Neonatal hemochromatosis

Ethical, Legal, Psychologic, Social, and Economic Issues

INTRODUCTION

Alpha-1 antitrypsin (AAT) deficiency is a common genetic disorder, defined as an insufficient amount of serum AAT, a plasma protein with antiproteolytic activity. This genetic disorder predisposes to chronic obstructive airway disease, chronic liver disease, and rarely to skin and vasculitic disorders (see LUNG DISEASE section and LIVER AND OTHER DISEASES section).

There has been gathering interest in genetic testing for AAT deficiency for several reasons. First, AAT deficiency is perceived to be an "uncommon" cause of lung and liver diseases by health care providers and, hence, symptomatic individuals with AAT deficiency are undiagnosed or misdiagnosed. Consequently, such patients may undergo unnecessary testing and procedures and/ or fail to receive appropriate therapy or counseling regarding preventive measures, for example, smoking cessation. Second, there is an interest in identifying asymptomatic individuals al high risk of having AAT deficiency so that they can be advised to lead healthier lifestyles that may prevent or delay the onset of disease (1). Finally, in populations where the prevalence of AAT deficiency may be high, some type of conditional, targeted population screening may be recommended.

To respond to the interest in genetic testing for AAT deficiency, a Genetics Writing Group was assembled under the auspices of the American Thoracic Society, the European Respiratory Society, the American College of Chest Physicians, the American Association for Respiratory Care, and the Alpha-1 Foundation, to develop recommendations for genetic testing. The Genetics Writing Group was composed of 12 members with backgrounds in medicine, philosophy, economics, law, genetics, and health care policy.

SPECIFIC QUESTION TO BE ADDRESSED

The general charge to the Genetics Writing Group was to perform a systematic review to answer the following specific, focused clinical question: "Does genetic testing for AAT deficiency improve outcomes in individuals with AAT deficiency compared with no genetic testing?"

The Genetics Writing Group defined the scope of this clinically focused question by identifying the following categories of inclusion criteria:

Types of Genetic Testing

a. Diagnostic detection testing

b. Predispositional detection testing

c. Screening

The Genetics Writing Group defined three types of genetic testing. The first two types of testing fall under the general category of "detection" testing. The first type is labeled "diagnostic" testing, defined as evaluating for the presence of AAT deficiency in a person with symptoms and/or signs consistent with an AAT deficiency-related disease. Essentially, diagnostic testing is undertaken for diagnosis of the underlying cause of a specific medical condition and the ethical imperative for such testing is similar to the testing performed in sorting out the differential diagnosis of any other medical condition.

The second type of detection testing is labeled "predispositional" testing, defined as identifying asymptomatic individuals who may be at high risk of having the genetic predisposition for developing AAT deficiency-related diseases. Positive results on such testing do not necessarily mean that the disease will inevitably occur; rather, they replace the individual's prior risks based on population data or family history with risks based on genotype or phenotype (2).

The third type of genetic testing is labeled "screening," which refers to programs designed to search in populations for persons possessing certain inherited predispositions to disease. The hallmark of screening is that there be no previous suspicion that any given individual has the condition (3).

Types of Outcomes

* Medical benefits: Prevention or delay of disease, regression of disease already present, or delay in the progression of abnormalities already present

* Explanation of disease

* Psychologic effects, both adverse and beneficial

* Social discrimination/stigma

* Economic effects

Types of Individuals

Symptomatic individuals.

* Persistent obstructive pulmonary dysfunction

* Liver disease

* Necrotizing panniculitis

* Multiorgan vasculitis

Asymptomatic individuals at high risk of having AAT dificiency.

* Individuals with a family history of AAT deficiency

* Individuals with a family history of obstructive lung disease or liver disease

* Fetuses

Carrier testing in the reproductive setting.

* Individuals at high risk of having AAT deficiency

* Partners of individuals with AAT deficiency

Asymptomatic individuals with no known higher risk of having AAT deficiency.

Targeted populations: newborn, adolescent, adult

METHODS

Data Sources and Search Strategy

We searched the MEDLINE and HealthSTAR databases from their inception to the beginning of 2001. We used the terms genetic test/genetic screening/mass screening, AAT deficiency, controlled study, randomized controlled trial, and meta-analysis. We also applied these search terms to the genetics of any disease, as observations on the efficacy of genetic testing in diseases with similar characteristics (e.g., adult onset, availability of treatment, and/or preventive measures) may provide insight concerning potential outcomes of AAT genetic testing. Finally, we contacted leading clinicians and researchers in the field of AAT deficiency and obtained the database of the Alpha-1 Foundation to identify additional studies.

The initial search strategy yielded reports of two uncontrolled, nonrandomizcd neonatal screening programs for AAT deficiency (4, 5). No studies were found regarding the efficacy of genetic testing of symptomatic individuals or asymptomatic individuals at high risk of developing a genetic disease.

Alternative Method of Developing Recommendations

Because of the scarcity of studies investigating the efficacy of genetic testing, we pursued an alternative strategy for developing recommendations for genetic testing. This strategy consisted of three parts:

1. First, we determined the individual issues that, in and of themselves, either supported or opposed genetic testing for AAT deficiency (6, 7). The relevant issues considered important for genetic testing included (a) the prevalence of AAT deficiency, (b) the penetrance of AAT deficiency-associated diseases, (c) the clinical impact or disease burden of AAT deficiency-associated diseases, (d) the accuracy of genetic testing, (e) the efficacy of augmentation therapy, (f) the efficacy of providing information about changing health-related behaviors, (g) the psychologic effects of genetic testing, (h) the social effects of genetic testing, (i) the economic costs of genetic testing, and (j) the ethical obligations and constraints regarding genetic testing (e.g., informed consent from adolescents).

2. The next step consisted of determining the weight of each issue, or how strongly each issue supports or opposes each type of genetic testing, by examining the level or strength of the evidence of each issue, via systematic review method. Essentially, systematic reviews of these individual issues would determine the implication that each issue had, in and of itself, for genetic testing, that is, whether it favors, detracts, or is neutral in supporting the case for testing. For example, the mere existence of augmentation therapy would strongly argue for recommending genetic testing for individuals with symptoms. But, if Grade I evidence is lacking for the efficacy of this treatment, then the potential implication of this issue for testing is downgraded.

The scientific evidence was evaluated, using the U.S. Preventive Services Task Force criteria (8) (Table 1). Tables of evidence were derived from systematic reviews of available studies.

Specific search strategies for the issues considered important in genetic testing for AAT deficiency included the following:

a. What is the prevalence of AAT deficiency in the population?

b. What is the penetrance of AAT deficiency-associated diseases, (i.e., percentage of AAT individuals that present with clinical disease: lung, liver, skin, vasculitis, etc.) and what is the prevalence of AAT deficiency-associated diseases in the general population?

c. What is the clinical impact of AAT deficiency-associated diseases on individuals, that is, morbidity and mortality?

d. What is the accuracy of genetic testing for AAT deficiency?

e. Does intravenous augmentation therapy improve survival and/or physiologic lung function in individuals with AAT deficiency compared with no treatment?

f. Does providing information about risks of developing these diseases to individuals favorably affect health-related behaviors (e.g., smoking cessation, change in occupations)?

g. What are the psychologic effects of genetic testing for AAT deficiency and other similar chronic, genetically related diseases?

h. What are the social effects of genetic testing for AAT deficiency and other similar chronic, genetically related diseases?

i. What are the economic implications of genetic testing for AAT deficiency?

j. What are the ethical implications of genetic testing for AAT deficiency?

To broaden the reach of the systematic reviews on the issues involving the efficacy of providing information about changing health-related behaviors, the psychologic effects of genetic testing, and the potential social discriminatory effects of genetic testing, we searched the literature for studies on other newborn or adult-onset chronic genetic disorders that are amenable to either preventive measures or specific medical treatments. These diseases included cystic fibrosis, breast cancer, hereditary hemochromatosis, hereditary nonpolyposis colon cancer, familial adenomatous polyposis, and familial hypercholesterolemia. We also performed systematic reviews of any studies evaluating the efficacy of genetic testing of symptomatic individuals, of asymptomatic individuals at high risk of developing a genetic disease, and of populations systematically screened for these other genetic conditions.

3. The final step in the development of recommendations consisted of subjectively weighing the issues relevant for each genetic testing scenario for each type of individual/group. For example, a genetic testing scenario would receive a recommendation for testing if many of the issues favorable for testing had large weights attached to them to the extent that they outweighed the weights attached to the issues that opposed testing.

The final recommendations were achieved by a consensus of the Genetics Writing Group. As relevant new evidence becomes available, our recommendations will need to be reevaluated.

It is important to emphasize that the various recommendations involving genetic testing reflect the informed judgment and deliberations of the Genetics Writing Group concerning whether the medical, psychologic, and ethical benefits of genetic testing (e.g., effects of treatment, enhancing efforts at changing health-related behaviors, or providing an explanation of disease) outweighed in general and for the particular type of case any psychologic or social harms, economic costs, or ethical concerns. In addition, it is critical to recognize that the Genetics Writing Group did not engage in some sort of utilitarian calculation in developing the recommendations, as many of the recommendations reflect a balancing of competing rights and responsibilities-for example, balancing a patient's right of privacy against the physician's responsibility to promote health. Finally, we acknowledge that certain individual cases may present exceptional considerations that warrant a conclusion different from what we draw. The recommendations are therefore offered as a guide and not as a rule.

BACKGROUND: GENETICS OF AAT DEFICIENCY

Deficiency of AAT is an autosomal, codominant genetic disorder and by itself is not a disease, but a predisposition to later development of a disease. Low serum levels of AAT, in conjunction with other genetically determined characteristics and environment influences, result in the development of a disease state (e.g., pulmonary or liver disease).

