Biomedical subjects
Publications and source records attributed to P Vajro.
We report the case of a girl affected by ulcerative colitis with high serum levels of creatine kinase and lactate dehydrogenase due to the presence of macroenzymes. Our observation suggests that the knowledge of this association may be helpful when evaluating ulcerative colitis patients with unexplained isolated elevation of one or more serum enzyme activities.
We report a 3-year-old Italian patient with the hyperornithinaemia, hyperammonaemia, homocitrullinuria (HHH) syndrome who presented with neurological deterioration after an intercurrent infection. Hyperammonaemia, coagulopathy and moderate hypertransaminasaemia were detected on hospital admission. Severe hepatocellular necrosis with hypertransaminasaemia (aspartate aminotransferase 20,000 UI/L, alanine aminotransferase 18,400 UI/L) and coagulopathy (PT < 5%) rapidly developed within few days, prompting evaluation for liver transplantation. A protein-restricted diet and arginine supplementation were immediately started, with a rapid improvement of the patient's neurological conditions and normalization of liver function tests and blood ammonia. The diagnosis of HHH syndrome was based on the presence of the typical metabolic abnormalities. Molecular analysis of the SLC25A15 gene showed that the patient was heterozygous for two novel mutations (G113C and M273K). The diagnosis of HHH syndrome should be considered in patients with fulminant hepatitis-like presentations. Early identification and treatment of these patients can be life-saving and can avoid liver transplantation.
We report the case of a girl affected by giant cell hepatitis associated with autoimmune haemolytic anaemia. Both conditions were severe with a number of life-threatening episodes of liver failure and anaemia unresponsive to several immunosuppressant drugs but cyclophosphamide. After a low-dose long-term treatment with this drug the patient is stably well without any therapy. A review of therapeutical options in this condition is also presented.
BACKGROUND AND AIMS: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. METHODS: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. RESULTS: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. CONCLUSION: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.
Hepatitis C virus infection in infancy largely depends on vertical transmission. The transfer of hepatitis C virus from mother to child is almost invariably restricted to children whose mother is viremic, and the rate of transmission seems to be influenced by maternal virus load, although, in the single patient, the levels of viremia cannot be used as predictors of pediatric infection. In fact, the flow-chart for screening children at risk for vertically transmitted hepatitis C virus infection takes into account maternal viremia. In children born to anti-hepatitis C virus antibody positive, hepatitis C virus-RNA negative mothers, alanine aminotransferase and anti-hepatitis C virus should be investigated at 18-24 months of life. If alanine aminotransferase values are normal and anti-hepatitis C virus is undetectable, follow-up should be interrupted. In children born to hepatitis C virus-RNA positive mothers, alanine aminotransferase and hepatitis C virus RNA should be investigated at 3 months of age: (1) hepatitis C virus-RNA positive children should be considered infected if viremia is confirmed by a second assay performed within the 12th month; (2) hepatitis C virus-RNA negative children with abnormal alanine aminotransferase should be tested again for viremia at 6-12 months, and for anti-hepatitis C virus at 18 months; (3) hepatitis C virus-RNA negative children with normal alanine aminotransferase should be tested for anti-hepatitis C virus and alanine aminotransferase at 18-24 months, and should be considered non-infected if alanine aminotransferase is normal and anti-hepatitis C virus undetectable; (4) anti-hepatitis C virus seropositivity beyond the 18th month in a never-viremic child with normal alanine aminotransferase is likely consistent with past hepatitis C virus infection.
We describe 3 children (2 siblings aged 10 and 3 years, and 1 sporadic case aged 13 years) with cerebellar vermis defect associated with oligophrenia, congenital ataxia, and hepatic fibrocirrhosis. Differently from what is reported in COACH syndrome, coloboma and renal involvement were absent. Since in one patient hepatic involvement was subclinical and early therapy seemed to prevent disease progression, the presence of liver disease should be carefully investigated in any patient with ataxia and midline cerebellar defects.
BACKGROUND: Compulsory vaccination of children against hepatitis B virus (HBV) infection was introduced in Italy in 1991. PATIENTS AND METHODS: To evaluate the current importance of pediatric HBV infection, we studied 359 HBsAg-positive children admitted to 16 centers in Italy from 1991 to 1998. 185 patients were natives of Italy and 174 (39 immigrants and 135 adopted) came from highly endemic countries (eastern Europe: 60.9%, Asia: 16.7%, Africa: 14.9% and Central and South America: 5.7%). RESULTS: Transaminase Levels were moderately altered in both Italian (mean 134 UI/L) and foreign children (mean 168 UI/L). In total, 77% of ItaLian children and 88% of foreign children tested HBeAg positive. High transaminase levels and HBeAg positivity were more frequent in adopted children. Follow-up of 317 patients showed that the incidence of HBeAg/anti-HBe serum conversion was similar in all cohorts, but in adopted children it occurred at an earlier age and was associated with HBsAg clearance in 5%. CONCLUSION: HBV is not frequent in Italian children today, but it is common among children coming from highly endemic areas. The vaccination of nonimmune native populations must be strongly recommended.
