Alpha 1-PI for emphysema due to alpha 1-Antitrypsin deficiency

Alpha 1-PI for emphysema due to alpha 1-Antitrypsin deficiency

Ira D. Horowitz

[Alpha.sub.1] -PI for Emphysema Due to [Alpha.sub.1] -Antitrypsin Deficiency

[Alpha.sub.1] -antitrypsin deficiency is a genetic disorder that may result in premature pulmonary emphysema. Affected persons are deficient in the protective protein, [alpha.sub.1] -proteinase inhibitor ([alpha.sub.1] -PI). The diagnosis should be considered in patients with signs of emphysema by age 40 (especially nonsmokers), those with predominantly lower lobe disease and those with a family history of premature emphysema. Recently, human [alpha.sub.1] -PI has been purified and is available to prevent the development of disabling emphysema in affected individuals. Weekly infusion of the concentrate is effective in raising serum levels and is very safe, with only rare minor adverse effects.

In 1963, Laurell and Erickson (1) discovered the relationship between a rare inherited protein deficiency and the development of emphysema. The protein was identified as [alpha.sub.1] -antitrypsin. It was so named because trypsin was the first enzyme found to be inhibited by its action, although subsequent investigations showed that the protein inhibits numerous other enzymes. Patients with deficiency of this protein were noted to develop emphysema in young adulthood, presumably because of the unopposed action of enzymes on lung tissue. The human disease state has retained the name [alpha.sub.1] -antitrypsin deficiency, but the deficient protein is now referred to as [alpha.sub.1] -antitrypsin deficiency, but the deficient protein is now referred to as [alpha.sub.1] -proteinase inhibitor ([alpha.sub.1] -PI), reflecting a better understanding of its effects.

[Alpha.sub.1] -Antitrypsin Deficiency

The current “protease-antiprotease” theory of the pathogenesis of emphysema suggests that most human emphysema develops when the protective effects of [alpha.sub.1] -PI, the predominant protective substance in the lung, are overwhelmed by the destructive effects of proteolytic enzymes, largely released by polymorphonuclear leukocytes (PMNs). Thus, the balance that normally exists between destruction and protection of lung tissue is disrupted (Figure 1).

Support for this hypothesis has come from animal experiments showing that pretreatment of hamsters with [alpha.sub.1] -PI prevents papain-induced emphysema. (2) In humans, perhaps the most critical PMN enzyme responsible for the development of emphysema is elastase. (3) Neutrophil elastase attacks numerous connective tissue proteins of the alveolar interstitium, including elastin and collagen types I and III. (4) [Alpha.sub.1] -PI is responsible for more than 90 percent of the antielastase activity in the lung. (5) The substance inactivates neutrophil elastase by forming a tight, noncovalent bond. (6) Other proteases inhibited by [alpha.sub.1] -PI include chymotrypsin, cathepsin G, plasmin, thrombin, tissue kallikrein, factor Xa and plasminogen. (7)

Genetics and Molecular Biology

[Alpha.sub.1] -PI, a glycoprotein with a molecular weight of approximately 52,000 daltons, is manufactured predominantly in the liver and, to a lesser degree, by mononuclear phagocytes. [Alpha.sub.1] -PI consists of a folded polypeptide chain of 394 amino acids with three carbohydrate side chains. (8)

The gene responsible for the expression of [alpha.sub.1] -PI is located on chromosome 14; the defect leading to [alpha.sub.1] -antitrypsin deficiency is caused by a mutation on this gene. (9) The two parental [alpha.sub.1] -PI genes are codominantly expressed, meaning that the phenotype is a result of the two parental [alpha.sub.1] -PI alleles being expressed equally. (10)

More than, 75 [alpha.sub.1] -PI variants have been identified, although some have been found only in single individuals or in one family. (11) The variants are due to a single amino acid substitution that induces an abnormality in intracellular processing. As a result, reduced amounts of [alpha.sub.1] -PI are secreted by the liver. (8)

The [alpha.sub.1] -PI variants can be categorized into four groups: normal, deficient, null and dysfunctional. (10) Letters are used to identify the different alleles according to the protease inhibitor system. The M variant is the most common normal form, and the Z variant is the most significant deficient form. A patient with the phenotype ZZ typically has [alpha.sub.1] -PI levels from 10 to 15 percent of those found in persons of the MM phenotype. (12) In addition to being found in reduced amounts, the Z variant is not as effective as normal variants in inhibiting neutrophil elastase. (13)

The rare null-null phenotype is characterized by no detectable [alpha.sub.1] -PI levels in the serum. This phenotype leads to an even greater susceptibility to the development of emphysema, with patients rarely living beyond 40 years of age. (14)