Reasonable evidence from epidemiologic studies suggests there is a serum threshold level above which the lung appears to be protected (9). This serum threshold lies at 11 [mu]M, about 35% of the average normal level. The AAT protein is an extremely polymorphic molecule; approximately 100 alleles of the AAT gene have been identified and categorized into an arrangement designated as the protease inhibitor (PI) system (10). Of these alleles, more than 30 genetic variants have been identified that lead to deficient levels of AAT. The normal and deficient AAT alleles can be identified by isoelectric focusing, the techniques currently used for definitive diagnosis (11), and are assigned a letter code (A to Z). AAT alleles are expressed in a codominant fashion and the AAT protein phenotype is described on the basis of these alleles, that is, it is referred to as the PI phenotype.

The most common allele is referred to as M; most individuals have a protein phenotype PI*MM. AAT genotypes that confer an increased risk for developing lung disease are those in which deficiency or null alleles, combined in homozygous or heterozygous states, encode AAT levels below the protective threshold. The most frequent deficient AAT allele is the Z variant, and individuals who are PI*ZZ homozygotes have plasma levels of AAT that are about 15% of the normal plasma concentration and are at the greatest risk for developing AAT deficiency-associated lung disease. The S variant is more frequent in the Mediterranean area and the homozygous form is associated with plasma levels about 60% of normal. The remaining frequent types of AAT phenotypes include PI*SZ, PI*MS, and PI*MZ. Evidence from the literature (see LUNG DISEASE section) suggests that individuals with the SS, SZ, MS, or MZ phenotype are at increased risk of developing AAT deficiency-associated diseases. The null alleles (homozygotes designated as PI QOQO) are associated with the most severe deficiency, producing no active AAT, or less than 1% of the normal amount of plasma AAT.

Suspicion of AAT deficiency can be confirmed quantitatively and qualitatively. Quantitative plasma AAT levels are usually determined by rocket immunoelectrophoresis, radial immunodiffusion, or, more recently, nephelometry (see LUNG DISEASE section). Subjects with abnormal blood levels should be investigated further to provide a qualitative evaluation of their AAT disorder. Even subjects with a borderline normal AAT plasma level (12-35 [mu]M or 90-140 mg/dl) should undergo qualitative testing, because these levels may correspond to an intermediate-level phenotype (SZ, SS, MZ, and MS). Also, a relative with asymptomatic or misdiagnosed AAT deficiency may be uncovered within the family.

SYSTEMATIC REVIEWS OF THE EVIDENCE FOR THE EFFICACY OF GENETIC TESTING

Diagnostic Detection Testing

We found no studies investigating the effectiveness of detection testing programs of symptomatic individuals for AAT deficiency or for other genetically related, chronic diseases. Studies of effectiveness of future detection testing programs should include the beneficial medical effects as well as the psychologic, social, and economic costs that may accrue from testing.

Predispositional Testing of Asymptomatic Individuals at High Risk

The "gold standard" approach for evaluating testing in these individuals would be a randomized trial involving testing, surveillance, and treatment. However, such a trial would require a large number of participants, take many years to carry out, and be expensive. Accordingly, we found no controlled trials or observational studies comparing outcomes in asymptomatic individuals at high risk who were tested for AAT with individuals who were not tested. Studies of genetic testing for genetically related, chronic diseases were also not available.

In the absence of such studies, quantitative and/or semiquantitative decision analysis may be informative in assessing the efficacy of genetic testing. Two such decision analyses have been performed for breast cancer (12, 13), showing that genetic testing of individuals at high risk may be associated with improved outcomes (Table 2). This conclusion is conditioned on the efficacy of the preventive measures and the likelihood that individuals testing positive will undergo the preventive measures (e.g., surveillance and mastectomy or hormone treatment).

Screening Programs

The initial search strategy yielded reports of two uncontrolled, nonrandomized neonatal screening programs for AAT deficiency (4, 5) (Table 3). No randomized, control study determining the efficacy of screening programs for AAT deficiency has been performed. One nonrandomized, noncontrolled study on neonatal screening for AAT was performed in Sweden (4). The experience with this neonatal screening program showed favorable long-term outcomes on smoking initiation rates and pulmonary function (14-18). The smoking rates of adolescents identified with AAT deficiency at birth were lower compared with those of age-matched control subjects (16) and the pulmonary function test results of AAT-deficient nonsmokers were significantly better than those of AAT-deficient smokers (18). Adverse psychologic effects from the receipt of genetic knowledge of having a potential to develop a future disease were not observed, as adolescents identified at birth with AAT deficiency had psychosomatic complaints that were similar to those of a matched control group (17). However, psychologic distress was experienced by the parents of these children and interactions between mother and child were problematic (19-25).

Another neonatal screening program conducted in Oregon also suggested favorable long-term results with such a program (5). Specifically, 22 adolescents with homozygous AAT deficiency had normal pulmonary function and, whereas smoking attitudes did not differ from control subjects, smoking initiating rates were significantly lower (p = 0.02), suggesting that screening followed by family-based smoking intervention may lead to a nonsmoking lifestyle.

The efficacy of neonatal screening programs has been investigated in several studies involving cystic fibrosis (Table 3). Specifically, seven cystic fibrosis neonatal screening trials have been performed with follow-up periods ranging from 1 to 10 years. Two of these studies were randomized, controlled clinical trials that reported significant beneficial effects in the screened population (26-28). The five other reports were case-control trials that also showed beneficial medical effects in the screened population (29-34).

The AAT deficiency and cystic fibrosis neonatal screening experiences suggest the efficacy of instituting preventive measures in individuals identified early on as having a genetic condition. Although AAT deficiency and cystic fibrosis are similar in that preventive measures are available, they differ in that the onset of disease occurs later in AAT deficiency compared with cystic fibrosis. Accordingly, the success of preventive measures for cystic fibrosis may depend on identification of the genetic condition shortly after birth, whereas a later time period for the identification of AAT deficiency may be as effective as neonatal screening, for example, during the adolescent period.

SYSTEMATIC REVIEWS OF THE INDIVIDUAL ISSUES RELEVANT FOR GENETIC TESTING

Tables of evidence (Tables 4-7) were constructed regarding the individual issues relevant for developing recommendations for genetic testing. Because many of the aforementioned issues are reviewed in the other sections of this statement, the reader is referred to those sections at the appropriate places for complete discussion and tables of evidence. Table 8 shows for each issue a summary of the conclusions from the evidence, the strength of the evidence, and the implications for testing.

Prevalence of AAT Deficiency

Estimates of the prevalence of the PI*ZZ phenotype in the general population have varied considerably, depending on the population used to derive the estimate (e.g., AAT deficiency occurs predominantly in Caucasians), the ethnic mix of the population, and the analytic method of phenotyping. On the basis of the newborn screening program in Sweden, the prevalence of AAT deficiency (PI*ZZ phenotype) in Sweden is estimated at 1 in 1,575 (4, 35). Direct population screening studies in the United States indicate that the prevalence of individuals with AAT deficiency is between 1 in 2,857 and 1 in 5,097 (36-38). On the basis of a U.S. population of about 260 million, 80,000 to 100,000 individuals with AAT deficiency (symptomatic and asymptomatic) are expected. As only 3,000-4,000 individuals have been diagnosed with AAT deficiency, these figures suggest that AAT deficiency is presently undiagnosed or is not manifest by disease in a large proportion (about 95%) of individuals with this genetic condition. Hence, although AAT deficiency is considered a rare genetic condition, it is as common as cystic fibrosis, which has a prevalence rate in Caucasians from 1 in 1,700 to 1 in 6,500. These prevalence data, by themselves, provide moderate support for screening programs in European and North American countries, but lack relevance for ethnic populations where the frequency of an allele associated with ATT deficiency is low. Also, these prevalence data have no relevance for diagnostic or predispositional genetic testing programs (Table 8).

Penetrance and Prevalence of AAT Deficiency-related Clinical Disease

Pulmonary disease. The penetrance of chronic obstructive pulmonary disease (COPD) among subjects with severe AAT deficiency is not properly known because many PI*ZZ individuals are never identified. In a study of 54 individuals who were clinically healthy when AAT deficiency was identified, only one-third, almost all smokers, had developed COPD between 30 and 60 years of age (39). This suggests that the existence of AAT deficiency alone is not enough to induce lung disease.

Estimates of the absolute prevalence of AAT deficiency-related pulmonary disease in the general population are based on several reports demonstrating the yield of detection testing in populations of targeted individuals. In a sampling 965 patients with COPD, Lieberman and colleagues observed severe deficiency of AAT (PI*ZZ phenotype) in 1.9% and intermediate deficiency (primarily MZ phenolype) in 8.0% (40). Testing performed by the AAT deficiency Detection Center in Salt Lake City on 16,748 individuals with chronic bronchitis, emphysema, or asthma, or with a family history of AAT deficiency, detected AAT deficiency in 3.1% of the total samples (1). Of these, one individual had the PI*SZ phenotype and the remainder had the PI*ZZ phenotype. Finally, a large number of heterozygotes was also detected; for example, 1.1% of the individuals were of the PI*SZ phenotype. Extrapolating from the estimate of the U.S. National Health Interview Survey (41) that 2.1 million individuals have emphysema, emphysema caused by AAT deficiency is expected in about 40,000-60,000 persons.

These estimates for the penetrance of AAT deficiency and the absolute prevalence of AAT deficiency-associated pulmonary disease in the general population provide strong support for diagnostic detection testing for individuals who belong to an ethnic population for which there is, a priori, evidence that the frequency of the allele is not low (Table 8). These data have no relevance for predispositional testing or for screening.

Liver disease. Liver disease associated with AAT deficiency is less common than the prevalence of lung disease (see LIVER AND OTHER DISEASES section for a more detailed discussion). Two major distinct clinical entities have been identified: neonatal liver disease and adult-onset liver disease.

