Alpha-1 antitrypsin (α1-AT) deficiency is one of the most common hereditary disorders among Caucasians, characterized by reduced level or absence of serum α1-AT and is a high risk for developing pulmonary emphysema and/or liver disease (1). Although α1-AT is an important cause of emphysema in 3rd and 4th decade of life and a usual cause of liver disease in children, but it may causes pulmonary disease in children. α1-AT is a glycoprotein produced by the liver. Its primary function is to protect the lungs tissue from proteolytic enzymes released from dead bacteria or leuckocytes in the lung. Protease concentration of the leukocytes may be an important factor in severity of pulmonary disease with a given level of α1-AT (2,3).
Aim of this article is reporting a 13 year old boy with α1-AT deficiency that presented with chronic bronchopulmonary involvement and repeated hospital admission without apparently liver parenchymal disorder.
The patient was a 13 years old male child of second degree consanguineous parents who was admitted to emergency ward of our hospital presented with respiratory distress, fever, productive cough predominantly in lying down position from one week ago. He had history of recurrent bronchopneumonia from about 5 years ago with repeated hospital admission and conservative management with several courses antibiotic and mucolytic therapy. He had history of exertional dyspnea from sometimes ago. He was a boy with normal birth weight, however sever failure to thrive, anorexic and malnourished at this time. There was no history of foreign body aspiration. He had no history of chronic diarrhea or any features of hepatic and enteral problem. His weigh was 18.300 kg, height 111cm, head circumference 51cm, cooperative and mentally normal. He had tachypnea (Respiratory Rate; 43), Palse Rate: 96, body temperature: 38.8, examination of oronasopharynx was normal. Chest appeared normal apparently. In auscultation there were bilateral course crepitations and generalized wheezing in both lungs. Sinuses X-Ray was normal but only mild opacity of left maxillary sinus. Chest x-ray showed diffuse emphysema and pulmonary hilar infiltration and cystic bronchietasis. An HRCT showed bilateral bronchectasis with pulmonary fibrosis. There was no evidence of foreign body or lymphadenopathy. The figures show some of images that were taken from the patient in different times (Figure 1-3).
Hemogram showed: WBC: 26300, Neutrophil count: 62%, Lymphocyte: 36%, eosinophil: 2%, BUN: 10.8, Creatinin: 0.65, SGOT: 12, SGPT: 58, ALP: 230, Ca: 9.6, P: 3.8, Na:145, K:4, PT:14, PTT: 46, Serum Albumine: 5.18gr/dl, Alpha-1-globulin: 0.05gr/dl, Alpha-2-globulin: 0.7gr/dl, Beta globulin: 1.27gr/dl, Gamma globulin: 2.8gr/dl, A/G ratio: 1.08, IgG:1300mg/dl, IgA: 210mg/dl, IgM: 105mg/dl, ABG= Po2: 78mmHg, O2-Sat: 85.7%, PH: 7.31, Pco2: 24.6mmHg, Hco3: 12.1, 5 unit PPD test: 4mm diameter, sweat chloride test: Na: 44, Cl: 52. Serum α1-AT level: 18mg/dl. Profile of serum protein electrophoresis is shown in Fig 4. Sputum was negative for acid fast bacillus.
Bronchoscopy showed evidence of bilateral bronchiectasis with profuse sputum.
Family history was negative for tuberculosis or allergic respiratory disease.
His father was cigarette smoker for long time.
α-ATD was first identified in 1963, together with its association with the inherited form of early onset of sever lower zone panacinar emphysema. α1-AT is synthesized in the liver and protects lung alveolar tissues from destruction by neutrophil elastase and other proteases (4,5).
α-ATD is a common autosomal recessive condition (1:1600 to 1:1800) in which liver disease results from retention of abnormal polymerized α1-AT in the endoplasmic reticulum of hepatocytes, and emphysema results from alveolar wall damage (6).
α1-AT constitutes about a 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction (7).
The clinical consequences of α1-ATD in childhood might be presented as neonatal jaundice, cholestasis, chronic liver disease; hemorrhagic disease and sometimes lung disease, membrano proliferate glomeroulonephritis, panniculitis, nectotizing vasculitis and early onset emphysema especially in smokers are associations with α1-ATD in adult life (8,9).
