**5.5 Alpha-1 protease inhibitor (A1PI) deficiency**

A1PI , also known as alpha1-antitrypsin, is a serine proteinase inhibitor(serpin) that is produced mainly in the liver and found in the bloodstream and permeates tissues including the lung. A1PI inhibits various serpins including pancreatic trypsin, chymotrypsin but the main target is the neutrophil elastase(Brantly et al,1988;Travis,1989 as cited in Shapiro SD,2010). A1PI is also an acute phase reactant, with its serum concentration rising during pregnancy, during infections, after severe burns, and in the presence of malignant tumors. Smoking elevates the serum A1PI concentration by about 20%.

A1PI is coded by a single gene with two alleles on chromosome 14q32.1 producing a glycoprotein composed of 394 amino acids. The A1PI gene is highly pleomorphic and more than 75 alleles are known, and they have been classified into normal (normal serum levels and normally functioning A1PI), null (undetectable A1PI in the serum), deficient (serum A1PI levels lower than normal), and dysfunctional (A1PI levels are normal but does not function normally)(Brantly et al,1988 as cited in Shapiro SD,2010).

Most variants of A1PI arise point mutations with a single amino acid substitution. The Z variant(most common and severe disease) results from the substitution of a lysine for a glutamic acid at position 342, which changes the charge and the electrophoretic mobility of the molecule(Yoshida et al,1976 as cited in Shapiro SD,2010). The mutant protein polymerizes and the aggregated form causes hepatic cell injury., The Z protein is also incompletely glycosylated, which may interfere with the protein's excretion from the liver into body fluids. (Ekeowa et al,2009;Gooptu & Lomas,2008 as cited in Shapiro SD,2010). The protein looses its physiologic function of inhibiting the NE.

Current Overview of COPD with Special Reference to Emphysema 131

The natural history of COPD probably starts at pre-conception age related to genetics and intra-uterine lung development and growth, extending into early life events such as childhood and adolescent lung growth and injury from infections as well as later events

Since the disease progresses slowly over the years, the earlier stages of the disease are often "silent" and mostly unnoticed by the patient. Exertional dyspnea, the earliest symptom, primarily from dynamic hyperinflation from exercise induced tachypnea, results in subconscious preferential sedentary lifestyle and thus avoiding the symptoms till later

The intrauterine growth of lung includes development of conducting airways, gas exchange structures, including respiratory bronchioles and alveoli, but branching of alveolar wall continues postnatally for several years and usually complete by the first decade of life(Ten Have-Opbroek,1981 as cited in Shapiro SD,2010). Subsequent growth of the lung is due to increase in alveolar size and increase in airway diameter, but not in number. Maximal lung function is attained in young adulthood and remains relatively constant as a plateu for some years before declining in a slowly accelerating manner in older age(Weiss & Ware,1996 as cited in Shapiro SD,2010). The decline averages 20 mL/yr increasing in an accelerating

Smoking adversely affects the entire course, with interference in maximal lung capacity attainment if smoking starts in the early growth phase, to shortening of duration of the plateu phase, to rapid decline in lung function in later age(Burrows,1990 as cited in Shapiro SD,2010). This effect is very well depicted in the "Fletcher-Peto curve" shifting the plot downwards and earlier in age (Fletcher, 1976). The average COPD patient who smokes loses almost twice the lung function than usual(about 2 L of FEV1 over 50 years, an average decline of about 40 mL/yr). Acute exacerbations have descending step-ladder like effect with acute drops over short period with incomplete recovery resulting in faster drop of lung function(Burrows,1990 as cited in Shapiro SD,2010). Smoking has a predictable dosedependent deleterious effect on the lung function and cessation of smoking has beneficial slowing of disease progression if initiated early enough in course of disease (Anthonisen et