Liver disease in newborns and children: The Swedish newborn screening program demonstrated that about 70% of PI*ZZ newborns have abnormal liver function tests and about 10% develop clinically significant cholestasis (4). Approximately 2.5% of individuals with AAT deficiency die of cirrhosis by age 18 years (42).

Liver disease in adults: The natural history of liver disease in adults is less well known than in children. Serial case-control and retrospective cohort studies (see Table 7 in LIVER AND OTHER DISEASES section) show that individuals with AAT deficiency have an increased risk for cirrhosis and hepatocellular carcinoma. These studies demonstrate the importance of sex and age as determinants of developing cirrhosis, as the risk of cirrhosis in AAT-deficient individuals is about 2% in individuals under the age of 50 years, but reaches a peak of 15-19% for elderly males greater than the age of 50 years (43, 44). Regarding prevalence of chronic liver disease in the general population, several reports have observed that the prevalence of PI*ZZ in patients with chronic liver disease is about 0.8% (see Table 8 in LIVER AND OTHER DISEASES section).

Regarding primary liver cancer, several reports have shown that the risk of liver cancer is relatively high in homozygotes with cirrhosis, whereas the risk in heterozygotes is small (see LIVER AND OTHER DISEASES section).

These data provide strong support for diagnostic detection testing in patients with chronic liver disease (Table 8).

Necrotizing panniculitis. The frequency of necrotizing panniculitis in individuals with AAT deficiency is unknown, but is probably low (i.e., less than 0.1%) as only 1 patient in the National Heart, Lung, and Blood Institute (NHLBI, National Institutes of Health, Bethesda, MD) Registry (n = 1,129) had necrotizing panniculitis (1). There are no data on the prevalence of AAT deficiency in individuals with necrotizing panniculitis. The low prevalence of necrotizing panniculitis in individuals with AAT deficiency and the unknown prevalence of AAT deficiency in patients with necrotizing panniculitis do not provide support for or against detection testing (Table 8).

Multisystemic vasculitis. AAT deficiency has been shown to be involved in immune processes. PI*Z heterozygotes have been reported to be at increased risk of developing uveitis, rheumatoid arthritis, and other collagen vascular diseases (see LIVER AND OTHER DISEASES section). There are reports linking the Z allele to systemic vasculitis and glomerulonephritis (45-47). Also, numerous studies have confirmed a strong relationship between hetero- and homozygous AAT deficiency PI*Z and small vessel-necrotizing vasculitides, in particular, Wegener's granulomatosis and microscopic polyangiitis (48-53). As shown in Table 13 in the LIVER AND OTHER DISEASES section, the link between the PI*Z allele and antiproteinase-3 (anti-PR-3 or antineutrophil cytoplasm antibodies [C-ANCA]) is convincing. In each studied cohort of C-ANCA-positive patients, at least one PI*ZZ homozygote is identified; that is, about 2% of all patients with anti-PR-3-positive multisystemic vasculitis can be expected to be PI*ZZ homozygous, the remaining PI*Z individuals being heterozygotes. The evidence that homozygotes and heterozygotes are overrepresented among patients with anti-PR-3-positive vasculitic syndromes provides moderate support to diagnostic detection in individuals with vasculitis (Table 8). There is a need for studies focusing on the potential effects of augmentation in this patient group.

Clinical Impact of AAT Deficiency

Justification for genetic testing for a genetically related disorder is enhanced if the clinical burden (i.e., morbidity and mortality) is significant.

Pulmonary disease. (A detailed analysis of the evidence demonstrating the impact of AAT deficiency on the lung is provided in the LUNG DISEASE section.) The severity of airflow obstruction in AAT deficiency, age at presentation of respiratory symptoms, and physiologically demonstrable airflow obstruction vary widely. Briefly, lung function is generally well preserved in the first two decades of life (5, 14). Specifically, in follow-up studies of adolescents with PI*ZZ identified at birth normal lung function or at most marginal deviations of no clinical importance were found (14,15). A decline in pulmonary function may begin to occur in the third and fourth decades of life (see LUNG DISEASE section). Available estimates of yearly decline in FEV^sub 1^ among smokers range from as low as 42 ml/year to as high as 317 ml/year (see Appendix 1 in LUNG DISEASE section) (54-60).

Several series have reported early death among individuals with AAT deficiency-associated lung disease. In one study of 246 individuals, the median age at death for smokers was estimated to be about 40 years and 65 years for never-smokers (44). In a study evaluating survival among 120 PI*ZZ individuals referred to the National Institutes of Health, Brantly and coworkers reported that the actuarial survival to age 60 years among PI*ZZ subjects was 16% compared with an expected age-matched U.S. survival rate of 85% (61). Similar mortality rates have been observed in other series (57, 59, 62, 63). Ascertainment bias may have caused mortality rates in these studies to be overestimated. AAT deficiency is, however, also reported in elderly nonsmokers (64).

Enhanced morbidity and mortality due to the effects of AAT deficiency on the lung provide strong support for all types of testing (Table 8).

Liver disease. A detailed analysis of the clinical burden of liver disease due to AAT deficiency is provided in LIVER AND OTHER DISEASES (see Table 8 in that section). Briefly, of newborns with AAT deficiency, 17% have symptoms of liver disease in infancy, about 10% of newborns with AAT deficiency develop clinically significant hepatitis, whereas 2.5% die of cirrhosis by age 18 years. For adults, cirrhosis of the liver occurs in about 5-15% of AAT-deficient adults, with higher figures for the elderly, particularly among never-smokers, who escape severe emphysema. The overall risk of liver disease in adults is about 20-fold increased compared with the general population. The risk in heterozygotes is much smaller. The enhanced morbidity due to AAT deficiency-related liver disease provides strong support for all types of genetic testing (Table 8).

Necrotizing panniculitis. Necrotizing panniculitis is characterized by inflammatory and necrotizing lesions of the skin and represents the least common of the well-recognized complications of AAT deficiency, with about 40 cases reported in the literature as of 1999 (65). In a recent World Health Organization report, a prevalence of less than 1 case per 1,000 was mentioned. Typically, necrotizing panniculitis starts with painful, hot, tender nodules on thighs and/or buttocks in an individual with AAT deficiency (mean age, 40 years). The prognosis is variable and can be lethal. The clinical impact of necrotizing panniculitis provides strong support for genetic testing (Table 8).

Multisystemic vasculitis. (See references 48 and 49.) It has been suggested that the presence of an AAT deficiency state in vasculitic patients enhances the risk of fatal outcome (66). The clinical impact of multiorgan vasculitis provides strong support for genetic testing (Table 8).

Efficacy of Therapeutic Measures

Pulmonary disease. Approval for the use of pooled plasma alpha-1 antitrypsin concentrate (Prolastin; Bayer, West Haven, CT) for treatment of severe AAT deficiency was based on studies demonstrating the "biological efficacy" of intravenous augmentation therapy (67, 68).

Several studies suggest that augmentation therapy may improve survival or reduce the rate of decline in lung function (see Appendix 10 in LUNG DISEASE section). Briefly, two retrospective cohort studies (Grade II-2 level of evidence), a German-Danish study (69) and the NHLBI Registry (60), suggest that the annual decline of FEV^sub 1^ may be slowed in patients with moderate impairment (initial FEV^sub 1^%predicted

A prospective German study (70) involving 443 patients with severe AAT deficiency who received weekly intravenous infusions of AAT in addition to their regular medication showed that the mean decline in FEV^sub 1^ was approximately half the rate of decline previously reported for untreated index cases (54, 57, 63, 71). Finally, a randomized control study (Grade I level of evidence) showed a trend toward slower loss of lung tissue on computed tomography scanning in augmentation therapy recipients compared with control subjects (p = 0.07), but no effect of intravenous augmentation therapy on decline in FEV^sub 1^ (67).

The available evidence on the efficacy of intravenous augmentation therapy provides mild support for the consideration of diagnostic genetic testing (Table 8). The efficacy of intravenous augmentation therapy is not relevant when considering the appropriateness of predispositional testing or screening, as individuals being tested are asymptomatic and without spirometric changes and, hence, treatment modalities are not a consideration (Table 8).

Liver disease. Other than liver transplantation, there are no known treatments for AAT deficiency-induced liver disease.

Necrotizing panniculitis. Augmentation therapy appears safe and effective (see references 175-178 in LIVER AND OTHER DISEASES section). Dapsone, either alone in less severe cases, or combined with augmentation therapy, may be of additional value.

Accuracy of Genetic Tests for AAT Deficiency

As reviewed in the LUNG DISEASE section, available tests to determine both the serum AAT level and the phenotype are highly accurate. The availability of accurate testing techniques satisfies one of the important conditions in support for genetic testing for AAT deficiency (Table 8).

Efficacy of Providing Genetic Risk Information about Changing Health-related Behaviors: Preventive Measures

Support for genetic testing for any adult-onset genetic condition increases to the extent to which there are behavioral risk factors that can be modified in response to detecting genetic mutations in individuals. Accordingly, to effect reductions in morbidity and mortality, individuals identified as having genetic mutations predisposing to future diseases will be advised to adhere to changes in lifestyle and frequent surveillance (72, 73). Psychologic factors, however, may prevent individuals from adopting preventive health behaviors.

For AAT deficiency, two major risk factors have been identified: cigarette smoking and environmental pollutants (see LUNG DISEASE section [Table 6 and Appendices 3 and 4] for an analysis of the evidence for these risk factors).

Cigarette smoking. Theoretically, the existence of cigarette smoking as a risk factor for developing or enhancing AAT deficiency-related disease would provide support for diagnostic testing, as a positive test can encourage individuals either to stop smoking or not to take up smoking. This risk factor also has potential implications for predispositional testing and screening, as a positive test can motivate individuals to avoid this risk factor. However, whether the receipt of genetic information concerning an enhanced risk of developing a disease will lead to a modification of health-related behaviors is not clear. The following summarizes the available data on the effects of the receipt of genetic information about cigarette smoking as well as other health-related behaviors that enhance the risk of other adult-onset, genetically related disorders.

