Tomas Sveger

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.

Waist measurement correlates to a potentially atherogenic lipoprotein profile in obese 12–14–year-old children

Epidemiological studies have indicated a relationship between overweight and cardiovascular disease. The present investigation was undertaken to identify anthropometric variables in childhood which may reflect the risk of cardiovascular disease in terms of unfavourable changes in apolipoprotein and lipid concentrations. Twenty‐nine obese 14‐year‐olds and 32 obese 12‐year‐olds were recruited from a school screening programme and anthropometric data reflecting overweight and fat distribution were subjected to analysis of covariance, with blood pressure, apolipoprotein and lipid concentrations as dependent variables. Results from the two groups were adjusted for puberty, gender and screening group, allowing pooling of data. After such an adjustment, waist circumference was significantly correlated (r= partial correlation coefficient) to high density lipoprotein (HDL) cholesterol (r = ‐0.08, p < 0.05) and triglycerides (r=+0.24, p < 0.01). The waist:hip ratio was significantly correlated to HDL‐cholesterol (r= ‐0.10, p < 0.01) and triglycerides (r =+0.22, p < 0.01). BMI was significantly correlated to triglycerides (r=+0.25, p < 0.001), and diastolic blood pressure (r=+0.08, p < 0.05). The partial regression coefficients for waist circumference versus apolipoprotein B (r=+0.07) and the apolipoprotein B:A‐I ratio (r=+0.06) were as strong as those for waist:hip ratio (r=+0.03 and r=+0.05, respectively). Our results demonstrate that abdominal obesity is associated with an unfavourable lipid profile in obese 12–14‐year‐old children. This may be related to an increased cardiovascular risk later in life. The waist measurement appears to be a convenient and informative anthropometric indicator of such metabolic alterations.

Lung function in adolescents with alpha 1-antitrypsin deficiency

Children with α1‐antitrypsin deficiency, screened at birth, were followed prospectively. At 16 years of age, 150 adolescents (103 PiZ, 1 PiZ‐, 1 PiS‐, 45 PiSZ) were interviewed using a standardized questionnaire and asked to participate in an extensive lung function study including part or all of the following tests: FVC, FEV1 before and 15 min after four inhaled doses of salbutamol, TLC, RV and FRC. Fifty age‐, sex‐ and height‐matched adolescents participated as controls. No significant differences in age, height or weight were found between the PiZ, PiSZ and control groups. No significant differences were found in respiratory symptoms, parental smoking history or the smoking habits of PiZ, PiSZ and control subjects. Asthma occurred in 10.7% of PiZ, 6.5% of PiSZ and 4% of control adolescents (p = 0.33). Only 3 of 100 PiZ and 1 of 45 PiSZ adolescents were smokers. No significant contribution of α1‐antitrypsin Pi‐type was found to explain the variation in lung function variables studied. We conclude that children with α1‐antitrypsin deficiency have a favourable prognosis and normal lung development up to 16 years of age. Anti‐smoking advice was found to be reasonably successful; only 3% of those answering the questionnaire had started to smoke.

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha1-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

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.

Psychological Consequences of Neonatal Screening for α1Antitrypsin Deficiency (ATD).: Parental Attitudes toward "ATD-Check-ups" and Parental Recommendations Regarding Future Screening

ABSTRACT. The parents of 61 children with ATD typically attended repeated doctors appointments concerning the childs ATD during the first years of life. Many (30‐40 %) of the parents felt somewhat relieved about the ATD after the first appointment. Parental attitudes toward the appointments varied considerably within the sample, being related to the physicians reported knowledgeability‐understandability regarding ATD and emotional supportiveness (toward mothers). Most parents were positive and few were negative toward the childs ATD having been identified at this age. Repeated blood tests for the childs liver function were experienced negatively by most parents. The parents’recommendations concerning screening and follow‐up of ATD in children are presented.

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.

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.

An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal semi-dominant disorder caused by defects in the low density lipoprotein receptor (LDLR) gene and is a well-documented risk factor for developing cardiovascular disease. The LDLR genes of five Swedish children with FH were examined in this study. Initial mutation screening was performed by denaturing gradient gel electrophoresis (DGGE) with enzymatically amplified exon-sized fragments, each containing a tailing GC-rich requence. The GC-clamped fragments had been synthesized with a restriction site adjacent to the intron-corresponding sequence to allow detachment of the clamps, thereby rendering the fragments suitable for subsequent analysis by single-strand conformation polymorphism (SSCP) analysis of samples from patients with no DGGE-detectable mutations. In addition, all the LDLR genes of the patients were screened for large alterations by restriction fragment length polymorphism analysis. Following this strategy, seven different, potentially disease-causing mutations were detected in the five children with FH. Six of the alterations, five single-base substitutions and one dinucleotide deletion, have not previously been described. DGGE detected six of the mutations and SSCP the seventh.

Identifying children at high somatic risk: parents' long-term emotional adjustment to their children's alpha 1 antitrypsin deficiency

ABSTRACT– The parents of 61 children at high somatic risk due to α1‐antitrypsin deficiency (ATD) were followed‐up 5–7 years after the identification of the ATD and studied regarding their long‐term emotional adjustment to the childs ATD. This was assessed both by a physician who interviewed the parents in their home and independently by a psychologist who systematically scored selected parts of the interview transcripts for specified variables. Notable agreement was found in the separate assessments performed by these two researchers. At follow‐up, 58% of the mothers and 44% of the fathers had predominantly negative feelings (worry, guilt) about the childs ATD. About half of the mothers and a third of the fathers were judged to have poor long‐term emotional adjustment. Considerable continuity was found in mothers’ feelings across the 5–7 years since identification of the ATD.