Lesson 11, Volume 16—Update on a₁-Antitrypsin Deficiency

By Charlie Strange, MD, FCCP

Objectives

1. Outline the natural history of lung disease associated with a₁-antitrypsin (AAT) deficiency.
2. Define the benefits of AAT-deficiency diagnosis.
3. Review new information on the frequency of AAT-deficiency liver disease.
4. Define current therapy for AAT deficiency.
5. Review future options for AAT-deficiency therapy.

Key words

a₁-antitrypsin deficiency; COPD; emphysema

Abbreviations

AAT = a₁-antitrypsin; DLCO = carbon monoxide diffusing capacity of the lung; NHLBI = National Heart, Lung, and Blood Institute

Alpha₁-antitrypsin (AAT) deficiency is the most commonly recognized genetic abnormality responsible for pulmonary emphysema. Since the discovery of this risk for COPD in 1963 by Laurell and Erickson,¹ studies of gene frequency, patterns of inheritance, clinical manifestations, and natural history of disease have been defined. The most common genetic mutations have been identified; the abnormalities of protein excretion and defects of neutrophil elastase inhibition have been elucidated. Lastly, the protein has been produced recombinantly and trials of replacement therapy with new inhaled products have begun. Although a lifelong cure for this disease remains elusive, the rate of progress that has been made in this disease in the past 40 years has been phenomenal.

Genetics

The Pi (protease inhibitor) ZZ protein abnormality associated with the most common severe deficiency occurs with a frequency of approximately 1/1,600 in Caucasians of northern European descent,² ranging to approximately 1/5,000 in the general US population.³ When compared with other diseases such as cystic fibrosis (frequency 1/2,750), the gene frequency is similar. When applied to the US population, 80,000 to 100,000 individuals are predicted to have PiZZ (also called Pi Z) severe deficiency. It should be noted that < 5,000 persons in the United States are known to carry the diagnosis. One difference between AAT deficiency and cystic fibrosis lies in the fact that AAT deficiency does not universally produce lung disease, particularly in nonsmokers. Because the life expectancy may be near normal in nonsmokers, more individuals live to adulthood. Although disease prevalence is higher in Caucasians, African-American, Hispanic, and Asian populations also have this condition.

Some confusion has been associated with the differentiation between phenotype and genotype in AAT deficiency. Phenotypes in genetic disorders typically refer to the clinical expression of the gene being discussed. However, the clinical expression of AAT deficiency is dependent on the protein being expressed. Bands of protein on electrophoresis were named alphabetically, with the normal protein (designated M) reflecting the genes (genotype) that produce those proteins (phenotype). The most commonly abnormal gene responsible for producing the Pi Z protein (the Glu to Lys substitution at position 342 at the AAT locus on chromosome 14) occurs at a critical point of protein folding that prevents egress of the Pi Z protein from the hepatocyte. Therefore for clinical purposes, expression of protein phenotype will remain the nomenclature used in this disease. Diagnostic testing should request serum AAT phenotype and concentration since the concentration alone is an acute-phase reactant and may change with clinical events.

Lung Disease

Symptomatic obstructive lung disease typically presents between the ages of 32 and 41 years, with persistent symptoms of dyspnea, cough, and wheeze for an average of 5 years before diagnosis.^4,5 These series likely have a selection bias toward younger patients because AAT testing may not be performed as often when COPD presents at 60 to 70 years of age. Most patients who develop symptomatic disease are previous cigarette smokers, although patients who are nonsmokers clearly can develop severe emphysema. Conversely, some patients with AAT deficiency who smoke heavily do not develop emphysema.

Spirometric results and the carbon monoxide diffusing capacity of the lung (Dlco) are usually abnormal once emphysema is established. Both spirometry and measurement of Dlco are necessary to determine degree of impairment, since the two tests are not always well correlated in AAT deficiency.⁶ Patients with severe emphysema can occasionally have a normal FEV₁ or a normal Dlco.

