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Björn Fischler

Publications and source records attributed to Björn Fischler.

15 recordsLinked to original sources
PubMed2006

Clinical and molecular genetic features of ARC syndrome.

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Abnormalities, Multiple↗
PubMed2006

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.

Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational-analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)--or "neonatal hepatitis" suggesting PFIC--that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or "neonatal hepatitis" suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13-52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Recombinant FVIIa in children with liver disease.

INTRODUCTION: The aim of this study was to investigate the clinical and biochemical effects of recombinant activated factor VII (rFVIIa) in the treatment of bleeding in children with liver disease. PATIENTS AND METHODS: 12 patients (0.3-15.9 years) with chronic liver disease were included. The indication for treatment was life threatening bleeding and failing conventional therapy (group A, 7 patients) or as prophylaxis before invasive procedures (group B, 6 patients). One patient received treatment on both indications. rFVIIa was administered as intravenous bolus doses of 34-163 microg/kg (median 66 mug/kg) alone or in combination with packed red cells and/or octreotide and/or fresh frozen plasma. The follow-up included repeated INR and haemoglobin measurements as well as clinical evaluation. RESULTS: In group A rFVIIa was given on 22 occasions and bleeding decreased, was unchanged, increased or could not be evaluated on 10, 7, 2 and 3 occasions respectively. On 14 occasions rFVIIa and octreotide were administered simultaneously, in 8 of those bleeding decreased. In group B no bleeding complication was seen, interpreted as a positive effect. One thrombotic event was suspected but could not be verified by computerized tomography. CONCLUSIONS: rFVIIa may be beneficial in the short-term management of life threatening bleeding in some children with liver disease. This effect may be further enhanced with the additional use of octreotide. Furthermore, rFVIIa is useful for prophylaxis at invasive procedures, even without additional treatment with fresh frozen plasma. The possible risk of portal vein thrombosis needs to be considered.

Adolescent↗
PubMed2005

Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection.

PURPOSE: The aim of this report was to study the amount and distribution of immunoglobulin deposits in liver biopsies from infants with biliary atresia (BA) and correlate the results to the cytomegalovirus (CMV) infection status. METHODS: Stored liver biopsies from 18 patients with BA and from 6 control patients without liver disease were immunohistochemically stained to detect IgG and IgM deposits. The intensity of the immunoglobulin staining was evaluated by a semiquantitative scoring scale. Ongoing CMV infection was defined as the detection of CMV-IgM in serum and/or the isolation of CMV in the urine and was noted in 9 of the patients with BA. RESULTS: When analyzing the immunoglobulin deposits on the hepatocellular canalicular membrane the intensity score for IgM deposits was significantly higher in biopsies from patients with BA infected with CMV than in those without. No canalicular staining was detected in control biopsies. CONCLUSIONS: The results support the possibility that immunologic mechanisms are of importance in the pathogenesis of BA and that a CMV infection may trigger such mechanisms.

Adult↗
PubMed2005

Mutation in the sterol 27-hydroxylase gene associated with fatal cholestasis in infancy.

BACKGROUND: Inborn errors of bile acid synthesis are rare but potentially treatable causes of neonatal cholestasis. We here present a cholestatic infant with an ongoing cytomegalovirus infection who despite intensive treatment died of severe liver disease at 4 months of age. METHODS: The urinary steroids were investigated by electrospray mass spectrometry and gas chromatography mass spectrometry. Oxysterols in plasma were analysed by isotope dilution mass spectrometry. Mutations in the sterol 27-hydroxylase gene were detected by PCR. RESULTS: Glucuronidated bile alcohols, which are known to be excreted by patients with cerebrotendinous xanthomatosis (CTX) were detected in the urine. Analysis of plasma revealed markedly reduced levels of 27-hydroxycholesterol. Mutation analysis showed the presence of a stop codon in exon 7, confirming the diagnosis of CTX, a rare disease not previously diagnosed in Sweden. CONCLUSIONS: Fetal and neonatal deaths among siblings of patients with CTX have been reported previously and the present case supports the contention that reduced activity of the sterol 27-hydroxylase may predispose to the development of neonatal cholestasis. The associated viral infection may have further precipitated the liver disease. Since CTX, like other inborn errors of bile acid synthesis may be treated with bile acids an early diagnosis is essential. Thus, the analysis of urine by electrospray mass spectrometry is highly recommended in the investigation of patients with neonatal cholestasis.

Cholestanetriol 26-Monooxygenase↗
PubMed2005

Vaccination of the immunocompromised child.