Smoking prevention. Because of the powerful addictive properties of smoking (e.g., even with maximal support, smoking cessation occurs in only a small proportion of smokers [22% sustained quitters at 5 years in the Lung Health Study]), counseling nonsmokers not to smoke may be more successful than efforts aimed at smokers. Two studies (Table 4) have demonstrated the efficacy of providing genetic information about AAT deficiency to individuals identified at birth as having AAT deficiency on initiation rates of smoking. These investigations were cohort-controlled studies (Grade II-2 evidence) that observed lower frequency of adolescent smoking in individuals with AAT deficiency identified at birth compared with matched control subjects. Specifically, Thelin and colleagues showed that the smoking rate of adolescents (18-20 years old) previously found to have AAT deficiency during neonatal screening in Sweden was significantly lower than that of a demographically matched control group, that is, 6 versus 17% (16). Wall and coworkers observed that 22 individuals identified to be PI*ZZ at birth had a lower rate of current smoking or of trying smoking cigarettes than did an age-matched cohort (5).

These data provide moderate support for screening programs aimed at newborns and adolescents, as well as for diagnostic and predispositional testing of adult nonsmokers (Table 8).

Smoking cessation. Institution of smoking cessation efforts in asymptomatic, current smokers identified with AAT deficiency may prevent or delay onset of disease or prevent progression of disease in symptomatic individuals. It is unknown, however, whether the quit rates of smokers with AAT deficiency-associated lung disease would be greater with the receipt of genetic information about having a genetic susceptibility to a lung disease compared with the standard information given about the adverse effects of smoking. Similarly, it is unknown whether asymptomatic smokers at high risk of having AAT deficiency would have higher quit rates after receiving genetic risk information of developing AAT deficiency disease compared with just knowing that they might have a familial dispositional to having AAT deficiency-associated disease.

No studies have investigated the effects of receiving genetic information about smoking quit rates in individuals with AAT deficiency. However, two studies (Table 4) have investigated the effects of providing individuals with genetic risk information of developing tobacco-induced carcinoma on their smoking quit rates. Lerman and coworkers showed that the quit rate of smokers 2 months after receiving minimal contact quit-smoking counseling and information that they had an inherited susceptibility to the carcinogenic agents in tobacco, obtained via genetic testing, were not higher than those of smokers who received only minimal contact quit-smoking counseling (74, 75). In a follow-up study, the lack of efficacy of genetic feedback on enhancing smoking rates persisted at 12 months (75). However, there was a significant impact of genetic feedback on the likelihood of a quit attempt at 12 months. Hence, genetic susceptibility feedback has the intended effects on motivation to quit and, therefore, its success may be dependent on a more intensive smoking cessation treatment for the heightened motivation to translate into smoking cessation. Also, the initial increases in depressive symptoms observed at the 2-month follow-up in the genetic susceptibility feedback group were not sustained at the 12-month follow-up.

These studies suggest that providing genetic information concerning the future risk of developing tobacco-induced lung disease is not efficacious in motivating individuals to quit smoking. It may be interesting to speculate that such genetic information may be only as efficacious as just receiving general information about the adverse effects of cigarette smoking. Accordingly, these data do not provide support for or against any of the types of genetic testing (Table 8).

Research is needed to investigate the impact of genetic testing on smoking cessation efforts for the AAT population. Such research can inform the development of clinical practice standards to ensure that the potential medical benefits of genetic testing are not outweighed by the psychologic costs. If patients' anxiety about their predisposition for future disease is not addressed adequately in the context of genetic counseling, they may be less likely to follow the screening and lifestyle recommendations they receive.

Regardless of whether the information from a genetic test encourages smoking cessation, some might argue that the information nevertheless confers greater responsibility on the patient for the negative consequences of (continued) smoking. Research is needed to investigate what impact such allegedly greater responsibility would have on health care and financing.

Health-related behaviors that enhance the risk of other adultonset genetic related disorders. Several studies have explored the effects of receiving information about having a genetic predisposition for a future disease on other health-related behaviors. Two studies involving women who were at increased risk for developing breast cancer (one or more first-degree relatives with breast cancer) suggested that adherence to screening recommendations may be suboptimal due to psychologic distress (76, 77). In a study of women notified of an abnormal mammogram, those who experienced high levels of psychologic distress after notification were less likely to perform subsequent breast self-examination than those with moderate levels of distress (78). However, in another study involving women with normal, low-suspicion, and high-suspicion mammograms, although women with high-suspicion mammograms had substantial mammography-related anxiety and worries about breast cancer, all three groups had similar adherence rates to subsequent mammograms (79).

One other study analyzed the semistructured interviews of parents of children who had received a positive screening test result, informing them that their child was at risk for having familial hypercholesterolemia. During the course of the interviews, it became apparent that not all parents were aware that their child had been screened for a genetic condition. When parents perceived the test as detecting a raised cholesterol level that reflected primarily a dietary phenomenon, the condition was perceived as controllable and less threatening. When the test was seen as detecting a genetic problem, the condition was perceived as uncontrollable and more threatening (80).

These studies support previous evidence showing the lack of efficacy of the receipt of genetic information in altering health-related behaviors (i.e., smoking cessation), and emphasize that how people think about disease, particularly the perceived controllability of a disease, is an important determinant of what they do about it (81).

Change of occupation in response to receipt of genetic information. Several studies suggest a role for environmental factors in the development of AAT deficiency-associated pulmonary disease (see LUNG DISEASE section). Accordingly, another potential preventive measure for AAT deficiency-related diseases includes occupational counseling to minimize breathing polluted air. Although it may be likely that individuals would change their occupations in response to receipt of genetic information about risk assessment of developing AAT deficiency-related diseases, no evidence is available to support this conclusion (Table 8).

Psychologic Effects of Genetic Testing

Genetic tests are different from standard diagnostic tests in several ways. First, the tests differ in their relevance for the person's concept of self. Second, the tests differ in their relevance for the person's current health versus future health. A typical nongenetic, diagnostic test pertains to a person's current health and directs a specific course of medical treatment. A predictive genetic test pertains to future health and may or may not lead to any immediate treatment or changes in prevention behavior. Finally, genetic testing is distinct because the test result provides the basis for predictions not only about the individual tested but also about that individual's parents, siblings, and offspring. Hence, genetic testing has immediate implications for the entire family, implications that must be discussed and anticipated before testing. It is these differences that account for the unique psychologic issues and effects of testing that arise in the context of genetic testing for tested persons and their families. They also raise important ethical issues regarding confidentiality and privacy, and duty to disclose, which we discuss in ETHICAL ISSUES INVOLVED WITH GENETIC TESTING (see below).

Evidence of the psychologic impact of genetic testing comes from observational studies (Grade III evidence) and prospective studies comparing the effects between carriers and noncarriers (Grade II-2 evidence). These studies involved testing for AAT deficiency as well as for other genetic disorders: cystic fibrosis, hereditary hemochromatosis, familial hypercholesterolemia, and the hereditary cancer syndromes (breast-ovarian cancer susceptibility [BRCA1 gene], familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer). The results obtained from these other genetic disorders may or may not be relevant to genetic testing for AAT deficiency.

Symptomatic individuals. Theoretically, symptomatic individuals who test positive for a genetically related disease in which medical therapies are available may gain psychologic benefits from finding an explanation for their symptoms and from the knowledge that symptoms can be treated.

On the other hand, there may be potential adverse psychologic effects from a positive test. For example, there may be difficulty maintaining a healthy concept of self caused by feelings that the seed of one's own destruction lies in one's predetermined biologic makeup. In addition, there may be feelings of guilt due to thoughts that one may have passed on the genetic condition to one's offspring.

Only limited evidence is available on the psychologic effects of genetic testing for symptomatic individuals with AAT deficiency (82). In a survey of individuals with AAT deficiency-associated diseases, equal numbers of respondents reported adverse and beneficial effects of having a genetic disease on their relationships and their marriages. However, it is not known whether any of the psychologic effects are due to knowledge of having a genetic disease or to having impaired health.

These data, in and of themselves, are of limited value in providing support either for or against diagnostic testing and are of no relevance for predispositional testing and screening (Table 8).

Further research is needed to investigate the psychologic effects from being tested positive or negative for AAT deficiency.

Asymptomatic individuals at high risk.

Adults. (See Table 5.) In contrast to studies involving symptomatic individuals, more information is available concerning the psychologic impact of predispositional testing on asymptomatic adult individuals at high risk of developing a genetically related disease that is amenable to preventive measures or specific treatment modalities. No studies determining the psychologic effects of predispositional testing in individuals at high risk for AAT deficiency have been performed. In the absence of such data, we decided to review the relevant data for genetic conditions that share common characteristics with AAT deficiency, for example, single-gene defect, adult onset, and the existence of preventive and therapeutic measures. As these diseases include the cancer syndromes, we do recognize, however, that data generated from individuals with cancer syndromes may not be generalizable to those with AAT deficiency.

Although it is readily recognized that receipt of a positive test result may be associated with adverse psychologic effects, such a testing result may also incur psychologic benefits by reducing uncertainty and providing an opportunity for appropriate planning.

Four prospective studies were identified that explored the psychologic reactions to genetic testing for breast cancer. Croyle and coworkers reported initial psychologic outcomes for 60 women, members of a large Utah-based kindred of northern European descent, who received genetic test results (83). These investigators examined levels of general distress (anxiety) and specific test-related distress (thoughts and feelings about the test results) 1-2 weeks after the women had received their test results, during an in-person visit with a genetic counselor and a psychologic counselor. In a follow-up telephone interview, the average level of general distress reported by the group of women declined, but carriers demonstrated more distress than noncarriers at the follow-up interview. Carriers exhibited higher levels of test-related distress compared with noncarriers. These data, however, are limited by the fact that all the study participants are members of one large, Utah-based kindred.

