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Bernhard Liebl

Publications and source records attributed to Bernhard Liebl.

13 recordsLinked to original sources
PubMed2006

Occurrence and daily variation of phthalate metabolites in the urine of an adult population.

Phthalates like di-(2-ethylhexyl) phthalate (DEHP) are commonly used as plasticizers and their metabolites are suspect of especially reproductive toxicity. The aim of our study was to assess phthalate exposure in adults by measuring urinary phthalate metabolite levels and to explore individual temporal variability. Urine samples were collected by 27 women and 23 men aged 14-60 years during 8 consecutive days. We quantified four monoesters, four oxidative DEHP metabolites, and two secondary metabolites of di-isononyl phthalate (DiNP) by a LC/LC-MS/MS method. If we analyzed all 399 available samples independent of classification, the highest median values of primary metabolites in this study were found for mono-n-butyl phthalate (MnBP: 49.6 microg/l), followed by mono-isobutyl phthalate (MiBP: 44.9 microg/l), mono-benzyl phthalate (MBzP: 7.2 microg/l), and mono-2-ethylhexyl phthalate (MEHP: 4.9 microg/l). The median concentrations of the oxidized metabolites of DEHP were 8.3 microg/l for mono-(2-carboxymethylhexyl) phthalate (2cx-MMHP), 19.2 microg/l for mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), 14.7 microg/l for mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), and 26.2 microg/l for mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP). The concentrations of the two DiNP secondary metabolites mono (oxoisononyl) phthalate (oxo-MiNP) and mono(hydroxyisononyl) phthalate (OH-MiNP) ranged from <LOD to 304 microg/l (median: 3.0 microg/l, 2.9 microg/g creatinine) and <LOD to 698 microg/l (median: 5.5 microg/l, 5.2 microg/g creatinine), respectively. Phthalate metabolite levels did not consistently differ by sex or age. There was substantial day-to-day variation of urinary levels with considerable within-subject variability. Intraclass correlation coefficients adjusted for sex and age ranged between 0.21 and 0.48 for unadjusted metabolite levels and between 0.20 and 0.57 for creatinine-adjusted levels. The secondary metabolites of DiNP were detectable in nearly all samples and were therefore sensitive biomarkers of DiNP exposure. Our results of within-subject variability suggest that exposure assessment should not be based on a single urine measurement.

Adolescent↗
PubMed2006

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment.

New technology enables expansion of newborn screening (NBS) of inborn errors aimed to prevent adverse outcome. In conditions with a large share of asymptomatic phenotypes, the potential harm created by NBS must carefully be weighed against benefit. Policies vary throughout the United States, Australia, and Europe due to limited data on outcome and treatability of candidate screening conditions. We elaborated the rationale for decision making in 3-methylcrotonyl-coenzyme A (CoA) carboxylase deficiency (MCCD), which afflicts leucine catabolism, with reported outcomes ranging from asymptomatic to death. In Bavaria, we screened 677,852 neonates for 25 conditions, including MCCD, based on elevated concentrations of 3-hydroxyisovalerylcarnitine (3-HIVA-C). Genotypes of MCCA (MCCC1) and MCCB (MCCC2) were assessed in identified newborns, their relatives, and in individuals (n = 17) from other regions, and correlated to biochemical and clinical phenotypes. NBS revealed eight newborns and six relatives with MCCD, suggesting a higher frequency than previously assumed (1:84,700). We found a strikingly heterogeneous spectrum of 22 novel and eight reported mutations. Allelic variants were neither related to biochemical nor anamnestic data of our probands showing all asymptomatic or benign phenotypes. Comparative analysis of case reports with NBS data implied that only few individuals (< 10%) develop symptoms. In addition, none of the symptoms reported so far can clearly be attributed to MCCD. MCCD is a genetic condition with low clinical expressivity and penetrance. It largely represents as nondisease. So far, there are no genetic or biochemical markers that would identify the few individuals potentially at risk for harmful clinical expression. The low ratio of benefit to harm was pivotal to the decision to exclude MCCD from NBS in Germany. MCCD may be regarded as exemplary of the ongoing controversy arising from the inclusion of potentially asymptomatic conditions, which generates a psychological burden for afflicted families and a financial burden for health care systems.

Alleles↗
PubMed2005

Reduced incidence of severe metabolic crisis or death in children with medium chain acyl-CoA dehydrogenase deficiency homozygous for c.985A>G identified by neonatal screening.

