Jornal de Pediatria. Print version ISSN Association between alpha 1 antitrypsin deficiency and cystic fibrosis severity. J. Pediatr. (Rio J.) [online]. , vol Alphaantitrypsin deficiency affects mainly the lungs and the liver leading, in the . RESUMO – Racional – A deficiência de alfaantitripsina é uma doença pelo ambulatório de Gastroenterologia Pediátrica da Universidade Estadual de. This report draws attention to the alpha 1 antitrypsin deficiency in newborns presented as a cholestatic syndrome. Its sub-diagnosis constitutes a major.

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Alphaantitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alphaantitrypsin deficiency may be obtained by biochemical or molecular analysis. Objective – The purpose of this study was to use DNA analysis to examine the presence of an alphaantitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease.

Associação entre deficiência de alfaantitripsina e a gravidade da fibrose cística

The mutant antitripwina S and Z of the alphaantitrypsin gene were investigated in the 12 children. Alphaantitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl S allele and Taq 1 Z allele.

A correct diagnosis is important for effective clinical follow-up and for genetic counseling.

Alphaantitrypsin A1AT is a 52 kDa glycoprotein produced mainly by hepatocytes which release 2 g of this protein, per day, into the blood stream The main function of A1AT is to inhibit the action of neutrophilic elastase, a serine protease that hydrolyzes elastin fibers in the lungs Mutations in the gene encoding for A1AT produce a protein with no inhibitory capacity and may lead to the accumulation of A1AT in inclusion corpuscles in hepatocytes, thereby a reducing the normal serum levels of this protein 4.

This deficiency is reflected as lung emphysema, chronic bronchitis or bronchiectasis 9. The accumulation of mutant Dficiencia in hepatocytes may also lead to neonatal cholestasis, chronic hepatopathy or cirrhosis 33, The A1AT gene is highly polymorphic, co-dominant and is located on the longer arm of chromosome 14 14q The common variants migrate to the center of the gel and therefore belong to the M “middle” family.

Another variant, which moves slowly in the gel, is denominated S 5. This polymorphic “locus” is generally know as the Pi protease inhibitor system. Most of the variants produce A1AT of normal quantity and quality 7, 8, However, some alleles such as variants S and Z are associated with a deficient condition that attains polymorphic frequencies as Caucasian populations and cases of a null allele in which protein production is totally absent have been deficeincia The S allele results from the substitution of adenine by thiamin in exon III of the gene, which leads to glutamic acid at position being exchanged for valine and the consequent formation of an unstable protein structure 10, 11, The Z allele results from the antitripsnia of guanine at position by adenine in exon V of the gene and leads to the formation of a ddficiencia that collects on the inner rough surface of the hepatocyte endoplasmic reticulum 6.

The diagnosis of a deficient condition is usually made after quantification of the veficiencia levels of the protein together with electrophoretic profile after isoelectric focusing 23, A more precise diagnosis requires gene analysis using DNA based techniques 12, 14, Pediztria objective of this study was to identify S and Z allele carriers in patients suspected of having this deficiency and who showed pediatri and clinical characteristics of this disease.


During the period from February, to August,a ds number of patients were referred to the Pediatric Gastroenterological Service, State University of Deficienciq, Campinas, SP, Brazil, in order to investigate hepatic diseases. From this number only 12 patients did not show any definite diagnosis negative results to viral hepatitis, autoimmune hepatitis and Wilson’s disease.

Those patients were undergone to a molecular analysis of A1AT.

EPOC y déficit de alfaantitripsina | Archivos de Bronconeumología

A protocol was filled in with data on the levels of the following parameters: Percutaneous liver biopsies were obtained as described by MOWAT 24 using local anesthesia in patients fasted for at least 4 h, with venoclysis and normal prothrombin activity. Special staining was obtained using PAS periodic acid-Schiff followed by treatment with diastase. The persistence of eosinophil-appearing cytoplasmic granules even after use of diastase was considered positive for A1AT deficiency. Table 1 shows the patient’s age at the time of blood collection and the indication used for deciding for subsequent analysis.