Some individuals experience a rapid decline in lung function (Gottlieb et al.,1996 as cited in Shapiro SD,2010). Faster decline in lung function is noted in patients with low baseline lung function, less reversibility to β2-agonists, more severe bronchial hyperresponsiveness, mucus production, male sex, and frequent exacerbations(ATS,2010). Identification of slow and rapid decliners in longitudinal studies such as the Lung Health Study has allowed exploration of biomarkers to characterize these groups. Importantly, systemic markers of inflammation have been associated with poorer lung function, and, in some, studies, with an increased rate of decline in lung function (Fogarty et al.,2007;Shaaban et al.,2006; Sin &

Although early stage COPD is difficult to diagnose, newer studies have shown a poorer prognosis among these population primarily from adverse cardiac events (Ashley et al., 1975; Mannino et al., 2003 as cited in Shapiro SD,2010). The cardiac events may be linked to the extrapulmonary effects of COPD, especially elevated systemic inflammatory mediators.

Identifying and treating this group thus can have valuable prognostic benefit.

such as adult lung exposures to cigarette smoke and occupational inhalants.

stage.(O'Donnell et al.,2001 as cited in Shapiro SD,2010)

manner and by age 50, there is an average drop of FEV1 by 1L.

al,1994;Buist et al.,1976 as cited in Shapiro SD,2010).

Man,2003 as cited in Shapiro SD,2010).

The normal (M) alleles are found in about 90% of persons of European descent with normal serum A1PI levels(150 to 350 mg/dL or 20 to 48 µmol/dL); their phenotype is designated Pi MM. More than 95% of persons in the severely deficient category are homozygous for the Z allele(Pi ZZ) and have serum A1PI levels of 2.5 to 7 µmol/dL (mean, 16% normal)with an estimated prevalence between 1 in 1600 to 1 in 4000.This allele is mostly found in whites of northern European descent.

Rarely observed phenotypes associated with low levels of serum A1PI include the following: Pi SZ and persons with nonexpressing alleles; Pi null, found in homozygous form as Pi null-null and found in heterozygous form with a deficient allele as Pi Z null. Persons with phenotype Pi SS have A1PI values ranging from 15 to 33 µmol/dL (mean, 52% of normal). The threshold protective level of 11 µmol/dL (35% of normal) is based on the knowledge that Pi SZ heterozygotes, with serum A1PI values of 8 to 19 µmol/dL (mean, 37% of normal), rarely develop emphysema. Pi MZ heterozygotes have serum A1PI levels that are intermediate between Pi MM normals and Pi ZZ homozygotes (12–35 µmol/dL; mean, 57% of normal). There appears to be a small increase in risk of COPD in all Pi MZ individuals.

COPD in homozygous A1PI deficiency patients is characterized by premature development of severe panacinar emphysema usually in the basilar regions of lung (Silverman & Sandhaus,2009). The onset of dyspnea occurs at a median age of 40 years about 1-2 decades earlier than rest of the population(Silverman & Sandhaus,2009 as cited in Shapiro SD,2010). However smoking has supradditive effect on poorer prognosis both with earlier onset severity and poorer prognosis of the disease(Janus et al,1985 as cited in Shapiro SD,2010). Radiographically, disease is more prominent in PiZZ patients and worse in basilar regions, sometimes hairline arcuate shadows separating markedly radiolucent areas in the lung bases from the less severely involved upper portions of the lungs (Gishen et al,1982;Hepper et al,1978 as cited in Shapiro SD,2010).

A1PI deficiency is diagnosed by measuring the serum A1PI level, followed by Pi typing for confirmation. However, by the time they develop COPD symptoms, they already have significant liver disease often diagnosed in infancy/childhood with hepatomegaly or hepatosplenomegaly and evidence of cholestasis and elevation of hepatocellular enzymes. Screening for PiZZ in COPD patients is not recommended at present. Augmentation therapy with A1PI supplementation has been proposed for COPD patients with PiZZ genotype as per guidelines issued by ATS(ATS,1995)