The incidence of severe metabolic crises in medium chain acyl-CoA dehydrogenase deficiency (MCADD) patients homozygous for the common c.985A>G mutation, who had been identified by neonatal screening, was assessed prospectively and compared to retrospective cohort data in unscreened patients with identical genotypes. Logrank test showed a significant reduction of severe metabolic crises in the screened cohort (p<0.01). Neonatal screening appears to reduce the rate of severe metabolic crisis or death in the most prevalent subset of MCADD.

Acyl-CoA Dehydrogenase↗
PubMed2005

Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most frequent inherited defect of fatty acid oxidation, with a significant morbidity and mortality in undiagnosed patients. Adverse outcomes can effectively be prevented by avoiding metabolic stress and following simple dietary measures. Therefore, prospective newborn screening (NBS) is being proposed for this condition. However, technical validation of MCADD population screening and assessment of its overall benefit require broadening of the as-yet-scarce knowledge of the MCADD genetic heterogeneity unraveled by NBS and its phenotypic consequences. Here, we describe the entire spectrum of sequence variations occurring in newborns with MCADD in the population of Bavaria, Germany, in relation to the biochemical phenotype. Among 524,287 newborns, we identified 62 cases of MCADD, indicating a birth incidence of 1 in 8,456. In all of the 57 newborns available for analysis, two alterations within the MCADD gene (ACADM) were identified. The most prevalent alteration c.985A>G (Lys329Glu) occurred in 27 (47%) newborns in the homozygous and in 18 (32%) in the heterozygous state (63% of defective alleles). The mild folding variant c.199T>C (Tyr67His) was identified in nine individuals, six of them being compound heterozygous with c.985A>G (Lys329Glu). Neither of the prevalent alterations were found in the remaining nine newborns. A total of 18 sequence variations were identified; 13 of them were novel: eight missense mutations, one nonsense mutation, two splice variants, and two small deletions. The remaining five were previously reported in MCADD patients. The ACADM heterogeneity uncovered was larger as anticipated from previous c.985A>G (Lys329Glu) carrier screening data. In addition, we show that MCADD appears to occur as frequently in Turkish newborns as in the native German population. Our data validate that biochemical NBS for MCADD is a highly specific procedure for disease detection, with the identification of a significant share of milder biochemical phenotypes, such as c.199T>C (Tyr67His). These show statistically lower acylcarnitine markers, allowing us to distinguish subgroups within the spectrum of ACADM sequence variations that correlate to biochemical MCADD disease expression. Our data might provide technical and medical guidance for decision making in the worldwide efforts to introduce MCADD population screening.

Acyl-CoA Dehydrogenase↗
PubMed2004

Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany.

UNLABELLED: The lack of epidemiological data on the frequency and/or burden of organic acidurias (OA) and mitochondrial fatty acid transport and oxidation disorders (mtFATOD) is one reason for hesitation to expand newborn screening (NBS) by tandem mass spectrometry (MS-MS). From 1999 to 2000, the frequency of ten potentially treatable OA and mtFATOD was assessed by active nation-wide surveillance on cases presenting with clinical symptoms using the German Paediatric Surveillance Unit (ESPED) system. Case ascertainment was complemented by a second independent source: 3-monthly inquiries in the metabolic laboratories performing secondary selected screening for OA and mtFATOD. Frequency estimates for clinically symptomatic cases older than 7 days in a birth cohort of 844,575 conventionally screened children was compared to the frequency found in a cohort of 382,247 screened by MS-MS in Bavaria and Baden-Württemberg. The overall frequency of the ten conditions considered was 1:8,000 (95% CI 1:11,000-1:6,000) by MS-MS as compared to 1:23,000 (95% CI 1:36,000-1:17,000) in symptomatic cases presenting mainly with metabolic crisis. The contributions of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), other mtFATOD and OA were 29, 4 and 13 among the 46 cases identified by MS-MS, and 19, 1 and 13 among the 33 clinically symptomatic cases, respectively. Acute metabolic crisis, with a lethal outcome in four patients, was reported for 22/33 clinically symptomatic cases. No clinically symptomatic cases were reported from cohorts with screened by MS-MS. CONCLUSION: ten potentially treatable organic acidurias and mitochondrial fatty acid transport and oxidations disorders were more common than phenylketonuria with organic acidurias accounting for 28% of the cases detected by newborn screening and 39% of the cases identified on high risk screening. These conditions were related to considerable morbidity and mortality. Considerations for their inclusion in expanded newborn screening programmes might be warranted.

Acyl-CoA Dehydrogenase↗
PubMed2004

Evidence for increased internal exposure to lower chlorinated polychlorinated biphenyls (PCB) in pupils attending a contaminated school.