Three of the patients presented neonatal cholestasis as an initial deficjencia of chronic hepatopathy. The five patients with the ZZ genotype had reduced serum A1AT levels and the liver biopsy showed deciciencia oneneonatal hepatitis twoa paucity of interlobular bile ducts one and chronic hepatitis one. In this last case FSPeosinophil-appearing cytoplasmic granules were seen in periportal hepatocytes following staining with HE and posteriorly confirmed by PAS positivity and diastase resistance Figure 1.

The two patients with neonatal cholestasis EKBA and RHBP underwent a liver biopsy when they were 10 weeks and 13 weeks old, respectively, and showed eosinophilic PAS-positive, diastase-resistent globules.

Figures 2 and 3 show the results of the amplification and digestion of the S and Z alleles, respectively. Alphaantitrypsin deficiency is one of the most common genetic disorders that leads to hepatic disease in children and it is the most common genetic disease requiring liver transplantation 17, In this study, three patients diagnosed with an A1AT deficiency had neonatal cholestasis and in two of these, before a definite diagnosis of the deficiency was established, the cholestasis was considered idiopathic.

Five to 10 percent of the cases of idiopathic neonatal hepatitis reported in the literature are caused by an A1AT deficiency 3.

In five patients with this deficiency studied, the serum levels of A1AT were below the normal lower limit. However, this test did not absolutely confirm the diagnosis of the disease. A reduction in the serum levels of A1AT occurs in the respiratory anguish syndrome of neonates, in the terminal phase of hepatic failure, in cystic fibrosis and in situations in which there is great protein loss The serum levels in SZ genotypes, which could theorically result in liver diseases, are usually normal.

When neonatal cholestasis is present, it is fundamentally necessary a differential diagnosis with extrahepatic biliary atresia. Among these investigations, the liver biopsy is of major importance. The histopathological alterations seen in the liver biopsy of patients with A1AT deficiency may be the same as those observed in idiopathic neonatal hepatitis or in cases of extrahepatic biliary atresia The presence of predominantly periportal, intrahepatocystic globules that are strongly PAS positive after diastase digestion is a helpful indication of A1AT deficiency 13, 18, However, it is difficult to identify these globules before the 12 th week after birth In this study, patient EKBA had globules with the above characteristics in liver tissue at the age of 10 weeks.


No such globules were seen in patient JCI 13 weeks old. These results suggest that the presence of globules should be investigated using special staining in hepatic fragments obtained before the age of 12 weeks, although a negative result does not eliminate the possibility of A1AT deficiency. Biochemical analysis was not used in this study since DNA analysis, which is more precise, was possible.

An A1AT deficiency is relatively frequent in children who have hepatic disease of undefined etiology.

Deficiência de alfa 1 antitripsina : relato de caso

This diagnosis is subestimated, probably because imprecise diagnostic methods are used. Molecular analysis provides a more precise diagnosis and may also be useful for the genetic counseling of patients with hepatic disease of unknown etiology. Arq Gastroenterol antitripsiba 1: Cholestasis in the first three months of life. Prog Liver Dis ;6: Two novel nonradioactive polymerase chain reaction-based assays of dried blood spots, genomic DNA, or whole cells for fast, reliable detection of Z and Defixiencia mutations in the Alphaantitrypsin gene.

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Clinical consequences and strategies for therapy. Biologic basis of pulmonary fibrosis. New York; Raven Press: Dee deficiency caused by the alphaantitrypsin Nullmattawa gene.

An insertion mutation rendering the alphaantitrypsin gene incapable of producing alphaantitrypsin. Rapid DNA analysis of alpha 1-antitrypsin deficiency: Histopathological pediaatria of liver disease in alpha 1-antitrypsin deficiency.

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