α-1-Antitrypsin deficiency: a need for screening?

Screening, 1 (1992) 195-201 0 1992 Elsevier Science PublishersB.V. All rights reserved 0925-6164/92/%5.00

SCREEN 00026

a- LAntitrypsin deficiency: a need for screening? B. Niggemann” and IS. Paulb p University Childrens Hospital, Berlin, Germany, and b University Childrens Hospital, Heidelberg, Germany

(Accepted 22 May 1992)

a-1-Antitrypsin deficiency is one of the most common hereditary disorders. Cholestasis and cirrhosis in infants and emphysema in adults are the most important clinical manifestations.

Prevention of liver disease is not possible; transplantation is reserved for cases of severe cirrhosis. A preventive measure to slow down pulmonary decline is the creation of a nonsmoking environment; therapy is augmentation. We recommend selective screening for children with hepatopathy or recurrent respiratory symptoms, in order to identify heterozygote and homlozygote AT-deficient children, especially in view of promising therapeutic approaches currently under investigation. It should also be possible to conduct prospective studies with these individuals. General newborn screening is not yet justified. Key worak: a-I-Antitrypsin deficiency; Children; Liver disease; Lung; Screening

1ntroduc:tion a-1-Antitrypsin deficiency is one of the most common hereditary disorders. a-lAntitrypsin (AT) is a small monomeric glycoprotein with a molecular mass of approximately 52 kDa. It is predominantly produced in the liver and secreted by hepatocytes into plasma [l]. Its major function is the inactivation of proteases released by cells such as granulocytes [31]. It is therefore the main inhibitor of neutrophil elastase, a powerful proteolytic enzyme, which degrades extracellular structural proteins [l]. In addition to the lung, the liver is also affected by a deficiency of AT. ‘Whereas the clinical consequences of lung damage are closely correlated to the plasma concentration, the pathogenesis of liver disease is much less clear. AT is encoded by a single structural gene on chromosome 14q 31-32.3 [13]. The inheritance is codominant [13]. Plasma levels of AT are genetically determined by more than 75 allelic variants [l]. Well known alleles, which encode states of protease Correspondence to: Dr. B. Niggemann, University Childrens Hospital (KAVH), Dept. Pediatr. Pneumology and Immunology, Heubnerweg 6, D-1000 Berlin 19, Germany.

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inhibitor (PI) deficiency are M, S, Z and 0. The most common phenotype PI MM, with normal plasma concentrations, accounts for about 85% of the population. The occurence of AT deficiency varies in different populations. The prevalence of the most clinically important form of AT deficiency, the homozygote PI ZZ type, is about 1: 1500, the gene frequency about 0.026 in the European population [3 11. The sex ratio is Ml : Fl [31]. In the lung AT deficiency leads to degradation of structural proteins and emphysema due to insufficient protection against neutrophil elastase. This occurs by the 3rd or 4th decade of life in about 60% of PI ZZ individuals. AT deficiency is responsible for approximately 2% of all cases of emphysema. The age of onset in smokers is much lower than for non-smokers [31]. The lung function also deteriorates much more rapidly in smokers than non-smokers. Although clinical manifestations of symptomatic emphysematous lung disease are very rare in childhood [31], there are case reports [37]. The correlation between bronchial asthma and AT deficiency in childhood has been recently reviewed [24]. Liver manifestation of AT deficiency becomes apparent in about 10% of the PI ZZ infants within the first 2 months in the form of cholestasis [1,31]. While about 50% of homozygous infants have abnormal liver tests without clinical symptoms, development of cirrhosis is noted in about 20% of infants with cholestasis [ 11. About 2% of PI ZZ infants die from cirrhosis. Death may follow 2 months to 4 years after decompensated liver cirrhosis [13]. Prognosis of infants without cirrhosis is quite good and cholestatic symptoms usually subside spontaneously within weeks to 8 or 12 months [1,13]. Liver and lung manifestation are together very rare [l].

Screening criteria When assessing the need for newborn screening, several questions have to be considered: - frequency of the hereditary disease? _ severity of the disease? _ recognizable latent or early symptomatic stage? - facilities for diagnosis? - accepted form of treatment? - prevention possible? _ cost/benefit ratio? The following is an attempt to elaborate these questions about AT deficiency. Frequency of the disease

The prevalence of the homozygous PI ZZ phenotype varies from country to country: In the Scandinavian population it is about 1 : 1500 [30], in England about 1 : 3400 [13]. The homozygous form is therefore one of the most common hereditary disorders in Europe. Thus the prevalence is comparable to or even higher than many other screened hereditary disorders.

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Severity Iof the disease

Two to three percent of the homozygous infants suffer from cirrhosis in early childhood; 25% of these die in the first decade of life [13]. For PI ZZ adults there appears to be a significantly increased risk of cirrhosis and primary hepatoma in males over the age of 50 [ 131. Sixty percent of PI ZZ individuals are at risk of developing progressive pulmonary emphysema [ 131, usually in the 3rd or 4th decade of life [31]. A greatly reduced rate of survival was demonstrated, regardless of sex [16]. AT deficiency therefore represents a severe life-threatening disease in childhood and adulthood. Recognizable latent or early symptomatic stage

Liver manifestation can be diagnosed at an early stage by routine laboratory liver parameters and liver function tests before clinical signs may appear. Lung function tests cannot be performed in very young children, but symptomatic pulmonary manifestation only occurs rarely in childhood. However, a study from England reported signs of hyperinflation in some children with liver disease due to AT deficiency at the age of 3 to 16 years [9]. Facilities for diagnosis