Only one variant has been identified in the dysfunctional group; it is characterized by normal serum [alpha.sub.1] -PI levels but reduced antielastase activity. (10)

Clinical Manifestations

Age at presentation varies widely among patients with a deficiency of [alpha.sub.1] -PI. Some may develop symptoms of severe dyspnea by age 30, while others may never develop any clinical signs. The combination of cigarette smoking with [alpha.sub.1] -antitrypsin deficiency is very destructive, leading to a much earlier presentation of severe, symptomatic emphysema. (15) [Alpha.sub.1] -antitrypsin deficiency appears to predispose the lower lung regions to panacinar emphysema (Figure 2). (15)

In infants and children, deficiency of [alpha.sub.1] -PI usually presents as liver disease leading to cirrhosis. Adults with emphysema also may have liver involvement. On histologic examination, diseased livers contain characteristic periodic acid-Schiff (PAS)-positive, diastase-resistant hepatocyte inclusions that appear to be composed of an unexcreted [alpha.sub.1] -PI precursor. (16) To date, no cases of liver disease have been found in the null-null population, suggesting that the deposits in the liver found in patients with the other abnormal variants lead to the impaired hepatic function. (14) Liver transplantation has proved successful as a treatment modality, (17) resulting in normal serum levels of [alpha.sub.1] -PI.


A specific diagnosis can be made by measuring the serum level of [alpha.sub.1] -PI. A threshold level of 50 mg per dL (0.5 g per L) apparently determines whether a person will develop emphysema. (18) The MM phenotype is typically associated with levels of 220 mg per dL (2.2 g per L), with a range between 150 and 350 mg per dL (1.5 to 3.5 g per L). Patients with levels below 50 mg per dL (0.5 g per L) have an 80 percent chance of developing emphysema. Levels greater than 80 mg per dL (0.8 g per L) appear to be associated with no increased risk. (18,19)


The frequency of the deficiency state varies throughout the world. For example, the prevalence of type Z homozygotes (ZZ) is estimated to be one in 1,670 in Sweden and one in 2,047 to 3,450 in the United Kingdom. In studies in the United States, the frequency generally falls within the range of the European statistics, although it was found to be as low as one in 5,097 in a study performed in Seattle. (15,20-24) Approximately 50,000 American Caucasians are thought to have the Pi(ZZ) phenotype. Blacks and Asians appear to have a much lower frequency of the deficiency. (25,26)


Human [alpha.sub.1] -PI (Prolastin) is a sterile, lyophilized preparation obtained from plasma of normal donors. After donation, the substance is tested for human immunodeficiency virus (HIV) antibody and hepatitis B surface antigen. Just as replacement of antihemophilic factor, or factor VIII (Hemofil M, Koate-HS and HT, Monoclate), prevents the development of bleeding tendencies in hemophilia, [alpha.sub.1] -PI replacement therapy prevents the destructive action of elastase on acinar pulmonary tissue.

[Alpha.sub.1] -PI is not used in patients with the hepatic manifestations of [alpha.sub.1] -antitrypsin deficiency. In such cases, liver transplantation serves as replacement therapy. Transplantation is most often performed in children. The normal liver produces the correct form of [alpha.sub.1] -PI, and not only relieves the hepatic manifestations but also prevents the development of emphysema.

Unfortunately, liver transplantation is not feasible as a form of replacement therapy in patients with emphysema. The first line of therapy for patients with [alpha.sub.1] -antitrypsin deficiency-induced emphysema, as well as for any form of emphysema, is the avoidance of cigarette smoking and atmospheric pollution. [Alpha.sub.1] -PI replacement therapy will not reverse existing emphysema, but theoretically it should stop further accelerated destruction of lung tissue.


Use of [alpha.sub.1] -PI has been approved by the Food and Drug Administration; 60 mg per kg of the [alpha.sub.1] -PI concentrate has been proved safe and effective in maintaining serum trough levels of [alpha.sub.1] -PI above the threshold of 80 mg per dL (0.8 g per L). [Alpha.sub.1] -PI replacement therapy has a half-life of 4.5 days, permitting weekly dosing. (27) In addition, the infused drug can be recovered from alveolar lining fluid and remains effective in inhibiting neutrophil elastase. (12)

Warnings and Precautions

The few minor adverse effects of replacement therapy include rare episodes of fever, lightheadedness and dizziness. No contraindications to [alpha.sub.1] -PI therapy have been identified.