Lerman and coworkers reported the results of a larger and more diverse group of participants (84). Their findings were based on a 1- and 6-month follow-up interview assessment of 96 men and women who had received their BRCA1 mutation carrier results. In addition, the study included comparison data from 44 individuals who had been offered BRCA1 testing but had declined. Depression was assessed at baseline and follow-up, using the Center for Epidemiological Studies Depression Scale. Analyses of the findings revealed no increase in depressive symptoms in either carriers or noncarriers. Relative to those who declined testing, the noncarriers manifested a decline in depression from baseline to follow-up. In addition, the noncarriers showed some improvement in self-reported sexual functioning and role impairment.

In another study involving 327 male and female members of BRCA1/2-linked hereditary breast and ovarian cancer families, Lerman and colleagues (85) observed that among persons who reported high baseline levels of stress, depression rates decreased in noncarriers, showed no change in carriers, and increased in decliners (decliners versus noncarriers, p = 0.004). Finally, in an observational study involving 181 individuals from hereditary breast-ovarian carcinoma families who received BRCA1 testing, 80% of noncarriers reported emotional relief, whereas more than one-third of carriers reported sadness, anger, or guilt (86). No pretest comparison was performed in these individuals.

Studies investigating the psychologic effects of other hereditary cancer syndromes have shown various results and suggest that the results may be dependent on the type of counseling provided (87-89).

Although these studies provide important insights into psychologic responses to genetic risk testing, their selective sampling bias limits the generalizability of results. More specifically, these samples were not clinical cohorts of individuals seeking and/or referred for personal genetic cancer risk assessment, as they were derived from samples invited to participate in genetic epidemiologic research. As such, these samples differ from a clinic-attending sample of women seeking and/or referred for heritable ovarian cancer risk estimates.

In two of the studies involved with BRCA1 testing, it was found that psychologic adjustment to test results depends more on pretest psychologic adjustment than on the results themselves (83, 85). Finally, DudokdeWit and colleagues (90-92) observed that participants who were depressed before the test were more distressed after testing. Essentially, the test result did not additionally contribute to posttest distress.

The prima facie simple notion that the test result, as such, determines the distress experienced seems to be a misrepresentation of a more complex reality. Essentially, the psychologic impact of genetic testing may depend more on pretest psychologic distress than on the test result itself. Finally, there is evidence that individuals who choose to be tested are self-selected for a favorable psychologic response to testing, that is, these individuals feel that they are equipped to handle "bad news" (93). On the other hand, there may be individuals who avoid testing because they perceive themselves to be more vulnerable to adverse psychologic reactions. As these individuals' experiences are not represented in studies investigating the psychologic reactions of testing, such studies showing that psychologic reactions to testing are far less than catastrophic may be overly optimistic.

A qualitative analysis of the data on the testing of asymptomatic individuals at high risk of having a genetic predisposition to a future disease shows that the psychologic reactions are at best mixed. Also, most of these studies are limited by modest sample sizes, uncontrolled research designs, and self-selected subject participation. However, most of the evidence shows that, in general, noncarriers and carriers differ significantly in terms of short-term, but not long-term, psychologic adjustment to test results. Also, the posttest psychologic reactions may be more dependent on the psychologic state of the individual before testing. Although the psychologic reactions to testing are probably individualized, these data do provide moderate support for genetic predispositional testing.

More research is needed on the psychologic reactions of adult, high-risk individuals to being tested for AAT deficiency, as the observations obtained from other genetic disorders may not be generalizable to AAT deficiency.

Children. (See Table 6.) The primary objection to predictive testing of children is that youngsters who learn they could or will incur a serious genetic condition later in life will experience devastating emotional damage. Because this information would come to them at a stage when their distinctive identity is emerging, several observers fear they would suffer a diminished sense of self-esteem and worth. Because children have a limited understanding of illness, they might come to view themselves as sick and damaged and might blame themselves for having inadvertently done something to alter their genes. Furthermore, a positive test may affect parent-child relationships, as parents may tend to regard their children as being sick, a child with the mutated gene may tend to identify only with the affected parent, and a noncarrier child may harbor feelings of guilt for not carrying the mutated gene. However, predictive testing of children can provide some with substantial emotional benefits. The most obvious benefit is to those who test negative, for they will experience reduced uncertainty and anxiety. Some children who test positive may also be relieved to have the uncertainty that has hovered over them resolved.

At present, there are a limited number of studies that have determined the effects of predispositional testing on adolescents. Codori and colleagues (94) evaluated the psychologic effect of predictive genetic testing through surveys of children at risk for familial adenomatous polyposis. Their psychologic state was assessed before testing and 3 months later. The main outcome measures were self-report inventories of depression, anxiety, behavior problems, and competence. The study population consisted of 41 children, aged 6 to 16 years. Nineteen children were carriers of the gene mutation and 22 were noncarriers. All psychologic distress scores remained within normal limits after testing.

Rosenberg and colleagues conducted a longitudinal study involving children, aged 4-17 years, screened for familial hyperlipidemia and observed that children with hyperlipidemia (n = 34) had, 12 months after testing, higher mean scores on a behavioral assessment tool than did those without hyperlipidemia (n = 18), suggesting that identification of hyperlipidemia may have harmful psychologic effects in children (95). Finally, Tonstad performed a cross-sectional interview study of 154 single parents or pairs of parents with 182 affected children, aged 6-16 years, with familial hyperlipidemia and observed that greater than 90% of the parents of children with familial hyperlipidemia did not report psychosocial problems in their offspring and only 10 and 28% of the children stated they had worries about cholesterol or heart disease, respectively (96). Thus, screening and treatment need not be postponed for fear of these problems.

These few studies are too incomplete to draw any definitive conclusions regarding the balance of harms and benefits of testing. Accordingly, these data arc not helpful in providing any conclusions concerning support for or against predispositional testing. Any future testing of adolescents should be performed within a research setting that will assess the short-term as well as the long-term effects of such testing.

Family relationships. Findings reported to date have focused on the individuals tested rather than on their family relationships. Although individual psychologic functioning is an important outcome, evaluations that focus only on assessment of individual psychiatric sequelae (such as depression and anxiety inventories) can miss many of the important psychosocial consequences of genetic testing. Hence, patients who does not manifest clinically significant levels of depression or anxiety might nevertheless be faced with impaired relationships with their spouse, parents, or siblings. Siblings with different test results must often redefine the meaning of their relationship, as must parents and offspring who feel guilt, resentment, or envy concerning the test results of family members. The psychosocial context of a particular family can influence the adaptation of individuals in ways that are difficult to measure and evaluate. Another concern is the effects of disclosure of genetic test results on marital discord and relationships with friends. In a survey performed on patients with AAT deficiency, respondents were mixed in their reports concerning the effects of testing on their marriages and relationships with friends (82). Studies of other genetic conditions have also observed mixed effects on marital relationships (93,97-100).

Predictive testing, however, need not have only harmful consequences within families. It can provide families with the opportunity to foster closeness, honesty, and openness (93, 97, 99, 100). The risks of psychologic distress and family disruption are likely to be greater when testing is offered in clinical settings that do not provide adequate patient education, genetic counseling, informed consent, and follow-up.

These preliminary data demonstrate that psychologic effects on family members are probably individualized and, therefore, do not provide either support for or against predispositional testing.

Screening. (See Table 7.) General concern has been expressed concerning the potential adverse psychologic and social effects of screening healthy populations with no known previous genetic risk.

Children. The Swedish neonatal screening experience showed that the psychosomatic complaints of young adults, 18-20 years old, who were identified as having AAT deficiency at birth were similar to those of age-matched control subjects (17).

Parents and parent-child bonding. One concern with neonatal screening relates to the degree of parental stress and anxiety, as well as adverse effects on parent-child bonding, triggered by a positive result. In the nationwide neonatal screening for AAT deficiency in Sweden, longstanding adverse psychologic effects on mothers and on the mother-child relationship occurred (20-22, 25, 101-104). Such effects may have been due to the lack of counseling services available to families on notification of test results.

More evidence is available from the cystic fibrosis (CF) experience. For example, Helton and colleagues (105) found no significant differences in subjective ratings of depression and anxiety between parents of children identified at newborn screening and parents of children traditionally diagnosed. Also, most parents of infants with CF reported intentions to treat their child the same as they would a child without CF. Furthermore, almost all parents felt emotionally closer to the child because of the diagnosis of CF. Nevertheless, more than one-third of the same parents admitted to being overprotective and more than two-thirds of the parents felt they tended to focus attention heavily on physical symptoms.

Boland and Thompson compared the strength of overprotective child-rearing attitudes of 3 groups of mothers: (1) 16 mothers whose children were asymptomatic at the time of newborn screening, (2) 13 mothers whose children were symptomatic at the time of screening, and (3) 29 mothers whose children were diagnosed after the onset of symptoms. Results showed that newborn screening had not increased a mother's tendency to overprotect her child with CF and in some cases the tendency had decreased. Further, delay in diagnosis when screening was not conducted usually caused mothers considerable personal distress (106).

Preliminary data from the Wisconsin CF Neonatal Screening Project showed that parents of children diagnosed with CF through newborn screening did not show significantly higher stress scores than their healthy or "traditionally diagnosed" CF comparison families. They did, however, have high frequencies of "at-risk scores" warranting referral based on clinical cutoff levels for Total Parenting Stress scores (45%) and Child Demandingness subscale scores (50%) (107).