Measuring plasma concentration of AT represents a routine laboratory test and can easily be performed by every clinical laboratory. Normal serum electrophoresis does not exclude AT deficiency. In the case of decreased plasma concentration PI phenotyping is indicated. Several authors have described methods for measuring plasma concentration and PI typing from dried blood [7,14,17-19,22,26,28] or semiquantitative methods for detecting AT deficiency from very small amounts of blood [6]. Prenatal diagnosis by amniocentesis, chorionic villus biopsy or fetal blood sampling has been described by several authors [2,3,5,8,29]. All these tests could very well detect AT deficient patients within the first days of life. Forms of treatment

The management of liver disease is that used for chronic cholestasis and for cirrhosis [13]. There is no specific treatment for hepatic manifestations associated with AT deficiency [ 131. AT augmentation therapy is of no value, because low plasma concentrations are not the cause of the liver disease. Liver transplantation is still the treatment of choice and should be planned as soon as liver cirrhosis decompensates. Liver transplantation corrects the serum phenotype to that of the donor [13]. Concerning pulmonary emphysema there are several reports about intravenous augmentation therapy with AT preparations to re-establish the lung anti-elastase defences. [ 10,40,42]. This represents the current most advanced form of treatment for AT deficiency [lo]. However, there are still some questions remaining, e.g., when to initiate augmentation therapy, especially in children. Some efforts have been recently made to evaluate the advantage of aerosol augmentation therapy [ 1 I, 121. Before general clinical application further long-term studies will be needed. Gene therapy might be a promising approach in years to come (e.g.,

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the addition of normal human AT gene to the genome of cells of deficient individuals to permit the expression of the normal AT gene and consequently re-establishment of normal levels of AT) [lo]. Prevention Because smoking has been shown to be an important factor influencing the onset of emphysema as well as the rate of decline of lung function, non-smoking or preventing the beginning of smoking should be the main ‘therapeutic’ goal of advising patients with AT deficiency [41]. This probably also holds true for passive-smoking and exposure to other irritants in childhood, although there are no clinical studies so far. Respiratory infections should be treated with antibiotics at an early stage, if there is suspicion of bacterial involvement. There are no data about the prophylactic value of augmentation therapy in PI ZZ children without clinical manifestation. Costlbenejt ratio The costs of plasma concentration measurement of AT are low and do not exceed those for other screening tests. However, there are no data about the cost/benefit ratio in the literature. Discussion Several authors have published their experience with screening procedures for AT deficiency (Table 1). For neonatal screening the blood specimens were obtained by a heel-prick and collected on a filter paper during the first week of life within the general screening procedure or from cord blood. Therefore, no extra blood sampling is necessary. Cut-off levels were rather different in these studies: 0.40 mg/ml [25], 0.80 mg/ml [28], 1.63 mg/ml [15]. Follow-up studies 4 to 12 years later provide interesting insight into epidemiological data of AT deficient children identified by neonatal screening [34-361. While in most of the studies from the 70s the authors concluded that general screening of newborns was not warranted because there was no specific treatment for AT defiTABLE 1 Survey of the AT screening studies Years

Country

Number

Age of subjects

Literature

1971 1971-1974 1972-1974 1974-1977 1978 1984-1985 1984-1989 1987

Finland USA Sweden Netherlands Sweden Belgium Belgium USA

664 107,038 200,000 95,033 11,128 10,329 39,289 20,000

students first week first week first week 18 year olds cord blood first week blood donors

27 25 32 4 33 15 28 30

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ciency [2.3,25], more recent studies emphasized a re-examination of the indication for general newborn screening [I 5,411, because of the availability of treatment options such as augmentation therapy for lung manifestation. Psychosocial effects of screening for AT deficiency have been intensively studied by a Swedish group after nation-wide screening was discontinued due to observations that identification of AT deficiency in newborns seemed to have negative psychological effects in some families [20,21,38,39]. However, long-term follow-up 5 to 7 years later revealed no negative long-term consequences for the parents of children with AT deficiency with respect to reproduction rates, marital status and social class level, view of .their life situation, attitude about themselves as parents, view of the child’s personality and behaviour, concern for the child’s current health, or attitudes towards the pediatric health service in general [21]. Most parents said that they welcomed the fact that child’s AT deficiency had been identified at such an early stage [21]. On the other hand, early detection did not lead to a marked reduction of smoking habits in the parents [21]. Conclusion There are various screening options: (1) general newborn screening; (2) facultative screening as an offer to parents; and (3) selective screening of patients with pulmonary emphysema or liver disease at any age. Balancing all the mentioned arguments we propose a selective screening at present, because promising therapeutic possibilities are under investigation. General newborn screening seems not to be justified at the moment, since preventive measures (especially concerning liver manifestation) are not convincing. In a few years time general screening might replace selective screening, when the role of preventive measures on the prognosis of AT deficiency and the role of heterozygotes will become clearer. Further prospective and controlled pilot studies with large numbers of children are warranted for this reason. At present we would like to recommend use of a selective screening, with which risk patients can be detected. One argument for such a screening could be that we need to know which children show AT deficient phenotypes, in order to be able to conduct studies and to assess preventive measures. In our view, indications for selective screening are (1) infants and children with liver disease; (2) children with recurrent respiratory infections, bronchial asthma, pulmonary emphysema etc.; and (3) siblings and other family members of children with known AT deficiency. In all these cases plasma concentration should be determined. We propose, where concentrations are lower than approximately 1.2 mg/ml (nephelometric determination) phenotyping is advisable, because the probability of detecting a PI type of clinical significance is much more likely below this cut-off level. References 1 Birrer P, McElvaney NG, Chang-Stroman LM, Crystal RG. cr-1-Antitrypsin deficiency and liver disease. J Inher Metab Dis 1991;14:512-525.

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