The natural history of liver disease in alpha 1-antitrypsin deficient children

During 1972-1974, 200,000 Swedish infants were screened for alpha 1-antitrypsin deficiency. Of 127 PiZ (Protease inhibitor) children followed from infancy to 12 years of age, four PiZ children with neonatal liver disease have died; two of liver cirrhosis, one was found to have liver cirrhosis at autopsy, having died of aplastic anemia and the fourth died in an accident. Liver microscopy showed a mild increase of periportal fibrous tissue. Another PiZ child died of anaphylactic shock. At 12 years of age, none of the PiZ children have clinical symptoms of liver disease. No PiZ-, PiSZ, PiS- or PiFZ child has had any clinical symptom of liver disease. One PiSZ child died of sudden infant death syndrome. Laboratory analyses from birth through 12 years of age have shown increased S-Bilirubin levels in 11% of the PiZ infants, which normalized within the first half year of life. S-GT was abnormal in about half of the infants, but had normalized when checked at 8 and 12 years of age in all but 6-3% of the PiZ children. The percentage of abnormal S-ALAT test results have decreased from 73% during the first year of life, to about 15% at the age of 12. The range of the abnormal levels also decreased considerably. Abnormal S-GT or S-ALAT levels were found in about 20% of the PiSZ infants, the proportion decreasing to 2% at the age of 12.     

Clinical Follow-up and Parental Attitudes Towards Neonatal Screening

ABSTRACT. Sveger, T. and Thelin, T. (Departments of Paediatrics and Psychiatry, University of Lund, Malmö General Hospital, Malmö, Sweden). Four-year-old children with α₁-antitrypsin deficiency. Acta Paediatr Scand, 70:171, 1980. –Two hundred thousand infants born in Sweden between November 1972 and September 1974 were screened at birth for a,-antitrypsin (a, AT) deficiency. At age 4 years 172 of 183 children with a, AT deficiency were examined and compared with 80 randomly selected control children. The children with a, AT deficiency had the following Pi types: 118 PiZ, 50 PiSZ, 2 PiZ-, 1 PiS-, and 1 PiFZ. Two PiZ children have severe liver cirrhosis and 1 PiZ boy had died of aplastic anemia. Abnormal levels of serum alanine aminotransferase (S-ALAT) were found in one PiSZ and 47 PiZ children. Upper and lower respiratory infections, otitis, eczema, urinary infections or complications of child diseases did not occur more often in children with α₁ AT deficiency than in controls. More parents of α₁ AT deficient children had stopped smoking and their fathers smoked significantly less. Forty parents of children with α₁ AT deficiency PiZ answered a questionnaire concerning their reaction to, knowledge about and attitudes towards neonatal screening for α₁ AT deficiency. Many parents reported having reacted with lack of understanding, shock or depression upon learning that the child had α₁ AT deficiency. About 4 years later 44 % reported still lack of understanding, and 18 % depression or feelings of guilt. About two-thirds had not fully understood why a , AT deficiency had been identified, despite the fact that they had seen their doctor 3–4 times for check-ups and counselling since birth.     

The Natural History of Liver Disease in (α1-Antitrypsin Deficient Children

ABSTRACT. During 1972–1974, 200 000 Swedish infants were screened for α₁-antitrypsin deficiency. Of 127 PiZ (Protease inhibitor) children followed from infancy to 12 years of age, four PiZ children with neonatal liver disease have died; two of liver cirrhosis, one was found to have liver cirrhosis at autopsy, having died of aplastic anemia and the fourth died in an accident. Liver microscopy showed a mild increase of periportal fibrous tissue. Another PiZ child died of anaphylactic shock. At 12 years of age, none of the PiZ children have clinical symptoms of liver disease. No PiZ-, PiSZ, PiS- or PiFZ child has had any clinical symptom of liver disease. One PiSZ child died of sudden infant death syndrome. Laboratory analyses from birth through 12 years of age have shown increased S-Bilirubin levels in 11% of the PiZ infants, which normalized within the first half year of life. S-GT was abnormal in about half of the infants, but had normalized when checked at 8 and 12 years of age in all but 6-3% of the PiZ children. The percentage of abnormal S-ALAT test results have decreased from 73% during the first year of life, to about 15% at the age of 12. The range of the abnormal levels also decreased considerably. Abnormal S-GT or S-ALAT levels were found in about 20% of the PiSZ infants, the proportion decreasing to 2% at the age of 12.     