One of the primary factors that has been suggested to impact on whether or not newborn screening affects the relationship between parent and child is follow-up communication and counseling. Grossman and colleagues (108) reported that families who received genetic counseling after screening for sickle cell anemia both gained and retained knowledge about the sickle cell trait and, therefore, experienced less anxiety about the unknown. The effectiveness of genetic counseling has been shown to be related to the parents' prescribed burden of the disease. The more accurate the interpretation of test results received by parents, the more accurate their perception of how the child's special needs would play a role in the family's life. Miscommunication and/or misunderstanding of the entire screening process may cause undue stress for parents, who generally have little personal knowledge about specific genetic disorders. An important consideration related to the possibility of mass newborn screening for any disease is the feasibility of providing professional follow-up counseling to all families to ameliorate the stress that early testing may cause.

These data provide support for a recommendation that newborn screening not be done unless adequate counseling is provided and early diagnosis is essential for the institution of preventive measures (Table 8).

Adverse Social Effects: Discrimination/Stigma

The sensitive nature of genetic information creates concerns with the potential for breaches of confidentiality and the subsequent risk of genetic discrimination by employers and insurers (health, life, and disability). Within the European Community, health insurance discrimination would be expected to be rare, as most countries have national health insurance. However, if AAT-deficient individuals decide to purchase supplemental private insurance, then they may be subject to practices like those that may be occurring in the United States. Regarding workplace discrimination, in the United States, where health insurance is usually provided by the employer, genetic screening of employees has more serious implications. A position in Great Britain is that genetic screening in the workplace is justified only by concerns for the safety of the involved individual or that of third parties. Evidence of discriminatory practices comes mainly from descriptive studies and case reports (Grade III level of evidence).

The actual prevalence of discrimination cases involving individuals with AAT deficiency is unknown. An American mail survey of patients with AAT deficiency-associated lung disease showed that 15.8% reported losing their jobs and 10.5% reported losing their health insurance after diagnosis (82). The survey, however, did not report details of the reasons for loss of health insurance coverage, which may or may not have been coincident with their job loss. An individual with AAT deficiency received a determination from the U.S. Equal Employment Opportunity Commission (EEOC) that she was fired by her employer because of her disability. The individual with AAT deficiency had filed under one of the three prongs of the Americans with Disability Act to get a determination from the EEOC. She filed under the second prong, that is, "regarded as disabled" (109, 110). Other individuals with AAT deficiency have claimed employment discrimination due to their genetic condition (111).

Concerning other genetic disorders, in a study of the perceptions of 332 members of genetic support groups with 1 or more of 101 different genetic disorders in the family, it was found that as a result of a genetic disorder, 25% of the respondents or affected family members believed they were refused life insurance, 22% believed they were refused health insurance, and 13% believed they were denied or let go from a job (112). Other cases of alleged genetic discrimination by employers and insurers have been reported (113,114). Billings and coworkers illustrated these possibilities in a review of 39 cases of insurance or employment discrimination (32 insurance, 7 employment) (113). They found discrimination against the asymptomatic ill-those with a genetic predisposition who remain healthy-who usually lost their insurance after undertaking preventive care. Overall, the problems encountered included difficulty in obtaining coverage, finding or retaining employment, and being given permission for adoptions. Finally, in a postal survey, Low and colleagues (115) observed that 33.4% of members of seven British support groups for families with genetic disorders had problems when applying for life insurance, compared with 5% of applicants who answered questions on applying for life insurance as part of an omnibus survey.

Insurance companies may deny insurance to those they consider to be at too great a risk for an illness or to those with preexisting conditions. On the other hand, insurers may have little interest in whether potential policyholders have a genetic predisposition for a disease, perhaps because of the high turnover rate in health insurance policies. In a survey of genetics services providers, Fletcher and Wertz (116) found that refusal of employment or insurance was generally not related to genetic testing. In a survey of health insurers, Hall and Rich (117) found no well-documented cases of health insurers either asking for or using presymptomatic genetic test results in their underwriting decisions.

Regarding discrimination in the workplace, the U.S. EEOC went to court to stop a company from testing its employees for genetic defects (118). The commission asked that Burlington Northern Santa Fe Railroad be ordered to halt such testing on blood taken from employees who have filed claims for work-related injuries based on carpal tunnel syndrome. The test seeks to identify a genetic defect that some experts believe can predispose a person to some forms of carpal tunnel syndrome. Accordingly, the belief is that if an employee tests positive for the genetic test, the employer may be able transfer responsibility for the development of carpal tunnel syndrome to the employee.

Although it is difficult to quantify the incidence of genetic discrimination, there is a real concern that as these tests become prevalent, this issue will loom larger for insurers (119). In addition to actual discrimination is the fear of discrimination and the way that people's choices are limited as a result of this fear. For example, individuals may refuse to obtain testing and thereby not receive a diagnosis because of the fear of losing insurance and/or employment (120).

In the United States, genetic discrimination has been addressed in specific states legislation (121). These laws, however, are ineffective and are preempted by federal regulations relative to self-employed individuals (two-thirds of Americans are self-employed). There is now some protection in the workplace for the asymptomatic ill. In 1995, the U.S. EEOC stated in its compliance manual that healthy people carrying abnormal genes will be protected against employment discrimination by the Americans with Disabilities Act (122). Several European countries have also enacted specific policies prohibiting the obtainment and use of genetic information by insurers (123).

Economic Costs

Major determinants of the cost-effectiveness of screening are the prevalence and disease burden of AAT deficiency; the sensitivity and specificity of the genetic tests; the effectiveness of treatment and prevention measures in reducing the burden of disease; compliance with screening, diagnosis, and therapy; the costs of the administrative infrastructure needed to conduct the screening; and the costs of informed consent procedures, educational services, and counseling services. The cost-effectiveness of population screening for AAT deficiency is largely unknown and challenging to determine because technology and treatment modalities are changing rapidly.

Several investigators have looked at the costs associated with intravenous augmentation therapy in individuals with AAT deficiency. In a study relying on self-reported data regarding health resource utilization, augmentation therapy incurred substantial additional costs (124). The mean annual cost was $40,123 (U.S. dollars) for PI*ZZ individuals receiving augmentation therapy compared with $3,553 for those individuals not receiving such therapy. Several studies have used economic models to estimate the cost-effectiveness of augmentation therapy (125-127). For example, assuming a 30% therapy efficacy, Hay and Robin (125) estimated the cost per life-year saved ranged between $50,000 and $128,000, a value comparable to other widely used medical interventions. A more recent preliminary report of a cost-effectiveness analysis using a Markov chain model and data from the NHLBI Registry (60) shows that lifelong augmentation therapy (begun at age 46 years and with an FEV^sub 1^ of 49%predicted) costs $312,511 per quality-adjusted life-year, and that augmentation therapy has a less favorable incremental cost-effectiveness ratio (i.e., exceeds $100,000 [126]). These cost estimates for diagnostic testing, however, should be interpreted with caution, as the efficacy of augmentation has never been demonstrated in a randomized, controlled trial. The cost-effectiveness of a screening program would depend on whether the costs of screening, diagnosis, and therapy are justified by the compliance and effectiveness of preventive measures, and the effectiveness of therapeutic modalities.

ETHICAL ISSUES INVOLVED WITH GENETIC TESTING

(See Table 9.)

The Requirement for Informed Consent

Overarching principles. Informed consent has become an ethical standard in clinical care and human subject research. Genetic information can identify traits, predisposition to a disorder, and actual inheritance of a disorder. Although the obtaining of such information will help with the selection of treatment/preventive options in a relatively few genetic conditions, such information will undoubtedly have broader psychologic and social implications for almost all who consider undergoing such testing. Because of the unique issues related to genetic testing as opposed to routine testing, individuals have a right to receive the necessary information to make an informed choice regarding genetic testing. Correlatively, such a right imposes obligations on the health care profession to provide such information and to obtain the informed consent of individuals before testing. These rights and obligations are grounded in the principle of autonomy and the right to self-determination, based on the moral conviction that individuals ought to be able to shape their own plan of life, especially where sickness and health care are concerned. The informed consent process allows patients to weigh the benefits of testing against the possible risks and reduces misunderstanding.

The concept of informed consent in the realm of genetic testing has been broadly embraced by ethics task forces and commentators in the United States, Canada, Great Britain, and other European countries (128-133). Other commentators have written on theoretical concerns with implementing the principle of autonomy and conflicts with other principles regarding genetic testing (134, 135).

Regarding content, informed consent requires explaining to the patient, before the test, the nature and scope of the information to be gathered, the significance of positive test results, the nature of the disease in question, the presence and likely efficacy of treatment modalities, potential risks from social discriminatory practices, potential emotional impact on individuals and on family dynamics, and, if relevant, the risks involved in procreating (136). To this list may soon be added the duty to warn about the possible interests of insurers, employers, adoptive parents, or future marriage partners. The Swedish neonatal screening effort demonstrated that provision of important information is critical to the success of any genetic testing. Specifically, the incidence of adverse psychologic effects in parents of newborns testing positive for AAT deficiency was attributed to the manner with which parents were told about such testing and the absence of adequate psychologic support (22, 137). Furthermore, of the adolescents identified at birth as having AAT deficiency, 73% assessed the information they obtained about AAT deficiency as being satisfactory, 17% rated the information as being both good and bad, and 10% thought the information was unsatisfactory (17).