External and internal exposure to six WHO-indicator congeners of polychlorinated biphenyls (PCB 28, 52, 101, 138, 153, 180) as well as subjective health complaints of a group of 377 pupils attending a PCB-contaminated school were compared with a control group of 218 pupils attending a non-contaminated school. Indoor air of the contaminated school revealed total PCB concentrations (sum of six indicator congeners times 5) ranging between 690 and 20,800 ng/m3 (median 2044 ng/m3). The lower chlorinated congeners PCB 28, 52, 101 were the prevailing contaminants (median 33, 293, and 66 ng/m3). Using improved analytical procedures at least one of the lower chlorinated congeners could be detected in 95% of the blood samples of pupils attending the contaminated school. Median concentrations for PCB 28, 52, 101, and for the sum of lower chlorinated congeners were 6, 9, 5, and 22 ng/l blood plasma, respectively, whereas the corresponding values in the control group were all < 1 ng/l. In contrast, no significant differences were found for the higher chlorinated congeners (PCB 138, 153, 180) which were detected in 1-2 orders of magnitude higher concentrations in both groups. Due to the dietary intake of these congeners similar total PCB levels were found (95th percentile 1070 and 1010 ng/l plasma in participants of the contaminated and control school). Using the Giessen Subjective Complaint List for Children and Adolescents no statistically significant differences in health complaints were observed between both groups of children. It is concluded that exposure of pupils to PCB in indoor air of the contaminated school caused increased blood concentrations of lower chlorinated congeners. Compared to background levels the detected excess body burden was very low indicating no additional health risk. Exposure was not associated to any specific subjective complaints.

Adolescent↗
PubMed2003

Advances in analytical mass spectrometry to improve screening for inherited metabolic diseases.

UNLABELLED: Gas chromatography/mass spectrometry became available more than 30 years ago and has subsequently profoundly contributed not only in the identification of a wide range of inborn errors but also as a key tool for clinical diagnostic screening of genetic metabolic disease. Due to extraordinary advances in liquid chromatography and mass spectrometry (MS) developed in the last decade, the utilisation of MS and the potential number of applications for the purpose of metabolic screening is currently undergoing considerable expansion. CONCLUSIONS: This overview aims to describe only current new developments in clinically most relevant applications, in particular with focus on low molecular weight compounds.

Humans↗
PubMed2003

Data required for the evaluation of newborn screening programmes.

Tandem mass spectrometry offers the chance to improve newborn screening (NBS) for phenylketonuria and to expand screening programmes at minimal additional costs. So far, however, there are only limited data available on the incidence of a broader range of disorders presently being considered, their natural course, the benefits achievable and potential harm associated with screening. Based on a literature search and experience from the Bavarian extended screening trial, these questions are addressed using medium-chain acyl-CoA dehydrogenase deficiency (MCADD) as an example. The data retrieved are sufficient for estimation of the incidence of MCADD cases identifiable by NBS and for diagnosis following clinical symptoms. Clinically detected cases ascertained by active surveillance in populations with highly developed and freely accessible health care systems consistently amount to only 33% of those identified by NBS. This difference cannot be explained by the difference in the proportion of the homozygous 985A-->G mutation, which accounts for about 50% of cases identified in NBS. Further research is needed to assess the contribution of MCADD to unexplained deaths in infancy. Retrospective cohort studies enrolling at least 500,000 children would allow for a more precise estimate of the natural course of disease in particular with regard to less severe adverse outcomes. The most relevant gap in knowledge concerns the long-term outcome of children identified following symptoms and by newborn screening. Since randomised controlled trials are unlikely to be feasible on this issue, a standardised documentation protocol should be implemented in follow-up studies for cases identified either by high risk screening or newborn screening. A proposal for the content of such observational studies is made.

Acyl-CoA Dehydrogenase↗
PubMed2003

Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value.

Newborn screening procedures for congenital adrenal hyperplasia (CAH) are still suboptimal because of low specificity, particularly in premature infants. This study evaluated a multitiered strategy for reporting abnormal 17-hydroxyprogesterone screening values that simultaneously takes into account not only birth weight but also age at sampling. A cautious three-tiered cut-off scheme was used during the initial 24 months of CAH screening in Bavaria. Data were then reanalyzed using five birth weight classes to reflect more precisely the markedly higher values in low-birth-weight newborns. Because 17-hydroxyprogesterone values apparently decline with increasing age, these classes were then further subdivided into a total of 21 groups according to the age at sampling. Based on this reanalysis, we defined new multitiered cut-off levels and used them for the next 18 months. A total of 538466 newborns were screened from January 1999 to June 2002; 51 CAH cases were detected. Application of the new threshold values resulted in a 35% reduction of the total recall rate (from 1.13% to 0.74%) and an increase in the positive predictive value from 0.84% to 1.29% without reducing diagnostic sensitivity. This improvement of CAH screening can be achieved by simply using request forms that ask for both age and birth weight at the time of sampling.