We carried out an in-depth evaluation of psychosocial status in a sample of 18 children (mean age 6.8 yr, range 4.4-10.8 yr) who had suffered from severe liver disease and undergone orthotopic liver transplantation (OLT). Mean age at OLT was 3.4 yr. The assessment was psychoanalytically oriented and included individual sessions and testing procedures for children--the Children Apperception Test (CAT), the Weschsler Intelligence Scale for Children (WISC-R), the Weschsler Preschool and Primary Scale of Intelligence (WIPPSI), and the Human Figure Test--and a semi-structured interview with a separate questionnaire for parents. Patients were compared with an age- and gender-matched control group. The main findings in patients compared with controls were: IQ 91.6 (range 70-117) vs. 118 (range 94-135) (p<0.0001); immaturity of ego and drives (72.2% vs. 27.7%; p=0.018), fear of death (61.1% vs. 11.1%; p=0.04), anxiety of loss (50%, vs. 27.7%; p=NS), and depressive feelings (61.1% vs. 22.2%; p=0.04); a mild defect of body image (44.4% vs. 33.3%; p=NS) associated with recurrent representations of motionless (72.2% vs. 38.8%; p=NS) and inexpressive (88.8% vs. 16.6%; p<0.0001) human figures. Fantasies about OLT as a 'magic rebirth' or a 'body transformation' were detected in few patients (30%). Although a recurrent set of feelings, conflicts, and fantasies about OLT were expressed by children, individual specific psychological responses to this experience were often detected. In spite of the fact that approximately 50% of the parents mentioned emotional or behavioral disturbances of their child, only three parents were seriously concerned about this problem. The theme of transplantation was most often absent from communication between the child and their parents. Our results suggest that psychic 'working through' of the chronic liver disease and OLT experience is difficult for children. Further studies are necessary to verify whether changes of parental attitude to OLT as a 'family secret' may facilitate integration of the OLT experience in the child's personality development.
BACKGROUND: A retrospective-prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. METHODS: Anti-HCV-positive patients (or HCV RNA-positive infants) aged 1 month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. RESULTS: From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). CONCLUSIONS: Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.
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Epstein-Barr virus (EBV) genome numbers and RNA transcripts from the immediate-early EBV gene BZLF1 were monitored by means of polymerase chain reaction in peripheral blood lymphocytes (PBLs) of 44 children who received liver transplants. The 2 tests were compared, using several parameters to assess their value as predictors of posttransplantation lymphoproliferative disease (PTLD). All patients were infected with EBV. BZLF1 mRNA was positive in 70% of patients, with highest expression in those with largest virus load. Four patients developed PTLD that could not be unequivocally diagnosed by any of the parameters considered alone. Sensitivity of EBV genome number (>/=40,000 EBV copies/10(5) PBLs) and BZLF1 mRNA (BZLF1:glyceraldehyde-3-phosphate-dehydrogenase ratio >/=0.5) was 100%. Specificity of each of the 2 tests alone (98% and 58%, respectively) improved (to 100% and 83%, respectively) when measurement of serum IgG level was included. Because decreased virus load, but not BZLF1 mRNA expression, accurately predicted favorable responses of PTLD to therapy, monitoring of EBV genome numbers alone appears sufficient in children with liver transplants.
Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.
BACKGROUND: Occasional and transient increase in liver enzymes is reported during growth hormone (GH) treatment in girls with Turner syndrome (TS). METHODS: Retrospectively, the specific role of GH treatment on liver and muscular enzymes was evaluated in 78 patients (48 boys; age range 4.0-20.8 years) affected by GH deficiency (GHD) who had been treated with GH for at least 1 year (range: 1-15 years). All patients had normal serum levels of liver and muscular enzymes before GH therapy was started. RESULTS: A clinically asymptomatic and mild increase in serum transaminase levels was observed in 6 of 78 patients with GHD during GH treatment; 3 (3.8%) of the patients showed an isolated, transitory and self-limiting increase in serum liver transaminase levels which was noticed 6 to 12 months after GH treatment was started, and normalized spontaneously within 3 to 6 months, without stopping the therapy. Three additional patients showed a transitory mild increase both in aspartate aminotransferase (AST) and creatine phosphokinase (CK) which also normalized spontaneously within 3 to 6 months. The increase in transaminase levels was not related to the brand of GH preparations nor to the dosage administered. CONCLUSIONS: A mild, transient, self-limiting increase in serum transaminase may occur during GH treatment. Concomitant determination of CK serum levels may quickly differentiate muscular from hepatic hypertransaminasemia. Except for persistent cases, this condition does not generally require further investigations.
