[Severe aplastic anaemia in six children after non-A-E hepatitis without hepatic failure]. / Schwere aplastische Anämie bei 6 Kindern nach Non-A-E-Hepatitis ohne Leberversagen.

Aplastic anaemia can coincide with non-A-E hepatitis. Treatment follows a standardised study protocol of the German Society of Paediatric Oncology and Haematology (GPOH). Patients receive immunosuppression and/or bone marrow transplantation. We present six cases of aplastic anaemia after non-A-E hepatitis with different courses. In four of these children illness first presented with acute gastroenteritis. Five out of six children fully recovered, two of these with immunosuppression alone, three after bone marrow transplantation. One patient died due to complications of the bone marrow transplantation. In two patients steroid therapy was carried out to treat the hepatitis. This did not have any effect on the course of their aplastic anemia. We emphasise this common combination of aplastic anemia following non-A-E hepatitis. This overview underlines the necessity of regular blood testing after non-A-E hepatitis. Often gastroenteritis seems to precede illness thus perhaps indicating an infectious trigger.

Association of the interleukin-23 receptor gene variant rs11209026 with Crohn's disease in German children.

AIM: Genome-wide association studies have described variants within the interleukin-23 receptor (IL23R) locus to be associated with Crohn's disease (CD) and ulcerative colitis (UC). We investigated the association of rs11209026 (p.Arg381Gln) and rs7517847 (c.799-3588T>G) into German paediatric inflammatory bowel disease (IBD) patients and analysed IL23R transcriptional activity in colonic tissues. METHODS: The rs11209026 and rs7517847 nucleotide substitutions were determined in 353 German children with IBD (221 CD, 132 UC) and 253 controls using pre-designed TaqMan((R)) SNP genotyping assays. In selected IBD patients and controls, IL23R mRNA expression was measured using real-time PCR. RESULTS: The prevalence of the rs11209026 A allele was lower in CD patients, but not in UC patients, when compared with controls (1.8% vs 7.1%, p < 0.01). The rs7517847 variant, in contrast, was associated neither with CD nor with UC. IL23R expression was variable in IBD patients compared with controls without significant overexpression or downregulation. CONCLUSION: Our study provides additional support for the strong protection of the rs11209026 (p.Arg381Gln) variant against paediatric CD. IL23R was expressed in both CD and UC with a great variability. However, expression levels showed no significant association with the disease.

[Intraabdominal and hepatic infections in pediatric cancer patients]. / Gastrointestinale und hepatobiliäre Infektionen.

Common complications involved in treating pediatric patients with cancer are bacterial, viral and fungal infections of the gastrointestinal tract including esophagitis, gastritis, duodenitis, colitis and hepatobiliar infections. In many cases there are multiple factors that predispose these patients to gastrointestinal infections, such as granulocytopenia, T-cell dysfunction, and mucosal damage. In addition, newer therapies have changed the spectrum of infection that is seen in these patients. The profound T-cell suppression associated with therapies such as stem cell transplantation has led to the emergence of previously rare infections including cytomegalovirus and adenovirus. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Hematology/Oncology (GPOH) for diagnosis, prevention, and management of local as well as invasive infections of the gastrointestinal tract.

Differential diagnosis of cholestasis following allogeneic hematopoietic stem cell transplantation in children: the contribution of serum bile acid levels in relation to other liver function tests.

Hepatic complications associated with cholestasis occur frequently in hematopoietic stem cell transplant recipients. Since bile acid seems to be a sensitive indicator of beginning cholestasis, the authors monitored total serum bile acid levels in addition to the standard liver function tests in 23 recipients of allogeneic transplants between June 1999 and September 2000. The observations suggest that bile acid is an early and sensitive marker of hepatic GvHD but not as specific as bilirubin. For cholestasis in absence of hepatic GvHD bile acid seems to be more sensitive than bilirubin. Routinely monitoring of bile acid after hematopoietic stem cell transplantation is not indicated.

Serum leptin, gonadotropin, and testosterone concentrations in male patients with anorexia nervosa during weight gain.