The role of the physician in genetic counseling. At present, the public's knowledge of genetic diseases and the implications of genetic testing is poor. Understanding genetic testing involves learning complex concepts such as test sensitivity, carrier status, patterns of inheritance, risk/probability, and genotype-phenotype correlations. These gaps in the public's genetic knowledge suggest that genetic testing programs must include educational and counseling components. Unfortunately, there is a severe scarcity of genetic professionals both in the United States and in Europe, so implementation of widespread genetic testing must rely heavily on primary care providers and specialists (138). In addition to the paucity of genetic specialists relative to the potential demand for genetic testing, other reasons warrant the involvement of nongenetic professionals in genetic testing. For example, health care professionals are in an excellent position to elicit risk information. Also, health care providers are best able to determine whether a high-risk situation is present, as few people have sufficient understanding of genetics to recognize whether or not they or their children are at increased risk of inherited disease (133). With proper training and adequate knowledge of test validity, disease, and mutation frequencies in the ethnic groups to whom they provide care, primary care providers, specialists, and other nongenetic health care providers can and should be the ones to offer predictive genetic tests to at-risk individuals. Under some circumstances, for instance, when the family history is complicated or the symptoms in relatives do not point to a clear diagnosis, referral to a genetic specialist is appropriate before offering testing.

Despite the advantage of nongenetic providers being the gateway to genetic testing, there are some concerns. One is the limited knowledge of some of these individuals regarding genetics and genetic tests (139). Another concern is the tendency of nongeneticist providers to be directive in situations in which reproductive options to avoid the conception or birth of an infant with a serious disorder are considered (140). It has been recognized that nondirectiveness may not be achievable and may not always be desired by patients (141, 142). Another concern is whether primary care providers and specialists are able to devote sufficient time to informing patients about the risks and benefits of genetic testing, which has been estimated to exceed 1 hour (143). Recommendations have been made to address these issues (133).

Conclusion: Health care providers must provide individuals with the necessary information so that an informed and voluntary decision can be made, and must receive the individual's informed consent before any genetic testing.

Testing of children. Obtaining informed consent to genetic testing of children or adults who lack legal competency generally requires that a parent, surrogate, or guardian decide by proxy. In their joint statement, the American Society of Human Genetics and the American College of Medical Genetics recommended that "[t]imely medical benefit to the child should be the primary justification for genetic testing in children and adolescents," and that if the medical benefits "are uncertain" or will not accrue until a later time, genetic testing should generally be deferred (144). However, what constitutes a "timely medical benefit," what level of "certainty" should be required for the efficacy of a medical benefit, and what time period constitutes a "later time" are controversial issues (145, 146). Concerns about testing children have focused largely on the potential psychologic implications to the child, the impact on family relationships, the possibility of social discrimination, and the abrogation of the right of the child to make an autonomous choice about testing as adults. These concerns, however, include much empirical and conceptual uncertainty. Other factors that should be considered in the decision to perform genetic testing on children include the likelihood of occurrence (e.g., the existence of a family history or the degree of penetrance), the severity of the illness, the level of maturity of the child, and the concerns, values, and objectives of the parents and of the children involved in the decision.

Conclusion: Genetic testing of children should proceed only if:

1. The adolescent is mature enough to understand the issues involved with testing.

2. The adolescent gives his/her assent for testing.

3. The parents give their permission for such testing.

Do physicians have an ethical and/or legal duty to disclose the availability of predictive genetic testing to asymptomatic individuals? An important issue involves whether physicians have an obligation to disclose the availability of genetic tests to asymptomatic individuals and the potential for liability for failure to inform patients about such tests. This issue is more controversial for disclosure of genetic tests to parents of healthy children, because of concern with the potential of creating psychologic distress for the child and/or disruption of family dynamics. Liability would probably exist only if beneficial treatment exists and/or preventive measures could be instituted and failure to test or to test in a timely manner would result in harm. Such a situation may be relevant to those with an increased risk of having AAT deficiency.

Conclusion:

1. Health care providers have an obligation to disclose the availability of predictive genetic testing to adults at an increased risk of having AAT deficiency.

2. Health care providers should offer genetic counseling about AAT deficiency testing only on the request of the parents of a healthy child.

Research context. Stringent informed consent procedures are required for genetic testing in research settings. The American Society of Human Genetics has issued guidelines for informed consent for genetic research (147).

Confidentiality of Genetic Information

Genetic information is highly personal and can be associated with potential psychologic and social risks. Accordingly, ensuring the confidentiality of genetic information is an important principle.

Regarding social discrimination, there are fears that individuals may suffer from discrimination in relation to health insurance, life insurance, and employment. Breaches of confidentiality to health insurers are more of an issue in the United States, where universal health coverage does not exist. However, even in countries that provide their citizens with basic care, obtaining supplementary health insurance may be an issue if genetic information is not kept confidential.

Disclosure to relatives. The obligation of assuring confidentiality, however, is not an absolute principle in medical ethics. Such information may be disclosed, albeit only in exceptional cases involving the public interest or potential harm to third parties (128, 148). In the realm of genetic testing, the main ethical dilemma arises when an individual's genetic test results may have important implications for other family members. This possibility raises the question of whether such family members have a right to such information and, correlatively, whether there is an obligation on health care providers to disseminate such information. Some commentators would consider it a duty to warn relatives, on the basis of the concept that hereditary information is a family possession rather than simply a personal one (149). Others question why a mere biological link justifies an encroachment on an individual's privacy (150, 151). Among health care providers, there is equal representation of both viewpoints-the desire to disclose and the desire to protect confidentiality (151). Commentators have suggested that disclosure should be considered if the following factors are present: there is a high likelihood that the relative has the genetic mutation at issue (this would limit disclosure to the nuclear family), the disease is serious or fatal, effective treatment is available, the disease is transmitted dominantly with high penetrance, there is evidence that disclosure of the information would prevent or ameliorate the serious risk, there is no other reasonable way to avert the harm, and attempts to elicit voluntary disclosure have failed (152-154).

The American Society of Human Genetics has issued a statement concluding that providers performing genetic testing services for their patients have a "privilege" to disclose genetic risk information directly to relatives of a patient if necessary to mitigate a serious risk of harm (155). The U.S. Task Force on Genetic Testing opined that health care providers must make clear that they will not communicate results to relatives, except under extreme circumstances, which the provider should define. Providers should be explicit in describing the extreme situations in which they would inform other relatives (133). Finally, in Great Britain, an emerging consensus is that only under exceptional cases may confidential information be conveyed to relatives (128). Case law in the United States provides little guidance on this issue, with one court case deciding that the duty of health care providers to warn is satisfied by telling their patients that they should inform their family members, whereas another court opined that a duty to warn may require a breach of confidentiality in some cases (156, 157).

Conclusion: Before any genetic testing, health care providers should inform their patients that a genetic test can reveal medical information about relatives. Physicians should inform patients of the importance/benefits of other family members knowing about their chance of increased risks. If physicians contemplate that there may be extreme circumstances in which they believe they have an ethical obligation to reveal such information to family members, physicians should explicitly inform their patients of the nature of these extreme circumstances before testing.

RECOMMENDATIONS FOR GENETIC TESTING

(See Tables 10 and 11.) The different types of recommendations that could be given in testing situations is shown in Table 10. Recommendations of Types A and B entail a duty on physicians to disclose the availability of the test. Subsequently, testing should be performed only after informed consent is obtained from the patient. For recommendations of Types C and D, there is no duty to disclose the availability of the test.

The following recommendations are based on the weighting and the weighing of the individual issues important in the determination of genetic testing. The individual weights assigned to each issue were dependent on the assessment of the strength of the available evidence for each issue, whereas the weighing of these issues reflected a subjective balancing of these issues by the Genetics Writing Group. Hence, a recommendation of Type A signifies that many of the issues favorable for testing (e.g., high prevalence, large burden of disease, favorable evidence for treatment efficacy) had large weights attached to them and outweighed the issues that detracted from testing (e.g., potential for discrimination and costs). Lower grades of recommendations (e.g., recommendation Type B) reflected the following: (1) fair or poor evidence existed regarding the benefits to individuals; (2) weighing of the benefits and harms of testing were balanced; or (3) compelling issues involved with testing were more reflective of the different values and desires of individuals and their comfort level regarding genetic testing.

Diagnostic Detection Testing

1. Symptomatic adults with persistent obstructive defects on pulmonary function testing.

a. Emphysema

b. COPD

c (i). Asthma in which airflow is incompletely reversible after aggressive bronchodilator treatment

Recommendation Type A: Testing is recommended.

Rationale: Recommendation of Type A is justified by the following reasons. First, the prevalence of lung disease due to AAT deficiency is not insignificant. Second, AAT deficiency-associated lung disease carries a significant clinical burden. Third, studies (albeit observational in nature) suggest that administration of intravenous augmentation therapy may potentially enhance survival and decrease the progression of pulmonary disease. Fourth, suggestions for changes in health-related behaviors can be made to prevent further progression of disease. It is not known, however, if providing knowledge of having a genetic disease can influence smoking quit rates. Fifth, beneficial psychologic effects may also be gained from testing, resulting mainly from receiving an explanation of the disease process. Adverse psychologic effects, however, may also occur. Finally, identification of individuals with AAT deficiency may provide important economic benefits, for example, elimination of unnecessary diagnostic tests and/or incorrect therapeutic strategies for individuals not known to have AAT deficiency and prevention of costly exacerbations of obstructive pulmonary disease. All these potential benefits outweigh potential adverse social discriminatory effects.

It should also be emphasized that testing should be considered more strongly when other factors are present, for example, symptoms of emphysema occurring in younger patients, or a rapid decline in FEV^sub 1^, or if clinical symptoms are present in an individual with a strong family history of AAT deficiency. On the other hand, testing should be considered less relevant for members of ethnic groups in whom the frequency of ATT deficiency is known to be low, for example, western Pacific islanders. In settings where the prevalence of AAT deficiency is known to be much lower than in North America or Europe, a Type B recommendation for diagnostic testing is made.

Finally, a Type B recommendation for diagnostic detection testing is made for adults with bronchiectasis. One the one hand, AAT deficiency is underrecognized and bronchiectasis has been observed frequently in AAT-deficient patients in some series. On the other hand, available studies do not firmly establish the association between AAT deficiency and bronchiectasis.