The process of preparing [alpha.sub.1] -PI concentrate with heat treatment at 60 [degrees] C (140 [degrees] F) for at least ten hours appears to prevent the transmission of infectious agents, including the hepatitis B virus and HIV. (28) It is still recommended, however, that patients receiving [alpha.sub.1] -PI replacement therapy be given hepatitis B vaccine and, if treatment is to begin before safe antibody levels have time to develop, hepatitis B immune globulin.

Final Comment

Since there is no evidence suggesting that [alpha.sub.1] -PI replacement therapy would benefit the 98 percent of emphysema patients with typical smoking-related disease, [alpha.sub.1] -PI should be reserved for the relatively rare patient with [alpha.sub.1] -antitrypsin deficiency. It must be admitted that the effectiveness of replacement therapy in preventing emphysema in patients with [alpha.sub.1] -antitrypsin deficiency has not been demonstrated. The relative scarcity of patients available for study and the long-term nature of the disease itself may delay conclusive investigations for many years. (29) Furthermore, replacement therapy is expensive. In a 70-kg (154-lb) person, the treatment costs about $20,000 a year. Since current replacement therapy must be maintained for the life of the patient, the expense may be prohibitive in many cases.

The negative aspects of [alpha.sub.1] -PI treatment are balanced by the severely incapacitating and life-shortening nature of emphysema. Since the discovery of [alpha.sub.1] -PI, tremendous strides have been made in understanding the pathophysiology of this disease. In the future, patients with lung disease of other etiologies may benefit from this knowledge. Studies are currently evaluating inhalational drug delivery (30) and recombinant DNA technology for drug synthesis. (31) These studies may result in reducing the cost of [alpha.sub.1] -PI therapy and in determining the optimal dosage and route of administration.


[1.] Laurell CB, Eriksson S. The electrophoretic

[alpha.sub.1] -globulin pattern of serum in [alpha.sub.1] -antitrypsin

deficiency. Scand J Clin Lab Invest

1963;15:132-40. [2.] Martorana PA, Share NN. Effect of human

alpha-antitrypsin in papain-induced emphysema

in the hamster. Am Rev Respir Dis 1976;

113:607-12. [3.] Weissmann NG, Zurier RB, Hoffstein S. Leukocytic

proteases in the immunologic release of

lysosomal enzymes. Am J Pathol 1972;68:539-64. [4.] Bieth JG. Elastases: catalytic and biological

properties. In: Mecham RP, ed. Regulation of

matrix accumulation. Orlando, Fla.: Academic,

1986;2:17-320. [5.] Wewers MD, Casolaro MA, Crystal RG. Comparison

of [alpha.sub.1] -antitrypsin levels and antineutrophil

elastase capacity of blood and lung

in a patient with the [alpha.sub.1] -antitrypsin phenotype

null-null before and during [alpha.sub.1] -antitrypsin

augmentation therapy. Am Rev Respir

Dis 1987;135:539-43. [6.] Travis J, Salvesen GS. Human plasma proteinase

inhibitors. Annu Rev Biochem 1983;

52:655-709. [7.] Heidtmann H, Travis J. Human [alpha.sub.1] -proteinase

inhibitor. In: Barrett AJ, Salvesen G,

eds. Proteinase inhibitors. New York: Elsevier,

1986:441-5. [8.] Carrell RW, Jeppsson JO, Laurell CB, et al.

Structure and variation of human [alpha.sub.1] -antitrypsin.

Nature 1982;298:329-34. [9.] Long GL, Chandra T, Woo SL, Davie EW,

Kurachi K. Complete sequence of the cDNA for

human [alpha.sub.1] -antitrypsin and the gene for the

S variant. Biochemistry 1984;23:4828-37. [10.] Fagerhol MK, Laurell CB. The Pi system-inherited

variants of serum [alpha.sub.1] -antitrypsin. Prog

Med Genet 1970;7:96-111. [11.] Brantly M, Nukiwa T, Crystal RG. Molecular

basis of [alpha.sub.1] -antitrypsin deficiency. Am J

Med 1988;84(6A):13-31. [12.] Wewers MD, Casolaro MA, Sellers SE, et al.

Replacement therapy for [alpha.sub.1] -antitrypsin

deficiency associated with emphysema. N Engl

J Med 1987;316:1055-62. [13.] Ogushi F, Fells GA, Hubbard RC, Straus SD,

Crystal RG. Z-type [alpha.sub.1] -antitrypsin is less

competent than [M.sub.1] -type [alpha.sub.1] -antitrypsin as

an inhibitor of neutrophil elastase. J Clin Invest

1987;80:1366-74. [14.] Garver RI Jr, Mornex JF, Nukiwa T, et al. [Alpha.sub.1] -antitrypsin

deficiency and emphysema caused

by homozygous inheritance of non-expressing

[alpha.sub.1] -antitrypsin genes. N Engl J Med 1986;

314:762-6. [15.] Eriksson S. Studies in [alpha.sub.1] -antitrypsin deficiency.