The development of vaccination is a major achievement in modern medicine. However, children treated with immunosuppression may not at all, or only in part, receive routine immunization due to uncertainty of its risks and effect. There is a substantial lack of pediatric studies concerning the efficacy and safety of vaccination in this patient group. Experience from similar adult groups and children with HIV infection can be used as a model for other disease categories. With increasing knowledge of the immunologic basis of vaccination and how immunosuppressive drugs interfere with the immune system, improved vaccines could be tailored, and adequate, individualized guidelines issued.

Bacterial Infections↗
PubMed2004

Serum ALT levels as a surrogate marker for serum HBV DNA levels in HBeAg-negative pregnant women.

In Stockholm, Sweden, the majority of pregnant women positive for hepatitis B surface antigen (HBsAg) are hepatitis Be antigen (HBeAg) negative. Newborns to HBeAg positive mothers receive vaccination and hepatitis B immunoglobulin (HBIg). Newborns to HBeAg negative mothers receive vaccine and HBIg only if the mothers have elevated ALT levels. The aim of this study was to retrospectively evaluate ALT levels as a surrogate marker for HBV DNA levels in HBeAg negative carrier mothers. Altogether 8947 pregnant women were screened for HBV markers from 1999 to 2001 at the Virology Department, Karolinska Hospital. Among mothers screened 192 tested positive for HBsAg (2.2%). 13 of these samples could not be retrieved. Of the remaining 179 sera, 8 (4%) tested positive for HBeAg and 171 (95.5%) were HBeAg negative. Among the HBeAg negative mothers, 9 had HBV DNA levels > 10(5) copies/ml, and of these 7 had normal ALT levels indicating low sensitivity of an elevated ALT level as a surrogate marker for high HBV DNA level. Furthermore, no correlation was found between ALT and HBV DNA levels. Hence, it is concluded that the use of ALT as a surrogate marker for high viral replication in HBeAg negative mothers could be questioned.

Adult↗
PubMed2003

Cognitive and emotional outcome after pediatric liver transplantation.

The aim of the study was to evaluate the cognitive and emotional development after pediatric liver transplantation. A total of 21 patients, aged 4-16.9 yr (median 9.6 yr) were tested 1-9 yr (median 4.2 yr) after the transplantation. The pretransplant diagnoses included biliary atresia (eight patients), various metabolic diseases (n = 6), acute liver failure (n = 3), and miscellaneous (n = 4). The cognitive functions were tested with Wechsler preschool and primary scale of intelligence (WPPSI)-R or Wechsler intelligence scale for children (WISC)-III according to age. The Piers-Harris self-concept scale and the evaluation of human figure drawings according to Koppitz were used to detect emotional problems. All tests in all patients were performed by the same psychologist. A significantly lower result on cognitive tests was seen when compared with the expected normal values (p < 0.01). The number of patients with results within or under the lower normal range was higher than expected. Although the mean value of the Piers-Harris self-concept scale was normal, there was a large spread within the group. Indicators of emotional problems were found in the human figure drawings of 50% of the patients. To some extent, low cognitive scores coincided with low scores on self-concept scale and indicators of emotional difficulties. We conclude that the high degree of cognitive and emotional problems after liver transplantation is an important argument for routine psychologic follow-up and support in these patients.

Adolescent↗
PubMed2003

Optic nerve hypoplasia in cholestatic infants: a multiple case study.

PURPOSE: To present four infants with optic nerve hypoplasia and cholestasis. METHODS: All patients underwent detailed ophthalmological and hepatological assessment. Their endocrinological and neuroradiological examinations were re-evaluated. RESULTS: All four infants presented with cholestasis and were subsequently found to have optic nerve hypoplasia. One child was blind according to the WHO definition and two had low vision. The fourth child had unilateral optic nerve hypoplasia and was too young to be assessed with optotypes. All four children had central nervous system and/or endocrine dysfunction. However, only one child had septo-optic dysplasia. The longterm outcome of liver disease seemed favourable in all children. CONCLUSION: Early assessment by a paediatric ophthalmologist as well as a multidisciplinary approach is of great importance in cholestatic infants.

Blindness↗
PubMed2003

Chronic hepatitis C: updated Swedish consensus.