The Genetics Writing Group recognizes the problem of identifying heterozygotes from testing, many of whom will not receive augmentation therapy, as their serum AAT levels will not be severely depressed. According, these individuals will not reap the medical benefits of testing, although they may experience psychologic and/or social adverse effects. Further research is needed to determine the extent of the psychologic and social sequelae experienced by these individuals.

c (ii). Asthma with completely reversible airflow obstruction

Recommendation Type C: Testing is not recommended.

Rationale: There is no evidence available showing that individuals with asthma characterized by completely reversible airflow obstruction have an increased prevalence of AAT deficiency. In one study involving Swedish individuals identified at birth, the frequency of asthma was not different from that of the general population (14). Hence, it is recommended that testing not be performed, as these individuals are not likely to have AAT deficiency.

2. Adolescents with persistent obstructive defects on pulmonary function testing.

Recommendation Type B: Testing should be discussed, acknowledging that it could be reasonably be accepted or declined.

Rationale: A recommendation of Type B is being made because (1) efforts at preventing risky health-related behaviors may be more successful with timely diagnosis in this age group (e.g., efforts at smoking prevention and occupational counseling efforts at a time when adolescents are actively choosing future career opportunities), and (2) adverse psychologic effects have not been well established in adolescents who receive genetic testing. A recommendation of Type A is not made because of (1) the low prevalence of lung disease in adolescents, (2) a theoretical concern with the future autonomy rights of adolescents, and (3) potential social discriminatory effects.

3. Asymptomatic individuals with a persistent obstructive defect on pulmonary function testing.

a. No risk factors present for promoting AAT deficiency-related lung disease (i.e., nonsmokers and no exposure to environmental pollutants)

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: The existence of potential adverse psychologic and social discriminatory effects (including individuals identified as being heterozygous) coupled with the low likelihood of any medical benefits obtained from a positive test (augmentation therapy is unlikely to be given, as the presence of significant spirometric obstruction is unlikely; also, preventive measures will not be applicable because of the absence of risk factors) warrants that testing should be merely discussed, but not recommended.

b. Smoking exposure

Recommendation Type A: Testing is recommended.

Rationale: A positive test, in conjunction with the efforts of the clinical provider, may lead such individuals to stop smoking. However, one study showed that receipt of genetic risk information enhances motivation to quit smoking, but that smoking quit rates are not enhanced.

c. Occupational exposure

Recommendation Type A: Testing is recommended.

Rationale: A positive test may influence an individual to change occupation and prevent further decrements in pulmonary function.

4. Individuals with unexplained liver disease: neonates, children, adults.

Recommendation Type A: Testing is recommended.

Rationale: Testing can provide accurate diagnosis of the liver disease, as well as important prognostic information (e.g., the risk of liver cancer, which is increased in PI*ZZ individuals). These benefits need to be balanced against potential adverse psychologic and social discriminatory effects from genetic testing.

5. Adults with necrotizing panniculitis.

Recommendation Type A: Testing is recommended.

Rationale: Testing may provide accurate diagnosis of an unexplained disease and case reports have suggested efficacy of augmentation therapy.

6. Adults with multisystemic vasculitis: anti-PR-3-posltive vasculitis.

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Testing can provide explanation of the disease process, as several studies have demonstrated a convincing link between the PI*Z allele and anti-PR-3-positive vasculitis and one study showed that AAT deficiency in patients with vasculitis may signify an enhanced risk of fatal outcome. The effects of augmentation therapy in this setting, however, are unknown. Adverse psychosocial effects also need to be considered.

Predispositional Testing

1. Individuals (adults and adolescents) with a family member with AAT homozygosity.

a. Siblings

Recommendation Type A: Testing is recommended.

Rationale: If a tested individual is homozygous for AAT deficiency (i.e., PI*ZZ), then the sibling has a 25 to 100% chance of being a homozygote (these percentages depend on the genotypes of the parents; possibilities are PI*MZ and PI*MZ, PI*MZ and PI*ZZ, or PI*ZZ and PI*ZZ). If the affected child is PI*ZZ, then the highest probability is that the parents are PI*MZ and PI*MZ, but the other two possibilities should not be discounted, especially in northern European populations, where the prevalence in isolated population subgroups may be high.

b. Offspring

Recommendation Type B: Testing should be discussed, acknowledging that it could be reasonably be accepted or declined.

Rationale: Offspring can be homozygous only if the other parent is at least heterozygous. This potentially low prevalence rate for homozygosity coupled with potential adverse psychosocial effects warrants that testing be discussed rather than be recommended, even if obstructive pulmonary dysfunction and/or risk factors are present.

c. Parents

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: If the proband is homozygous for AAT deficiency, then either one or both of the parents is at least heterozygous. The evidence that even heterozygotes may be at risk for adverse health effects warrants a Type B recommendation.

d. Distant relative of the proband

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: If the proband is homozygous, a distant relative may have normal AAT alleles, be heterozygous, or be homozygous (a low likelihood). The low likelihood of being homozygous coupled with potential adverse psychosocial effects warrants a Type B recommendation.

2. Individuals (adults and adolescents) with a family member with AAT heterozygosity.

a. Siblings

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: If an individual is heterozygous for an AAT deficiency allele, then his or her sibling has a 25% chance of being a heterozygote. The evidence that even heterozygotes may be at risk for adverse health effects coupled with the high prevalence of being at least a heterozygote for an AAT deficiency allele warrants a Type B recommendation.

b. Offspring

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Offspring of a parent who is heterozygous has a 25% chance of being a heterozygote. The evidence that even heterozygotes may be at risk for adverse health effects coupled with this moderate prevalence rate warrants a Type B recommendation.

c. Parents

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: The prevalence of having a deficient allele is low, because if the proband is a heterozygote, then a parent can be either heterozygous or have normal AAT alleles. However, the evidence that even heterozygotes may be at risk for adverse health effects warrants at least a Type B recommendation.

d. Distant relative

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Distant relatives of a heterozygote proband may be at most heterozygous or have normal AAT alleles. Despite this low likelihood of being heterozygous, the evidence that even heterozygotes can be at risk for adverse health effects warrants a Type B recommendation.

3. Individuals with a family history of persistent obstructive lung disease or liver disease.

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Previous studies have shown that the prevalence of the PPZZ phenotype in individuals with lung disease or liver disease is less than 3 and 1%, respectively. The low likelihood of having AAT deficiency coupled with potential adverse psychosocial effects warrants a Type B recommendation.

4. Fetal testing for AAT deficiency.

Recommendation Type D: It is recommended that genetic testing not be performed.

Rationale: AAT deficiency-related diseases are not generally considered serious enough diseases to warrant genetic testing in the prenatal period, as such diseases occur in late-onset adulthood and the incidence of death among those children affected with AAT deficiency-related liver disease is low. If severe progressive liver disease has occurred in the neonatal period in a previous child, the risk for a subsequent PI*ZZ sibling to develop severe liver disease may be as high as 40% (158). Under these rare circumstances, the family should be informed about prenatal diagnosis as part of the genetic counseling endeavor.

Carrier Testing in the Reproductive Setting

1. Individuals at high risk of having AAT deficiency-related diseases who are planning a pregnancy or are in the prenatal period.

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Options for testing should be discussed, as a negative lest may relieve anxiety and a positive test may allow prospective parents to become emotionally prepared for parenting a child with AAT deficiency or to consider options for adoption.

No data exist regarding the level of interest in AAT deficiency genetic testing in this group. An Office of Technology Assessment survey demonstrated that 83% of Americans said they would take a genetic test before having children if it would tell them whether their children would be likely to inherit a fatal genetic disease. Hence, it is likely that a majority of individuals at high risk of having AAT deficiency would not desire such genetic testing, as AAT deficiency confers individuals with a genetic predisposition to having a relatively late-onset disease, rather than to having a certain fatal disease.

2. Individuals who are not at high risk themselves of having AAT deficiency, but are partners of individuals who are either homozygous or heterozygous for AAT deficiency.

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Rationale: Same as above.

Screening

1. Neonatal.

Recommendation Type D: It is recommended that genetic testing not be performed.

Rationale: Although the previous Swedish experience showed that adolescents identified at birth as having AAT deficiency had decreased smoking rates and no adverse psychologic effects, the demonstration of parental distress and adverse effects on the mother-child relationship, coupled with the potential of discriminatory effects and the unknown cost-effectiveness of such screening programs, warrants that newborn population testing not be performed at this time.

2. Adolescents: more than 11 years old.

Recommendation Type D: It is recommended that genetic testing not be performed.

Rationale: An adolescent screening program is potentially more logical than newborn screening, as preventive measures can be instituted at the time of testing and before onset of unhealthy lifestyle choices (e.g., smoking). However, other factors make the desirability of such a program problematic. For example, there is a concern with the potential of discriminatory effects and the cost-effectiveness of such a program. Also, the psychologic effects from the knowledge that one is heterozygous are unknown. Finally, the presence of adequate counseling may be problematic when testing involves a large population.

Recommendation Type B: Testing should be discussed, acknowledging that it could reasonably be accepted or declined.

In countries where the prevalence of AAT deficiency is high (e.g., about 1 in 1,500 or more), coupled with high smoking rates and the presence of adequate counseling services, a voluntary program would be acceptable.

3. Adults.

Recommendation Type D: It is recommended that genetic testing not be performed.

Rationale: As described above for adolescents. Recommendation Type B can also be made if similar conditions apply.

4. Smokers with normal spirometry.

Recommendation Type C: Genetic testing is not recommended.

Rationale: The low prevalence of AAT deficiency (prevalence may be lower than in the general population, as normal spirometry despite a history of smoking may indicate that such individuals may not have AAT deficiency), coupled with potential adverse psychosocial effects, makes such testing problematic.

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