α1-ATD is one of the 3 most common lethal genetic disorder as cystic fibrosis and down syndrome. It affects mainly Caucasians (whites) from northern Europe. New data were presented, demonstrating that it is a world wide racial and ethnic distribution, found in various populations of African blacks, Arabs, Jews in The Middle East, Central, Far East and Southeast Asians, as well as whites in Australians, Europe, New Zealand and North America. In a total population of 4.4 billion in the 58 countries surveyed, there are at least 116 million carriers (with Pi phenotypes PiSZ and PiMZ) and 3.4 million with deficiency of alleles combinations (phenotypes PiSS, PiSZ) for the two most prevalent deficiency alleles PiS and P1Z (10, 11). In our country there is no documental prevalence of this disorder (8, 12,13)
α-ATD should be considered in differential diagnosis of chronic pulmonary disease in childhood, obstructive Jaundice in the newborn, cirrhosis in children and adults, familial early onset obstructive lung disease in adult, and combined pulmonary and hepatic disease in childhood and adolescence. It is the most common genetic cause of liver disease and second indication of liver transplantation after than biliary atresia in children (14-16). α-ATD demonstrates the interaction of inflammation with environmental infectious and toxic risk factors and the notion that chronic lung or liver disease in adults may have their origins in childhood, therefore progression may be hated if appreciated in their early phases (13, 17).
α1-AT a glycoprotein, synthesized by liver hepatocytes and is found in most biologic fluids. It accounts for 90% of the area under the α1 peak in serum protein electrophoresis and is responsible for 80 – 90% of serum trypsin inhibitory capacity. Pattern of protein electrophoresis in a normal subject and a patient with α1-ATD is shown in fig 5.
Name of α1-AT derived from protease inhibitor (Pi) activity including elastase, proteases, collagenase, chymotypsin, plasmin and thrombin. α1-AT is an acute phase reactant, serum levels rising in response to infection, inflammation and stress (8, 18,19).
Antielastase activity protects elastin fibers of pulmonary tissue from proteolytic action of elastase like enzymes that are released from leukocytes and macrophages during process of natural decay or inflammation resulting from a variety insults. A deficiency or decreased serum level is of α1-AT activity is due to altered configuration of α1-AT molecule that prevents its release from hepatocytes, contribute to accelerated and even irreversible tissue damage. Not all α1-AT deficient individuals develop pulmonary disease strongly suggest other exogenous and endogenous risk factors variance in this disorder (15, 20).
The serological expression (phenotype) α1-AT is inherited as two autosomal codominant allele (genotype) of which there are nearly 24 allelic Pi variants, characterized by theire elecerophoretic mobility in starch and polyacrylamide gels. Serum level of α1-AT is under genetic control as determined by the serum Pi type. Profound α1-ATD (PiZZ with serum level 10-20% those of PiMM) should be suspected when there is low or flat alpha region on simple protein electrophoresis. The diagnosis of α1-ATD is based on altered migration of abnormal α1-AT molecule in serum specimens subjected to isoelectric focusing and analysis (15, 18, 21). The phenotype should be determined in all suspected cases.
The most common allele is M (PiM) and homozygous individuals (MM) produce normal amounts of α1 antitrypsin (serum levels 150-350mg/dl). The most common form of α1-ATD is associated with allel Z, or homozygous PiZ (ZZ). Serum levels of α1-AT in these patients are about 10-15% of normal serum levels. Patients with PiSZ and those with the null gene (no produce any α1-AT) are high risk for early onset lung destruction. Serum levels less than 80mg/dl suggest significant risk for lung disease (4, 16).
Our case had nearly flat α segment of protein electerophoretic profile of his serum and low level (18mg/dl) of serum α1-AT.
Pulmonary involvement presents as slowly progression dyspnea, though many patients initially have symptoms of cough or sputum production and wheezing due to progressive panacinar emplysema and bronchopulmonary destructive inflammatory process, evidenced by increased basilar lucency and infiltrative changes on chest X-Ray. As the disease progress, chronic cough exercise intolerance, chronic bronchitis and bronchiectasis add to clinical picture. Cigarette smoking and air pullotants definitely contribute to early onset presentation. Although pulmonary involvement usually presents in the third decades of life, due to clinical case variability and genetic variants, our case presented with pulmonary disease in childhood (22-24).
Treatment involves bronchodilation, physical rehabilitation, smoking cessation and intravenous augmentation therapy with α1-AT, aggressive treatment of pulmonary infection, routine use of pneumococial, influenza vaccine and lung transplantation (4, 25-29).
Conservative management advised and was done in our patient with marked improvement. Augmentation therapy with α1-AT was not available in our facility set.
Phenotyping is required to confirm α1-ATD. More than 100 variants of ATD have been identified but only one phenotype, PiZZ is responsible for nearly all cases of ATD emphysema and liver disease. SERPINA I gene that formerly known as Pi is located in the long arm of chromosome 14. Chest X- Ray, liver function tests, sweat chloride test, serum protein and immune electrophoresis and high resolution CT of chest might be required for definitive diagnosis and evaluation (3, 9).
This article suggest that if a child presents with chronic or repeated bronchopulmonary signs and lung destructive disorder, α1-AT work up should be done as same as the children present with cholestatic and or chrome liver disease.
Conflict of interest: none declared