BACKGROUND: Gilbert syndrome as a rule becomes manifest in adolescence or in early adulthood; it may be transferred by the donor to orthotopic liver transplant (OLT) recipients. METHODS: We examined the frequency of Gilbert syndrome in 46 OLT pediatric recipients who had a follow-up of 1 year or more. Diagnostic criteria included unexplained chronic or recurrent unconjugated hyperbilirubinemia; its increase after reduced caloric intake plus prolonged fasting, without changes of the proportion of conjugated bilirubin; and high relative amounts of serum unconjugated bilirubin IXa and prevalence of the monoglucuronide over the diglucuronide. RESULTS: Of the 46 patients, 42 had normal bilirubin values. Only four otherwise healthy OLT recipients showed hyperbilirubinemia and normal conjugated fractions. Liver donors had been four men. Hyperbilirubinemia persisted with a fluctuating pattern for the whole follow-up after OLT in all. Total bilirubin level in blood samples obtained after reduced caloric intake and prolonged fasting became notably higher than basal values, whereas the proportion of conjugated bilirubin remained stable. High relative amounts of unconjugated bilirubin IXa and prevalence of the monoglucuronide over the diglucuronide were found. Finally, DNA from liver donors' lymphocytes was available for one jaundiced and two nonjaundiced patients: tests for abnormalities in the promoter region of the gene for the enzyme bilirubin uridine diphospho-glucuronosyltransferase were in agreement with a diagnosis of GS in the former one, CONCLUSIONS: Gilbert syndrome may have an unusual early presentation in pediatric OLT recipients.
OBJECTIVE: To determine whether ursodeoxycholic acid (UDCA) is effective for treatment of obesity-related liver abnormalities in children. STUDY DESIGN: Thirty-one children (21 bboys; mean age, 8.7 years) had obesity-related persistent elevation of aminotransferase levels, which was associated with ultrasonographic images of bright liver in 27. A preliminary interview determined which patients were (n = 18) or were not (n = 13) likely to comply with a balanced low-calorie diet. Four subgroups emerged: patients who followed the diet (n = 11), patients treated with UDCA (10 mg/kg/d) given alone (n = 7) or added to the diet (n = 7), and untreated control patients (n = 6). RESULTS: Diet alone determined weight loss and resolved biochemical liver abnormalities in all patients. Addition of UDCA to the diet was no more efficacious than weight loss alone. UDCA alone was ineffective for the treatment of liver abnormalities in all cases, and results did not differ from those observed in the untreated control group. Improvement of ultrasonographic abnormalities was observed in patients who lost weight, irrespective of UDCA administration. CONCLUSIONS: UDCA is not effective for the treatment of obesity-related liver abnormalities in children.
Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.
UNLABELLED: We evaluated whether hepatic abnormalities represent a specific feature in girls with Turner syndrome (TS) or whether they are related to an increased susceptibility to hormonal therapies and/or other factors. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase were monitored in 70 patients with TS for a mean period of 7.6+/-4.2 years. An increase in serum liver enzymes was observed in 14 out of 70 girls (20%) at a mean age of 12.7 years; it was present at entry before hormonal therapy in 3 girls and developed thereafter during the follow up in the other 11. The increase in serum liver enzymes was never observed before the age of 7 years. In the majority of cases (10/14) it was drug related: in 50% the liver abnormalities were transient and self-limiting, in the remaining cases they required interruption of hormonal therapy. Hepatotoxicity was more frequently observed in girls treated with oestrogens or oxandrolone than in those treated with growth hormone. In a small number of cases, liver disease was either auto-immunity-related (2/14), or cryptogenic (1/14) with a benign and self-limiting course. Obesity was a frequent finding, but it played a likely pivotal role only in one patient. CONCLUSION: Hepatic abnormalities are relatively frequent in Turner syndrome and surveillance of liver function should be included in the management of these patients independent of initiation of hormonal treatment.
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