Amenorrhea in female patients with anorexia nervosa is associated with low leptin secretion, thus suggesting a causal link. In an attempt to address the hypothesis that leptin also influences the hypothalamo-pituitary-gonadal function in males, we studied three male patients with acute anorexia nervosa longitudinally. Serum levels of leptin, LH, FSH, testosterone, and SHBG were measured on a biweekly basis during weight gain. Leptin levels at low body mass index values were below the 5th percentile. During weight gain, leptin levels reached or surpassed the 95th percentile. The temporal dynamics of body mass index and fat mass were closely related to those of leptin concentrations in serum. Leptin increments were paralleled by increments of gonadotropins, testosterone, and the free androgen index (FAI). In each of the patients, serum concentrations of leptin were positively correlated with those of testosterone (P = 0.0001, P = 0.01, P = 0.07, respectively) and FAI (P = 0.0001, P = 0.0001, P = 0.09, respectively). In addition, in the combined data set of all patients changes of leptin over time were positively correlated with changes in LH (P = 0.01), FSH (P = 0.0001), testosterone (P = 0.002), and FAI (P = 0.002). In conclusion, these data suggest that leptin might also play an important role in the regulation of the hypothalamo-pituitary-gonadal axis and fertility in underweight males as has previously been shown in underweight females.

Evaluation of a rapid whole blood test to detect Helicobacter pylori infection in children.

BACKGROUND: Rapid, patient near tests for detecting antibodies against Helicobacter pylori are offered for clinical use. We evaluated the BM-Test (Boehringer Mannheim, Germany; identical to the Helisal Rapid Blood Test) in children with recurrent abdominal pain. METHODS: The BM-Test and 13C-urea breath test (UBT) were performed in 195 children (4-18 years). Symptoms were assessed using a 4-week diary. Upper endoscopy was performed in all UBT-positive children and in UBT-negative children with symptoms suggestive of organic disease. H. pylori status was considered positive if at least two of three methods (UBT, histology or rapid urease test) or culture were positive. RESULTS: After exclusion of children with previous H. pylori therapy (n = 8) and undetermined H. pylori status (n = 1), 61/186 (33%) children were H. pylori positive. The BM-Test in relation to H. pylori status revealed a sensitivity of 54%, specificity of 90%, a likelihood ratio of 5.2 for a positive, and of 0.4 for a negative test result. Accuracy of the test was independent of ethnicity, gender, age, family history for ulcer disease, frequency or severity of abdominal symptoms, epigastric tenderness, type of blood sampling (capillary versus venous) and DOB values of the UBT. In eight previously treated children, the test gave one false-positive and three false-negative results. CONCLUSIONS: Almost half of H. pylori-infected children and 10% of non-infected children were misclassified by the BM-Test. False-negative results are not related to young age or certain ethnic groups. The poor performance makes the test unsuitable for epidemiological and clinical use in children.

Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients.

OBJECTIVES: Progressive familial intrahepatic cholestasis (PFIC) usually presents with pruritus, jaundice, hepatomegaly, and growth failure. A group of PFIC is recognized by marked elevation of total serum bile acids, decreased serum apolipoprotein A-1, and high-density lipoprotein, but normal gamma-glutamyltranspeptidase and cholesterol. Although medical therapy generally fails, partial external biliary diversion (DIV) has been used with promising results for cholestasis. However, little has been reported of its effect on linear growth, synthetic liver function, and lipid metabolism. METHODS: DIV was performed on six noncirrhotic children with PFIC, all suffering from severe pruritus and cholestasis, refractory to medical treatment. Stature was below -1 (median, -2.3) standard deviation score (SDS) for height in all cases. All patients had markedly enhanced bile acids (307 +/- 72 microl/L), markedly decreased high-density lipoprotein (20 +/- 7 mg/dl), and apolipoprotein A-1 (58 +/- 37 mg/dl), but normal gamma-glutamyltranspeptidase and cholesterol. In addition, cholinesterase activity, monoethylglycinexylidide test, and Fischer's ratio indicated a significantly reduced synthetic liver function in all children but the youngest. RESULTS: After DIV, all patients were consistently relieved of pruritus, and experienced normalization of all liver function tests, including cholinesterase activity, monoethylglycinexylidide test, and Fischer's ratio, as well as the serum lipid profile within 1 yr. In addition, a marked catch-up growth (median, +/- 1.3 SDS) was evident after 1 yr in all cases. CONCLUSIONS: This report shows an excellent result of DIV in noncirrhotic PFIC patients and compares favorably with other reports. All patients experienced complete remission, including normalization of synthetic liver function and lipid metabolism. For the first time we have shown that DIV can also be associated with an accelerated growth in these patients.

[Chronic liver disease after treatment of malignancies in children]. / Chronische Hepatopathien nach Behandlung maligner Erkrankungen bei Kindern.