Young adults with α1antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition

The psychological and psychosocial consequences of screening for α₁-antitrypsin deficiency (α₁ ATD) were investigated when the subjects were 5–7 years old. The present study was conducted when the subjects were 18–20 years old, the foci of interest being their health, psychosomatic problems, knowledge about α₁ATD and the potential effect of that knowledge on their lives and future family planning. Samples of 61 PiZ and 61 demographically matched control subjects, 18–20 years old, were asked to participate. Written, structured questionnaires covered the following items: basic familial characteristics, psychosomatic symptoms, opinions on medical check-ups, information and views on future α₁ATD screening, whether the knowledge about α₁ATD had affected the life and family planning of α₁ATD individuals. Items concerning the “α₁ATD matter” were excluded in the questionnaires given to the controls. Questionnaire data were obtained from 50 α₁ ATD and 48 control individuals, 41 of each being matched α₁ATD-control pairs. No significant differences were found in demographic or educational backgrounds, psychosomatic complaints such as headache, sleep difficulties, stomach ache, tiredness or anxiety. Lung symptoms occurred more frequently in α₁ATD subjects (p= 0.05). Six per cent of the α₁ATD individuals planned working careers with a high risk of air pollution. The majority (86%) of the α₁ATD subjects perceived the contact with the medical services as positive; 14% as both positive and negative. The information concerning α₁ATD was assessed as satisfactory by 73%, as both good and bad by 17% and as unsatisfactory by 10%. All α₁ATD subjects advocated general screening for α₁ATD, the neonatal period being chosen as optimal by 94%. Half of the α₁ATD individuals thought that the knowledge of their high-risk condition had affected their lives, particularly their awareness of the dangers of smoking and environmental pollution. The majority, 88%, knew that they should avoid smoking to protect their lungs. In conclusion, no negative psychosocial consequences of the neonatal α₁AT-screening were found in early adulthood. The α₁ATD individuals were aware of the dangers of smoking and were of the opinion that α₁ AT-screening should be recommended.     

Plasma protease inhibitors in alpha 1-antitrypsin-deficient children

Seven plasma protease inhibitors were analyzed in 8-yr-old children-75 PiZ (severely deficient), one PiZ-(with a null gene), 32 PiSZ (moderately deficient), and 35 normals. In PiZ and PiSZ alpha 1-antitrypsin-deficient children, significantly higher concentrations of alph 2-macroglobulin (p less than 0.001) and antithrombin III (p less than 0.001) were found and significantly lower concentrations of alpha 2-antiplasmin (p less than 0.001), C1-inactivator (p less than 0.01) and plasminogen (PiZ p less than 0.02, PiSZ p less than 0.01). The inter-alpha-trypsin inhibitor concentrations differed in PiSZ children only (p less than 0.01). At this age the high alpha 2-macroglobulin levels may be of importance to protect the lung tissue against free proteolytic activity, while importance of the other differences are unknown or reflect changes of purely theoretical interest.     

Neonatal screening for alpha-1-antitrypsin deficiency

The results of a neonatal screening programme for alpha-1-antitrypsin deficiency are presented. Cord blood samples with an alpha-1-antitrypsin concentration below 1.628 mg/ml, as measured by an enzyme-linked immunosorbent assay method, were phenotyped by isoelectric focusing in polyacrylamide gels. Abnormal phenotypes were found in 51% of this group as compared with 11.3% in a control group (P0.0001). Twenty subjects detected by the initial quantitative alpha-1-antitrypsin determination had a highly pathogenic phenotype (PiZZ, PiSS, PiSZ). In the control group only moderately affected individuals were found (PiMS, PiMZ).Abbreviations ELISA emzyme-linked immunosorbent assay - PAGE polyacrylamide gel electrophoresis - HRP horseradish peroxidase     

Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency

We assessed lung function, liver function, and smoking attitudes and behavior in 22 adolescents with homozygous alpha 1-antitrypsin deficiency whose condition had been detected through neonatal screening in the early 1970s. All subjects had normal lung volumes, expiratory flow rates, and diffusing capacity except for two siblings with mild asthma whose values reverted to the normal range after administration of an inhaled bronchodilator. Liver function was normal in all subjects with the exception of one boy who had an isolated elevation of alkaline phosphatase activity. Smoking attitudes, as determined by questionnaire, did not differ from those of 130 control subjects, but smoking initiation rates were significantly lower (p = 0.02). We believe that the issue of neonatal screening for alpha 1-antitrypsin deficiency should be reexamined because augmentation therapy for adults with emphysema is now available, and screening followed by family-based smoking intervention may lead to a nonsmoking life-style. The latter is especially important because the current weight of epidemiologic evidence strongly suggests that in nonsmokers with this condition, severe emphysema may never develop or, if it does, it will do so at a much later age than in smokers.     

Liver involvement in alpha1-antitrypsin-deficient phenotypes PiSZ and PiMZ

The long-term outcome of 3 PiSZ and 57 PiMZ children affected by alpha1-antitrypsin deficiency-associated liver involvement during infancy was assessed. At 5 and 10 y of age all PiSZ and PiMZ children exhibited normal levels of liver enzymes. All families, except one, were deterred from smoking following counselling. CONCLUSION: Transient liver involvement observed during early infancy is likely to be a benign self-limiting process.     