Emphysema in AAT deficiency is usually panacinar, although some patients demonstrate centrilobular disease at autopsy or transplantation. Although the textbook chest radiograph for AAT deficiency demonstrates a basilar predominance of lucency, the National Heart, Lung, and Blood Institute (NHLBI) Registry of Patients Severely Deficient in AAT recorded a minority of patients with basilar-predominant disease.⁷

The natural history of AAT deficiency has been determined from series of individuals who received childhood testing and have been followed for nearly 30 years. To date, the FEV₁ increase throughout childhood has stayed within the normal range.⁸ Thereafter, FEV₁ decline is variable.

This variability in the expression of AAT deficiency is likely due to differences in other aspects of environmental exposure or genetics. Emphysema in individuals with normal AAT concentrations clearly has familial associations. Now that the human genome project has been completed, the number of genes associated with clinical disease will undoubtedly rise. Many of these genes will be found to have partial penetrance and interact with the environment for clinical disease presentation. Therefore, studies searching for modifier genes that explain the variability of clinical expression are being performed currently.

Early Detection

Because patients are often relatively young at clinical presentation with wheezing and dyspnea, asthma commonly has been treated before the diagnosis is established. The typical patient misdiagnosed with asthma has not undergone spirometry to confirm normality after appropriate treatment. The textbook description of AAT-deficiency individuals having panacinar emphysema causing hyperinflation and dyspnea as the only manifestation of disease can be misleading. The NHLBI Registry recorded symptoms of wheezing in 76%, regular sputum production in 50%, and cough in 42%.⁷ These symptoms are indistinguishable from patients with usual COPD and suggest that persistent airflow obstruction should prompt AAT testing, regardless of age.

Because 75,000 to 95,000 AAT-deficiency individuals remain undiagnosed in the United States, some interest in their clinical characteristics has been generated. This statistic suggests that many patients may be asymptomatic and live normal lives, as has been described in population cohort studies in which many nonsmokers have limited clinical abnormalities. More likely, the majority of patients can be found as established patients in COPD clinics where approximately 1 to 4.5% of patients have PiZZ AAT deficiency.^9,10 Studies of the prevalence of the PiMZ carrier state have recorded values as high as 17.8% of COPD patients.⁹ Because specific therapy is available, the identification of this disease makes a health impact. Current World Health Organization recommendations include AAT testing of all patients with COPD.¹¹ The benefits of diagnosis are outlined in Table 1.

Risk Factors for Progression of Disease

The risk factors for lung disease in AAT deficiency are incompletely understood. Good evidence exists that in the PiZZ phenotype, smoking,¹² and/or a dusty environment¹³ are risk factors for obstructive lung disease. More controversial is whether the carrier state (phenotype PiMZ) serves as a risk factor for obstructive lung disease. Populations of PiMZ heterozygotes have been identified from the general population and followed over time, with or without smoking. These studies show no difference in the frequency of COPD between PiMZ heterozygotes and PiMM control individuals.¹⁴

Other studies have examined the frequency of the Z protein in unselected populations of COPD patients. In these studies, more PiMZ heterozygotes are found than would be expected from population estimates.¹⁰ These studies were careful to avoid selection bias from family members with PiZZ being seen at the same clinic.

A recent evaluation of susceptibility genes for rapid progression of COPD was performed among 283 subjects with the most rapid FEV₁ decline in the Lung Health Study and compared with 308 subjects with no FEV₁ decline. Rapid decliners had an odds ratio of 2.8 for frequency of the PiMZ phenotype.¹⁵ This study solidifies the concept that PiMZ heterozygotes have a small excess risk for COPD that is interactive with smoking, the environment, and other familial factors for disease presentation.

Liver Disease

Liver biopsies or autopsies from AAT-deficiency individuals invariably show intracellular AAT protein regardless of the presence of clinical liver disease. Intracellular AAT accumulates within the cell and may polymerize. There is some evidence that these polymers may be responsible for cellular injury in some individuals. Specific inhibitors of the polymerization process hold the promise of treating liver disease by allowing egress of AAT protein that may be sufficiently functional to serve as adequate neutrophil elastase inhibitors.