Chemotherapy, which has greatly improved the prognosis of children with malignant diseases, is potentially hepatotoxic. Furthermore, there is a risk for viral hepatitis acquired by blood products. In this study we looked for hepatotoxicity and for chronic viral hepatitis during and after chemotherapy in 50 unselected children with malignant diseases. 29 children had been treated for leukemia or lymphoma, 19 for solid tumors, 2 for histiocytosis. All patients had been treated before 1991 and had received blood products not screened for hepatitis C-antibodies. In 18 girls and 32 boys aged 12.3 years (range 6.7-24.5 years) hepatitis B- and hepatitis C-serology and liver function tests were measured during a routine check-up 3.6 years (range 0.5-11.8 years) after the last chemotherapy. Liver function tests during chemotherapy were reviewed retrospectively. During chemotherapy 86% of children showed increased ALT and AST levels, 10% had levels above 500 U/l. At follow up 16 children (32%) had pathological liver function tests, especially slightly increased AST and ALT, 13 of these 16 patients had chronic hepatitis C. In contrast only 2 of 34 patients with normal liver function tests had a viral hepatitis (p = 0.001). Patients with elevation of AST and ALT above 100 U/l during chemotherapy had significantly more often a viral hepatitis than those with normal or slightly elevated aminotransferases. Our study shows that hepatocellular damage is a frequent complication following chemotherapy. However this progresses to chronic liver disease very rarely unless the patient acquired a viral hepatitis. The prevalence of chronic hepatitis C was very high in our patients. As screening of blood products for hepatitis C-antibodies is routinely performed since 1991 this problem is likely to have decreased.

Hereditary hemorrhagic telangiectasia with juvenile polyposis--coincidence or linked autosomal dominant inheritance?

Hereditary hemorrhagic telangiectasia (HHT) and familial juvenile polyposis (EJP) are two rare autosomal dominant disorders, Genetic heterogeneity has been shown for HHT and is likely for FJP as well. This paper describes the coexistence of both diseases in a girl and her father in addition to twelve members of five families and two sporadic cases reported in the literature. This implies a new phenotype which may be important in elucidating the underlying genetics in HHT and FJP. Clinical diagnosis of one disease should induce screening for symptoms of the other.

[Quality of life following liver transplantation in childhood]. / Lebensqualität nach Lebertransplantation im Kindesalter.

Orthotopic liver transplantation is now routinely performed in infants and children with end-stage liver disease and acute hepatic failure. Quality of life after transplantation depends on organ function, cure or recurrence of the original liver disease, need for further medical care, and complications associated with immunosuppression. Physical and psychomotor development as well as social integration are special aspects which are important for quality of life considerations in children. To illustrate these aspects we will discuss the clinical course of some of our patients.

Serum leptin and gonadotropin levels in patients with anorexia nervosa during weight gain.

Leptin plays an important role in reproductive function. In patients with acute anorexia nervosa, serum leptin levels have repeatedly been shown to be lower than in age-matched controls. We have previously hypothesized that the amenorrhea characteristic of anorexia nervosa is related to this low leptin secretion. In an attempt to address this hypothesis, serum levels of leptin and follicle stimulating hormone (FSH) and luteinizing hormone (LH) of 16 female inpatients with anorexia nervosa or an eating disorder not otherwise specified (atypical anorexia nervosa) were measured on a biweekly basis during weight gain. We hypothesized that a serum leptin level of 1.85 microg L(-1) would be associated with gonadotropin levels at or above the minimal level observed during the menstrual cycle in healthy adult fertile females. Our results revealed that increments of LH levels generally tracked increments of leptin levels during the first weeks of treatment. Similarly, in those patients with low referral leptin levels, FSH initially also tracked leptin levels. In contrast, a relationship between gonadotropin levels and leptin secretion was no longer discernible after LH and FSH levels had peaked. Those patients with exceedingly low leptin levels upon admission revealed a slow increase of gonadotropin levels. Our hypothesis of a threshold leptin level of 1.85 microg L(-1) was supported for LH only.

[Body weight regulation in anorexia nervosa with special attention to leptin secretion]. / Die Gewichtsregulation im Rahmen der Anorexia nervosa unter besonderer Berücksichtigung der Leptinsekretion.

Underweight is a key symptom in anorexia nervosa. In this review we summarize recent findings pertaining to weight regulation in this eating disorder. The observation that a body mass index below 13 kg/m2 upon admission for inpatient treatment is associated with a high mortality rate and chronic persistence of underweight is of obvious clinical relevance. A lowered leptin secretion, which results from the weight loss, is presumably of major importance for the development of amenorrhea. We discuss findings pertaining to a reduced body weight in other psychiatric disorders during adolescence in the light of Kretschmer's findings related to body frame and psychopathology.