In 1999 a Swedish national expert panel published recommendations for the treatment of chronic hepatitis C (HCV) infection. Recently, pegylated interferon (peg-IFN) products have been introduced, and an increased knowledge concerning treatment of acute HCV and HCV-human immunodeficiency virus (HIV) coinfection has been gained. As a result of this, an update of the Swedish recommendations was developed following an expert meeting in October 2002. The panel now recommends the use of peg-IFN together with ribavirin as the standard treatment. Owing to the excellent response rates in HCV genotype 2 and 3 infections, these patients can be treated for 24 weeks without preceding liver biopsy. For patients with genotype 1 infection (with a slightly below 50% sustained response rate after 48 weeks treatment) and only mild histological disease, treatment can be postponed until future better treatment options become available. In patients who fail to achieve a 99% reduction (2 log drop) in viral titre after 12 weeks of treatment, discontinuation of therapy is recommended. Patients previously treated with IFN monotherapy and not having achieved a sustained virological response are recommended the same combination treatment as treatment-naive patients. IFN monotherapy is recommended in patients with acute hepatitis C. For children with chronic HCV infection, combination treatment is mainly recommended in clinical trials. For HCV-HIV coinfected patients, combination treatment is recommended and preferably given when blood CD4 counts are above 350/ml and before antiretroviral treatment (ART) is needed. Concurrent ART or prominent liver fibrosis requires frequent monitoring because of the increased risk for mitochondrial toxicity and liver failure.

Adult↗
PubMed2002

Active, fulminant, lethal myocarditis associated with parvovirus B19 infection in an infant.

We report a case of fulminant myocarditis in an 11-month-old female infant who had no other clinical signs of parvovirus infection. The patient presented with severe respiratory distress and died in sudden cardiac arrest 3 h after admission. The clinical presentation was similar to that of an asthmatic attack. Autopsy revealed signs of acute lymphocytic myocarditis. Parvovirus DNA was demonstrated by polymerase chain reaction (PCR) analysis of tissue sections obtained from the heart, lungs, liver, kidneys, and spleen. Transmission electron microscopy of myocardial tissue showed crystalline arrays with the appearance of parvovirus. The results of immunohistochemical analysis for the detection of parvovirus antigens were negative, and no viral inclusions were demonstrable. We suggest that the current diagnostic procedure underestimates the prevalence of parvovirus-associated myocarditis. PCR analysis should be used as a complement in suspected cases, to enhance the rate of detection of the infection and to reach a correct diagnosis.

DNA, Viral↗
PubMed2002

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Adolescent↗
PubMed2002

A population-based study on the incidence and possible pre- and perinatal etiologic risk factors of biliary atresia.

OBJECTIVE: To study the incidence, etiologic risk factors, and outcome of biliary atresia. STUDY DESIGN: Register study using Swedish national health databases. The study population consisted of 1,204,791 children, corresponding to 99% of the entire cohort of Swedish children born between 1987 and 1997, with an end point of follow-up at 2 years of age. Cases with biliary atresia with and without major heart malformations were identified with indicators from various national health databases. RESULTS: Eighty-five cases with biliary atresia were identified, the incidence being 1 in 14,000. A major heart malformation was found in 13 (15%) cases. In a multivariate analysis, 4 independent risk factors were identified: high maternal age (odds ratio [OR] = 3.0), parity of at least 4 (OR = 2.2), prematurity (OR = 2.9), and low birth weight for gestational age (OR = 4.7). No significant differences were found in the distribution of birth months. The outcome did not differ between the two groups with and without major heart malformations, nor with respect to any of the risk factors. CONCLUSIONS: The Swedish incidence of biliary atresia is similar to that found in other European countries. The identified risk factors may suggest the existence of a maternal vulnerability and the importance of viral infections transmitted from mother to fetus/neonate.

Adolescent↗
PubMed2002

Ganciclovir treatment in infants with cytomegalovirus infection and cholestasis.

BACKGROUND: The authors have previously described an association between cytomegalovirus (CMV) infection and intrahepatic and extrahepatic forms of neonatal cholestasis. Pediatric use of the antiviral drug ganciclovir to treat patients with CMV infection has increased. In this study, infants with CMV infection and cholestasis were treated with ganciclovir. METHODS: Six infants with cholestasis (age, 3-16 weeks) and with signs of ongoing CMV infection were treated with intravenous ganciclovir for 3 to 7 weeks and observed for 4 to 31 months after treatment. Two patients had biliary atresia, one had suspected septo-optic dysplasia and three had no obvious cause for intrahepatic cholestasis other than ongoing CMV infection. RESULTS: Four patients, including one with biliary atresia, responded to the treatment, whereas two patients, including the one with septo-optic dysplasia did not. The latter patient had episodes of symptomatic hypoglycemia during the treatment, which was subsequently stopped. Liver function at the end of follow-up was good in four patients, intermediate in one, and poor in one. CONCLUSION: Ganciclovir treatment may be beneficial in infants with CMV-associated intrahepatic cholestasis, but controlled studies are needed. Because of the possible side effect of hypoglycemia, infants with cholestasis who have increased risk for such episodes should not be treated.

Antiviral Agents↗