Recent evidence has suggested that AAT-induced cirrhosis is often clinically silent, and is sufficiently frequent in the older nonsmoking AAT-deficiency population to warrant screening with transaminase levels, functional assays for clotting factors, or albumin for nonspecific clinical symptoms. Transaminase levels can be near normal in advanced disease.

In an autopsy-based, case-control study comparing 31 PiZZ patients and 124 control individuals matched by birth date and sex in Malmö, Sweden, the relative risk of cirrhosis was 8.3 (95% confidence interval, 3.8 to 18.3). A total of 43% of these patients (mean age, 64 years) had cirrhosis and 28% had primary liver carcinoma.¹⁶ As more patients are identified who have avoided cigarette smoking, the risk of liver disease associated with aging should be recognized.

There are no compelling data that alcohol intake increases the likelihood that an AAT-deficient individual will develop liver disease. It remains controversial whether the PiMZ population has an increased risk of cirrhosis. No specific treatment is yet available for AAT-deficiency liver disease, although clinical trials with chaperones to aid in AAT secretion from the hepatocyte are in progress.

Diagnosis

This autosomal codominant condition can be diagnosed with 100% accuracy by modern isoelectric focusing techniques or genotyping. The technology is available to obtain this testing for approximately $50 in reference laboratories. The blood test for total concentration and phenotype is provided free to patients by patient support and research groups (Alpha-1 Association and Alpha-1 Foundation).

Diagnosis allows therapy and stimulates family members to assess their risk factors for liver and lung disease. Although less smoking occurs in individuals given a phenotype by screening at birth,¹⁷ enthusiasm for neonatal screening in the United States has waned given the lack of genetic privacy laws. As many individuals with AAT deficiency live normal lives without lung or liver disease, the knowledge of a genetic condition may cause harm by stimulating anxiety or disrupting family harmony. Furthermore, a genetic diagnosis has been associated with genetic discrimination in the form of higher insurance premiums and job loss from employers who receive higher insurance bills. For these reasons, most large clinics attended by AAT-deficiency patients obtain and document verbal informed consent before conducting AAT testing.

Treatment

The basics of treatment differ little from usual care of the COPD patient. Smoking cessation, maximal bronchodilator therapy to control symptoms, corticosteroids for disease exacerbation, antibiotics for exacerbations of disease with purulent sputum, pulmonary rehabilitation, and vaccination with pneumococcal and influenza vaccines are all standards of care.

The smoking cessation experience of the AAT-deficiency population has been nothing short of phenomenal. There is good evidence that smoking activity is also reduced in teenagers at risk once AAT deficiency has been established. Although speculative, the direct biochemical links between cigarette smoke oxidants and AAT destruction and between cigarette smoking and activated neutrophil sequestration in the lungs present a disease-specific story that carries a strong message for most patients.

In 1987, the isolation of AAT from pooled plasma made possible studies of IV augmentation therapy. a₁-Proteinase inhibitor (Prolastin; Bayer Corp; Pittsburgh, PA) was demonstrated to replace the AAT concentrations of epithelial lining fluid and have a superb safety profile. Although it is a pooled plasma product, no confirmed HIV or viral hepatitis has been seen to date in recipients. Although the package insert still suggests immunization against hepatitis B virus, most AAT centers feel this is unnecessary.

Because the number of AAT-deficiency patients was believed to be insufficient to perform a placebo-controlled trial, this drug was the first drug approved by the US Food and Drug Administration without a randomized controlled trial. To obtain efficacy data, the NHLBI of the National Institutes of Health sponsored a US Registry that followed the course of lung function and symptoms over 6 years.