No evidence for involvement of the leptin gene in anorexia nervosa, bulimia nervosa, underweight or early onset extreme obesity: identification of two novel mutations in the coding sequence and a novel polymorphism in the leptin gene linked upstream region.

Mutations in the leptin gene can result in profound obesity in both rodents and humans. In humans, serum leptin levels correlate with body mass index (BMI: kg m(-2)). However, in patients with anorexia nervosa (AN) leptin levels are lower than in BMI-matched healthy controls. We had previously argued that genes involved in weight regulation should be considered as candidate genes for AN. To investigate this hypothesis we screened the coding region of the leptin gene and part of the leptin gene linked upstream region (LEGLUR) in 49 patients with AN and 315 children and adolescents with extreme obesity. Two novel mutations in the coding region (Ser-91-Ser; Glu-126-Gln), each found in a single proband, and a novel polymorphism in the LEGLUR (position -1387 G/A; frequency of both alleles approximately 0.50) were identified. Tests for association of LEGLUR polymorphism alleles were negative by comparing allele frequencies between 115 AN patients, 71 bulimia nervosa patients, 315 extremely obese children and adolescents, 141 healthy underweights and 50 controls that were not selected for body weight. Tests for transmission disequilibrium were also negative. Hence, an influence of variations in the leptin gene on eating disorders or extreme early onset obesity could not be detected.

Alpha-interferon treatment in HBeAg positive children with chronic hepatitis B and associated hepatitis D.

The main problem of children with HBeAg positive hepatitis B and associated hepatitis D is progression to liver cirrhosis with decompensation of liver function and need for liver replacement therapy within 15-20 years after infection. To determine whether interferon-alpha (IFN-alpha) therapy has a positive effect on HBV replication and inflammatory activity, we evaluated clinical and serological data of 8 children treated with IFN-alpha and 6 historic control patients without treatment. 4 of the nontreated patients seroconverted from HBeAg to anti-HBe between 7 to 17 years after initial diagnosis and showed decreased inflammatory activity in the liver. In the treatment group, the rate of seroconversion to anti-HBe (3 early, 2 late seroconverters) corresponded well to former trial results obtained in patients exclusively infected by HBV. Serum aminotransferase levels decreased or normalized in seroconverted children. In chronic HBV infection with associated hepatitis D (HDV) infection--compared to the spontaneous course of the disease--IFN-alpha therapy reduced inflammatory activity by earlier seroconversion to anti-HBe in responding patients. Moreover, viral replication and infectivity of hepatitis B was markedly reduced, but no effect on replication of HDV could be documented. Although long-term effects cannot be exactly estimated, at present IFN-alpha remains the only available treatment for HBeAg and anti-HDV positive children and seems to be of benefit for responding patients.

Safety and efficacy of interferon retreatment in children with chronic hepatitis B.

UNLABELLED: More than 50% of children with chronic hepatitis B do not respond to treatment with alpha-interferon. Since these patients continue to display high viral replication and progressive liver disease, retreatment should be considered. To date it has not been well evaluated whether a second course of treatment could increase the response rate. In two alpha-interferon retreatment trials in adult patients the response rate, defined by seroconversion from HBeAg to anti-HBe, ranged between 11% and 44%. One beta-interferon retreatment study in children reported a seroconversion rate of 32%. Regrettably, none of the studies included a control group observing the 'spontaneous' seroconversion rate after a first interferon cycle. Thus, a nonrandomized alpha-interferon retreatment study in children including control patients was performed. Alpha-interferon for retreatment was administered 3 times a week for 16-24 weeks in 15 children (5-16 years) at least 6 months after ceasing the first cycle. Four children received 5 MU/m2 of a natural alpha-interferon and 11 children 9 MU/m2 recombinant alpha-interferon 2b. Follow up was 18-47 months after initial treatment. In parallel, a control group of 19 unretreated children with comparable clinical and demographic data was followed for 12-39 months. HBeAg seroconversion was observed in 5 (33%) of the retreated children and in 5 (26%) of the control patients during follow up. The difference is not significant. In the initially nonresponding children, those with high ALT levels before the first treatment showed late HBeAg seroconversion more frequently than those with low ALT levels (P=0.017) irrespective of retreatment. The ALT level before retreatment was not a predictor for response. CONCLUSIONS: A second cycle of alpha-interferon during the 3 years following the first treatment in nonresponding children with chronic hepatitis B can be safely performed but did not increase HBeAg/anti-HBe seroconversion compared with the spontaneous seroconversion rate of patients without retreatment.

