. Panniculitis secondary to A1AT deficiency can be successfully treated with liver transplantation or intravenous infusion of A1AT.

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Congenital and Metabolic

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