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with α1-antitrypsin deficiency

Individuals identified in the Swedish neonatal α₁-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV₁) and FEV₁/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV₁/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV₁/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function     

LIVER DISEASE IN CHILDREN WITH ALPHA1-ANTITRYPSIN DEFICIENCY WITHOUT NEONATAL CHOLESTASIS

ABSTRACT. Thirteen children with α₁-antitrypsin deficiency (8 PiZ and 5 PiSZ) were investigated at ages ranging from 4 to 6. None had had neonatal cholestasis. Nine, mainly the PiZ individuals, had increased serum concentration of transaminases. Liver biopsy was performed in 7 patients with increased serum levels of transaminases. One of these patients had cirrhosis and 4 had moderate to severe fibrosis. The results indicate that α₁-antitrypsin deficient individuals, also without neonatal cholestasis syndrome run a high risk of developing serious liver disease, already in childhood. The cirrhotic patient was the only one who had increased excretion of bile acids in urine.     

Liver involvement in infants with PiSZ phenotype of alpha 1-antitrypsin deficiency.

Between July 1985 and June 1989, 19,432 newborns were screened during the first days of life to determine their Pi (protease inhibitor) phenotype. Fourteen infants were identified to be carriers of the PiSZ phenotype. Their clinical and biochemical follow-up data were recorded at 2, 5, and 12 months of age; only one case underwent a liver biopsy due to repeated abnormal liver enzymes. Three of 14 PiSZ infants showed some hepatic dysfunction at 2 and 5 months of age, but at 12 months all patients had normal liver function tests. None of them had clinical, biochemical, or morphological signs of neonatal cholestasis. The clinical and biochemical data related to the liver involvement are similar to those of the PiMZ phenotype, though the serum levels of alpha 1-antitrypsin in PiSZ carriers match those of the PiZZ group.     

Alpha1-antitrypsin and alpha2-macroglobulin in newborn infants

The levels of alpha₁-antitrypsin and alpha₂-macroglobulin in the plasma of 129 newborns were determined. The infants were divided into 3 groups according to their perinatal history.In healthy newborns with an uneventful perinatal history the normal values for alpha₁-antitrypsin were 1.97±0.44 g/l, and for alpha₂-macroglobulin 3.11±0.69 g/l. No changes in these levels were found during the first week of life. The levels of alpha₁-antitrypsin and alpha₂-macroglobulin showed significant correlation to each other.In healthy newborns with different complications in the obstetric history the levels of alpha₁-antitrypsin were not influenced, whereas alpha₂-macroglobulin decreased slightly during the first week of life. The levels of alpha₁-antitrypsin and of alpha₂-macroglobulin showed no further correlation to each other.In sick term and preterm newborns (n=18) alpha₁-antitrypsin was increased in 5 of 7 babies suffering from bacterial infections and lowered in 4 of 9 cases with respiratory disturbances. Alpha₂-macroglobulin was lowered in 15 babies. These results indicate different kinetics of the two antiproteases in vivo.With support of the Landesamt für Forschung des Landes Nordrhein-Westfalen     

Massive ascites and the heterozygous alpha 1 antitrypsin (α1AT) living related donor liver in the homozygous child

The following is a short report on the use of a heterozygous (PiMZ) alpha 1 antitrypsin (α1AT) living related donor liver in a homozygous (PiZ) child that was complicated by massive ascites early after transplant. This clinical report is then followed by a brief summary of present knowledge on the α₁AT protein and management of massive ascites in the pediatric liver transplant recipient.     

Adiposity,inflammation and fat-soluble vitamins in adolescents

ObjectiveEvaluate the association between inflammatory process, adiposity, and vitamins A, D, and E in adolescents, according to gender.MethodsCross-sectional study with adolescents aged 12–19 years old of both genders attending public schools in Recife. A questionnaire was used to collect data on socioeconomic level, lifestyle, and food intake of adolescents. Then, an anthropometric evaluation and a blood sampling were performed to analyze serum concentrations of α-1-acid glycoprotein, retinol, β-carotene, α-tocopherol, and 25-hydroxy-vitamin D.ResultsThe levels of α-1-acid glycoprotein were higher for abdominal obesity in both genders. Male adolescents with insufficient serum α-tocopherol levels had low levels of α-1-acid glycoprotein (p = 0.03) and an increased risk of 25-hydroxy-vitamin D and β-carotene deficiency in relation to total and abdominal fat; female adolescents had an increased risk of insufficient β-carotene with abdominal obesity (PR: 1.33; 95% CI: 1.2–1.5).ConclusionAbdominal adiposity implies a higher risk of inflammation and causes different changes to the levels of fat-soluble vitamins according to gender.     