Acta Med Scand 1965;177(Suppl 432):

1-85. [16.] Jeppsson JO, Larsson C, Eriksson S. Characterization

of [alpha.sub.1] -antitrypsin in the inclusion

bodies from the liver in [alpha.sub.1] -antitrypsin deficiency.

N Engl J Med 1975;293:576-9. [17.] Putnam CW, Porter KA, Peters RL, Ashcavai

M, Redeker AG, Starzl TE. Liver replacement

for [alpha.sub.1] -antitrypsin deficiency. Surgery 1977;

81:258-61. [18.] Larsson C. Natural history and life expectancy

in severe [alpha.sub.1] -antitrypsin deficiency, Pi Z.

Acta Med Scand 1978;204:345-51. [19.] Kueppers F, Black LF. [Alpha.sub.1] -antitrypsin and

its deficiency. Am Rev Respir Dis 1974;110:

176-94. [20.] Cook PJ. The genetics of [alpha.sub.1] -antitrypsin: a

family study in England and Scotland. Ann Hum

Genet 1975;38:275-87. [21.] Blundell G, Frazer A. [Alpha.sub.1] -antitrypsin phenotypes

in Northern Ireland. Ann Hum Genet

1975;38:289-94. [22.] Arnaud P, Galbraith RM, Faulk WP, Black C.

Pi phenotypes of [alpha.sub.1] -antitrypsin in southern

England; identification of M subtypes and

implications for genetic studies. Clin Genet

1979;15:406-10. [23.] Dykes DD, Miller SA, Polesky HF. Distribution

of [alpha.sub.1] -antitrypsin variants in a U.S.

white population. Hum Hered 1984;34:308-10. [24.] O’Brien ML, Buist NR, Murphey WH. Neonatal

screening for [alpha.sub.1] -antitrypsin deficiency.

J Pediatr 1978;92:1006-10. [25.] Pierce JA, Eradio B, Dew TA. Antitrypsin phenotypes

in St. Louis. JAMA 1975;231:609-12. [26.] Lieberman J, Gaidulis L, Roberts L. Racial distribution

of [alpha.sub.1] -antitrypsin variants among

junior high school students. Am Rev Respir Dis

1976;114:1194-8 [27.] Gadek JE, Klein HG, Holland PV, Crystal RG.

Replacement therapy of [alpha.sub.1] -antitrypsin deficiency.

Reversal of protease-antiprotease imbalance

within the alveolar structures of PiZ subjects.

J Clin Invest 1981;68:1158-65. [28.] Mitra G, Dobkin MB, Louie RE, Mozen MM.

Inactivation of viruses in therapeutic products

derived from human plasma. Am J Med 1988;

84(6A):87-90. [29.] Burrows B. A clinical trial of efficacy of antiproteolytic

therapy: can it be done? Am Rev

Respir Dis 1983;127:S42-3. [30.] Smith RM, Spragg RG. Production and administration

to dogs of aerosols of [alpha.sub.1] -proteinase

inhibitor. Am J Med 1988;84(6A):48-51. [31.] Rosenberg S, Barr PJ, Najarian RC, Hallewell

RA. Synthesis in yeast of a functional oxidation-resistant

mutant of human alpha-antitrypsin.

Nature 1984;312:77-80.

PHOTO : FIGURE 1. Effects of deficiency of [alpha.sub.1] -proteinase inhibitor ([alpha.sub.1] -PI) on lung tissue. If released into the lung, proteolytic enzymes produced by the polymorphonuclear leukocytes (PMNs) destroy the alveolar elastin and collagens. [Alpha.sub.1] -PI, which is elaborated by the liver and mononuclear phagocytes, acts to inhibit the action of elastase. In patients deficient in [alpha.sub.1] -PI, the normal processes become unbalanced, allowing the destruction of the alveolar interstitium.

PHOTO : FIGURE 2. Pathophysiology of emphysema. (A) In alveolar deflation, the connective tissue component of the interstitium relaxes and recoils, reducing the alveolar space and expelling the gases. (B) In alveolar inflation, the connective tissue component becomes tense, expanding the alveolar space and maintaining proper alveolar shape. (C) With emphysema, disruption of the connective tissue component results in an expanded and distended alveolar space that is static with little or no gas exchange. (D) Disruption of the connective tissue component leads to breakdown of the dividing walls of the airways and alveoli, resulting in panacinar emphysema.

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