[Possible pathophysiologic, diagnostic and therapeutic implications of new findings on leptin secretion within the scope of anorexia nervosa]. / Mögliche pathophysiologische, diagnostische und therapeutische Implikationen neuer Befunde zur Leptinsekretion im Rahmen der Anorexia nervosa.

OBJECTIVES: Leptin is a hormone synthesized in adipocytes and secreted into the bloodstream. It plays an important role in the regulation of body weight, the adaptation to semi-starvation and in reproductive function. Hence, clinical studies pertaining to anorexia nervosa can serve to further elucidate the functions of this hormone in light of the unique features of this disorder. METHODS: Circulating concentrations of leptin are exceedingly low during the acute stage of anorexia nervosa. Which symptoms result from these diminished concentrations must be clarified. Furthermore, research is required to evaluate whether or not a too rapid weight gain might induce a physiological counter-regulation which would predispose to renewed loss of weight. RESULTS: This review summarizes findings to date pertaining to leptin secretion in patients with anorexia nervosa. In addition, possible diagnostic, pathophysiological and therapeutic implications are discussed.

Heterotopic auxiliary liver transplantation in a 3-year-old boy with acute liver failure and aplastic anemia.

BACKGROUND: Auxiliary liver transplantation offers an alternative method to conventional transplantation in acute liver failure. It is especially challenging for children because lifelong immunosuppression may be avoided. However, experience with this procedure is rare and there is controversy about whether to place the graft orthotopically or heterotopically. METHODS: We present the case of a 3-year-old boy with acute liver failure due to non-ABC hepatitis complicated by aplastic anemia who underwent auxiliary liver transplantation. Segments 2 and 3 of the graft were implanted heterotopically in the right lower abdomen. RESULTS: Good liver function was immediately restored. Aplastic anemia resolved 3 weeks after transplantation. Immunosuppressive therapy was discontinued after 14 months, and the graft was left to atrophy. Thirty-nine months after transplantation the boy is alive and well with normal liver function tests and normal blood cell counts. CONCLUSIONS: Heterotopic auxiliary liver transplantation allowed recovery of the native liver in a child with acute liver failure and aplastic anemia due to non-ABC hepatitis.

Transmission of GBV-C/HGV from drug-addicted mothers to their babies.

BACKGROUND/AIMS: In 1995, a new flavivirus, GBV-C/HGV was identified. Little information is available on the clinical manifestations and epidemiology of GBV-C/HGV infection. We investigated the risk of mother-to-infant transmission in a group of GBV-C/HGV RNA positive women and followed up the GBV-C/HGV infected babies. METHODS: Twenty-eight anti-HCV positive women, of whom 25 have been intravenous drug users, and their children were included in the study. RNA was extracted from serum, reverse transcribed and amplified with primers from the NS5 region of GBV-C/HGV and 5'-UTR of HCV in a nested polymerase chain reaction. Amplified DNA fragments were gel purified and sequenced; the sequences obtained were subjected to a phylogenetic analysis. RESULTS: Transmission of GBV-C/HGV occurred in 10 (56%) of 18 infants born to GBV-C/HGV positive mothers; all these women were drug abusers. Only one (5%) of 19 babies whose mothers were HCV RNA positive by polymerase chain reaction, was infected with HCV during the follow up. High sequence homology in the NS5 region of GBV-C/HGV isolates in 10 mother-child pairs suggested mother-to-infant transmission. All 10 babies remained GBV-C/HGV RNA positive during follow up (2-12 months). None of the GBV-C/HGV infected infants became icteric or demonstrated any clinical or biochemical signs of liver disease. CONCLUSIONS: Mother-to-infant transmission of GBV-C/HGV may be high, at least in HCV-infected, drug-addicted women. In GBV-C/HGV RNA positive infants the rate of GBV-C/HGV persistent infection is high, but the infection is not accompanied by any symptoms of liver disease.

Hyperintense lesions of the globus pallidus on MRI in children with chronic liver disease.

UNLABELLED: In three children with chronic liver disease of different aetiology without obvious hepatic encephalopathy, bilateral and symmetrical hyperintensity of the globus pallidus in T1-weighted images was found on cranial MRI. Reversibility was shown in one child with autoimmune hepatitis after normalisation of liver function tests under immunosuppressive therapy. CONCLUSION: As central nervous system involvement in liver disease is only partially understood, brain imaging by MRI offers a potential additional tool to further elucidate the incidence and time course of previously undetected brain alterations.