Malignant liver disease in alpha1-antitrypsin deficiency

Ever since the first report by Sharp et al. (1) that alpha₁-antitrypsin deficiency (AATD) PiZ is associated with liver disease in infants and children, hepatologists were captured by this association. Whereas the major manifestation of alpha₁-antitrypsin (AAT) PiZ deficiency in infants and children involves the liver, many adults affected with this phenotype develop chronic obstructive lung disease. However, in addition to severe panacinar emphysema, adults with AATD also face the risk of the development of chronic liver disease and hepatocellular carcinoma (HCC).     

Assoziation von Mukoviszidose, Zöliakie und heterozygotem α-1-Antitrypsin-Mangel bei einem Kleinkind

Background. Cystic fibrosis associated diseases as coeliac disease or α-1-antitrypsin deficiency may remain undetected for a long time, as the leading symptoms may be explained by the underlying basic disorder CF. Case report. We report on a 4 year old caucasian cystic fibrosis patient with additional α-1-antitrypsin deficiency and coeliac disease. If a patient with cystic fibrosis fails to thrive despite intensive treatment, additional disorders, for example coeliac disease, must be excluded by means of serology and histology. An α-1-antitrysin deficiency syndrom in cystic fibrosis patients with hepatic manifestation may accelerate the progression of liver cirrhosis and increase the risk of acquiring pseudomonas aeruginosa.     

Increased type III/I collagen and α1(I)/α2(l) chain in a bronchopulmonary dysplastic lung

The type ratio of collagen III/I and molecule ratio of α₁(I)/α₂(I) were analysed in lungs from five infants with bronchopulmonary dysplasia (BPD) and seven control infants. All five BPD lungs showed typical characteristics, with pulmonary fibrosis and irregular cystic formation at postmortem examination. A pepsin digestion technique followed by interrupted gel electrophoresis was performed for the determination and molecular analysis of collagens III and I. The ratio of collagen types III and I were significantly increased in BPD lung (P < 0.005). The ratio of α₁(I) and α₂(I) were also significantly increased in BPD lung (P < 0.05). It is likely that collagen III is predominantly increased and that the α₁(I) trimer is formed in the active stage of BPD lungs.     

Primary prevention in a high-risk group: smoking habits in adolescents with homozygous alpha-1-antitrypsin deficiency (ATD)

The serious form of alpha-1-antitrypsin deficiency (ATD) Pi ZZ strongly predisposes the individual for pulmonary emphysema and premature death in adulthood, especially if exposed to tobacco smoking. General screening of all new-born children was conducted in Sweden during 1972–1974, the major purpose being to reduce exposure of the child to parental smoking while growing up and to prevent the child from starting to smoke. Sixty-one children with ATD neonatally identified through mass-screening, and their families, have been compared with a demographically matched control group regarding smoking habits, as studied through interviews and questionnaires on two occasions. When the children were 5–7 years old, the smoking rates among parents of the ATD children and especially among the ATD fathers exceeded smoking rates for controls. Thirteen years later no differences in parental smoking were found between the groups. At 18–20 years of age the ATD children reported smoking significantly less than the control children (p < 0.05). From the perspective of prevention, the goal of the neonatal screening to reduce the smoking rates among the parents of the ATD children was not attained, while it was achieved among the ATD children. The results indicate that a screening program with early detection of ATD effectively prevents adolescent children from starting to smoke. From ethical, medical and psychological points of view, a voluntary screening program for ATD in pre-adolescence is recommended.     

Homozygous alpha-1 antitrypsin deficiency (PiZZ) and bronchial asthma in childhood--is there a connection?]

Ten children and adolescents (aged four to 21 years) with the homozygous form of alpha-1-antitrypsin deficiency (PiZZ) were investigated with regard to obstructive airway disease. Besides the recording of the history, tests of lung function and allergy tests were performed. It was shown that bronchial asthma occurred in three out of ten patients. However, we could not demonstrate any statistically significant increased incidence of bronchial asthma in our unselected PiZZ-patients compared to the overall population. There was no indication of emphysema in any of the nine patients.     

HLA in juvenile liver disease with alpha-one-antitrypsin deficiency

The possible role of HLA phenotypes was investigated in the development of juvenile liver disease in persons with alpha 1-antitrypsin deficiency. Seventeen patients were investigated between the ages of 3-25 years. All of them had alpha 1-antitrypsin phenotype PiZ. After a longer follow-up a clinical diagnosis was established by the help of physical status, biochemical liver function tests and--in the cases of suspected liver disease--liver biopsy. The clinical course was correlated to the HLA phenotypes of the patients. In 2 cases all first degree relatives were investigated, as well. Our studies on the 17 unrelated patients indicated no correlation between HLA and juvenile liver disease in alpha 1-antitrypsin deficiency. The family studies confirmed these findings.