The NHLBI Registry demonstrated that augmentation therapy produced no difference in FEV₁ decline in nonsmokers using vs not using a₁-proteinase inhibitor. When FEV₁ decline was stratified by baseline FEV₁, a difference in FEV₁ decline was seen for individuals with a baseline FEV₁ between 35 and 49% predicted. In addition, 5-year mortality was 19% for the cohort, and deaths were almost exclusively limited to the patients with the lowest FEV₁ values. Patients who received augmentation therapy had statistically lower mortality.¹⁸

A German-Danish study compared the FEV₁ decline in German patients treated with a₁-proteinase inhibitor with that in Danish patients who did not receive augmentation therapy. FEV₁ decline in the treated group (–53 mL/yr) was significantly lower than in the untreated group (–75 mL/yr).¹⁹

A pilot prospective randomized trial has been performed in 56 Danish and Dutch patients in whom active treatment with 250 mg/kg of AAT monthly was shown to reduce the loss of high-resolution chest CT lung density by 50% compared with placebo albumin infusions. FEV₁ decline was no different between groups over the 2 years of the study.²⁰

IV AAT-augmentation therapy is administered at a dose of 60 mg/kg weekly. Drug pharmacokinetics favor weekly infusions. Clinical trials of inhaled AAT are raising the possibility that one tenth of the IV dose may be sufficient to normalize the elastase-antielastase balance in the lungs, yet proof of efficacy remains to be determined. Current infusion costs range from $50,000 to $60,000 yearly, the majority of which is drug cost. There is no indication to follow serum levels since the threshold value for lung protection remains speculative.

Gene therapy trials that would insert functional genes to make AAT are scheduled to begin in the near future for patients with lung disease. There is not yet a rational design of gene therapy that would improve liver disease.

Summary

Diagnosis and treatment of AAT deficiency has improved remarkably during the 38 years since its original description. Much of the scientific advancement has been aided by the patient groups—the Alpha-1 Foundation and Alpha-1 Association—that remain vocal advocates of rare disease research on Capital Hill and foster research programs.

Resources are being directed on many fronts to improve detection of PiZZ individuals, explore alternate modes of AAT augmentation, and understand the science of AAT trafficking within the hepatocyte. An active search for genes that modify the clinical expression of the PiZZ deficiency is underway, as these genes might open other avenues of therapy for AAT deficiency and for usual COPD.

References

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2. Sveger T. Alpha₁-antitrypsin deficiency in early childhood. Pediatrics 1978; 62:22–25
3. O’Brien ML, Buist NR, Murphey WH. Neonatal screening for alpha₁-antitrypsin deficiency. J Pediatr 1978; 92:1006–1010
4. Stoller JK, Smith P, Yang P, et al. Physical and social impact of alpha₁-antitrypsin deficiency: results of a survey. Cleve Clin J Med 1994; 61:461–467
5. Tobin MJ, Cook PJL, Hutchinson DCS. Alpha₁-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. Br J Dis Chest 1983; 77:14–27
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7. McElvaney NG, Stoller JK, Buist AS, et al. Baseline characteristics of enrollees in the National Heart, Lung, and Blood Institute Registry of alpha₁-antitrypsin deficiency: Alpha₁- Antitrypsin Deficiency Registry Study Group. Chest 1997; 111:394–403
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16. Elzouki AN, Eriksson S. Risk of hepatobiliary disease in adults with severe alpha₁-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma? Eur J Gastroenterol Hepatol 1996; 8:989–994
17. Thelin T, Sveger T, McNeil TF. Primary prevention in a high-risk group: smoking habits in adolescents with homozygous alpha-1-antitrypsin deficiency (ATD). Acta Paediatr 1996; 85:1207–1212
18. Survival and FEV₁ decline in individuals with severe deficiency of alpha₁-antitrypsin: the Alpha₁-Antitrypsin Registry Study Group. Am J Respir Crit Care Med 1998; 158:49–59
19. Wencker M, Banik N, Buhl R, et al. Long-term treatment of alpha₁-antitrypsin deficiency-related pulmonary emphysema with human alpha₁-antitrypsin: Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha₁-AT-study group. Eur Respir J 1998; 11:428–433
20. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha₁-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999; 160:1468–1472

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