17-alpha-Hydroxyprogesterone↗
PubMed2002

Very high compliance in an expanded MS-MS-based newborn screening program despite written parental consent.

OBJECTIVES: In Bavaria, Germany, an expanded MS-MS-based newborn screening program was implemented in 1999. The coverage of new additional conditions and novelty of technology required introduction of written parental consent. Here we evaluated the influence of the consent procedure on compliance by systematic demographic tracking. METHODS: Comprehensive information was provided for parents, professionals, and the public. Screening notifications were matched with all birth notifications on name and date of birth. Parents of children without screening notification were contacted and counseled. RESULTS: Between August 1, 1999, and July 31, 2000, 123,284 children eligible for screening were born. Of these, 116,652 were matched successfully. Among 6,632 parents contacted, 2,516 (2%) did not respond. Three thousand thirty-four children were screened but the parents initially refused to participate in tracking. Five hundred ninety-four were screened outside the program. Four hundred eighty-eight untested newborns were identified. Three hundred twenty-five screening failures due to logistic problems were tested subsequently. Screening was definitely refused by the parents of 163 children (0.1% of target population). CONCLUSIONS: With appropriate information provided and surveillance by tracking, high compliance with newborn screening can be achieved despite a written consent requirement.

Adult↗
PubMed2002

Expanded newborn screening in Bavaria: tracking to achieve requested repeat testing.

OBJECTIVES: Expansion of newborn screening programs may increase the risk of missing cases through procedural failures. A coordinated process quality assurance procedure to track recalls was, therefore, introduced in parallel to expansion (including MS-MS and 17alpha-OHP) in Bavaria. METHODS: Using comprehensive computerized registration and automated monitoring a state-funded center coordinated all individual measures to achieve complete testing of all repeat requests-case-specific contacts to physicians, midwives, and parents. Mailing and phoning from the center were supplemented by local public health activities including home visits if needed. RESULTS: Among 243,422 children tested in 1999 and 2000 overall recall was 3.62% (8,809 children): 0.30% (726) were due to sample inadequacy, 1.35% (3,282) to early sampling (<48 h), and 1.97% (4,801) to abnormal results. Of all recalls, 80.9% were received following the initial request, 1,679 (19.1%) required special efforts. Of these, 873 were achieved following a single and 601 following repeated central activities, and 102 were achieved following local support. Sixty-three cases of parental refusal and 47 untraceable children remained. Altogether, 98.8% recalls were achieved, corresponding to 99.96% of all tested children for which definite screening results could be obtained. CONCLUSIONS: Expansion of newborn screening programs does not necessarily mean unsolvable problems in tracking of recalls if adequate logistics is established in parallel.

Germany↗
PubMed2002

Uptake, clearance and metabolism of TEGDMA in guinea pigs.

OBJECTIVE: The resin monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based bonding, cementing and direct tooth filling materials. METHODS: In the present study the uptake and the clearance of 14C-TEGDMA applied via different routes were examined in vivo in guinea pigs. TEGDMA (0.02 mmol/kg by weight labeled with a tracer dose 14C-TEGDMA 0.7Bq/g by weight) was administered by gastric tube or by subcutaneous injection. Urine, feces, and exhaled carbon dioxide were collected for 24h after administration. The animals were killed 24h after the beginning of the experiment and various organs removed and 14C-radioactivity measured. RESULTS: It was apparent that 14C-TEGDMA was taken up rapidly from the stomach and small intestine after gastric administration and was widely distributed in the body following administration by each of the routes. Clearance from most tissues following gastric and intradermal administration was essentially complete within one day. Low fecal 14C-levels (<1% of the administered dose) and urinary levels of about 15% after 24h were noted with each route of administration. Direct measurement of exhaled carbon dioxide showed that 60-65% of the administered dose of 14C left the body via the lungs during 24h. It is likely that 14C-pyruvate is formed in vivo resulting possibly in the formation of toxic 14C-TEGDMA-intermediates. SIGNIFICANCE: Despite using a high administered dose, the peak TEGDMA levels in all tissues examined after 24h were at least 100,000-fold less than known toxic levels.

Analysis of Variance↗