Syndromic variability of Wilson's disease in children. Clinical study of 44 cases.

BACKGROUND: In children with Wilson's disease, no clinical or laboratory data are specific for diagnosis as in adult age. AIM: Clinical aspects and parameters of copper metabolism in a large series of pediatric cases are evaluated to establish certain criteria for diagnosis and for correct treatment, even in difficult cases. METHODS: In 44 children with Wilson's disease, clinical aspects, histological features, laboratory parameters and data of copper metabolism have been studied. Forty patients, treated with penicillamine, were followed up (median 77 months). RESULTS: The 44 cases were classified as: asymptomatic forms (nine cases, six of them siblings of affected subjects), chronic hepatitis (23 cases), hepatocerebral manifestations (four cases), decompensated cirrhosis (six cases), fulminant hepatic failure with hemolytic anemia (two cases). Ceruloplasmin levels were abnormal in 37 out of 43 tested cases, but normal in six (14%) who showed high basal and after penicillamine load urine copper excretion and increased hepatic copper content. Urine copper concentration was pathological in 35 out of 42 tested cases (83%), but normal in seven patients under six years. Hepatic copper levels were very high in all the 20 tested patients. Under treatment, 27 children had favourable outcome. One patient showed no evolution of disease, seven patients worsened because of non-compliance to the therapy (one underwent successful liver transplantation) or severe side effects. Five patients with failure died. CONCLUSIONS: Wilson's disease in children may present with a broad clinical spectrum, but the liver involvement is by far the most prevalent. The early diagnosis, based on clinical suspicion and results of copper metabolism investigation (including hepatic copper content evaluation in difficult cases) and appropriate treatment can prevent the progression of the disease.

Mineral oil lipoid pneumonia in a child with anoxic encephalopathy: treatment by whole lung lavage.

We describe a case of exogenous lipoid pneumonia in a child with anoxic encephalopathy who was taking mineral oil for constipation. Computed tomography produced images suggesting this condition, and the diagnosis was confirmed by demonstrating the presence of lipid-laden alveolar macrophages in the bronchoalveolar lavage fluid. Despite discontinuing the offending agent, the pulmonary infiltrates did not improve; however, successful resolution was obtained by whole lung lavage.

Zidovudine therapy of HIV-1 infection during pregnancy: assessment of the effect on the newborns.

Zidovudine (ZDV) administration during pregnancy has been suggested for the prevention of mother-to-child HIV-1 transmission. Reliable levels of the drug have been observed in the fetus and in the newborn. Seven HIV-1-infected pregnant women who declined to have abortions and whose immunological status required antiretroviral treatment were administered oral ZDV 18 mg/kg in four daily doses, the initial dose being administered anytime from the 16th to the 30th week of gestation up until the time of delivery. Follow-up of the seven infants from birth with a mean duration of 22 months (range 16-32 months) revealed mild drug-related toxicity: anemia in two infants and macrocytosis in all seven, both conditions resolved by the second month of life. All infants remained HIV-1 seronegative, according to the 1987 CDC classification, and all stayed clinically well. Other virological parameters including virus culture, in vitro antibody production, and polymerase chain reaction, repeatedly performed in the infants, remained negative. Although none of the mothers transmitted HIV-1 infection to the offspring, the size of this study and the relatively low transmission rate (13%) in Europe do not permit us to draw a definite conclusion about treatment efficacy in preventing maternal-fetal transmission. However, the drug caused only limited toxicity among the infants, and its administration to large numbers of mothers in treatment trials should be considered relatively safe for both mother and child.

Fluconazole in the treatment of candidiasis in immunocompromised children.

Fluconazole, a new triazole derivative, was evaluated in a pilot study of 34 episodes of candidiasis in 24 children. All the patients had predisposing conditions, such as human immunodeficiency virus infection, cancer, organ or bone marrow transplantation, neonatal age and malnutrition, and obstructive uropathy. The drug was administered at 6 mg/kg (body weight) once daily either orally or intravenously. Two patients with fungemia due to Candida parapsilosis required an increased dosage of 12 mg/kg. Clinical and microbiological success was achieved in 30 of 34 cases (88%). Drug-related transaminase increases were observed in two cases (6%). Fluconazole may represent an effective alternative to amphotericin B in the treatment of candidiasis in children. Comparative trials are necessary to assess optimal dosages and efficacy.

[The acquired immunodeficiency syndrome (AIDS) in childhood]. / La sindrome da immunodeficienza acquisita (AIDS) in età pediatrica.

There is an increasing concern about HIV infection in paediatric age, due to its increasing incidence in some countries, especially in Europe, and due to its social aspects. HIV infection has particular features, while occurring during paediatric age: infection of child frequently occurs during pregnancy (perinatal form of HIV infection), a period characterized by the immaturity of the immune system of the host. Encephalopathy is a frequent manifestation of the disease, recurrent fever episodes have a different pathogenesis than in adults, LIP (lymphocytic interstitial pneumonia) is a common manifestation of the disease and there is a higher progression rate to AIDS. Antiretroviral therapy, as zidovudine (AZT) in paediatric age is still on clinical trials, and only few preliminary data are available.

[Liver cirrhosis in childhood. Considerations on 22 cases with different etiology]. / La cirrosi epatica in età pediatrica. Considerazioni su ventidue casi a differente eziologia.

Although rather uncommon and multifactorial in etiology, liver cirrhosis is a severe and often rapidly fatal disease in pediatrics. In our institution, during the last 15 years, 22 children with liver cirrhosis have been followed. The underlying predisposing condition was HBV infection (8 cases), CMV perinatal infection (2 cases), Wilson's disease (4 cases), chronic cholestasis (2 cases) and alcohol abuse (2 cases); in 4 cases no predisposing condition was evident. In all cases the histological examination of the liver was the diagnostic cornerstone. The mean age at diagnosis was 6 years and 8 months, with an early onset especially in the posthepatitis cirrhosis. In 10 out of 22 patients, cirrhosis was not preceded by an history of chronic liver disease. Poor subjective symptomatology was present in 13 of the cases, hepatomegaly in all, splenomegaly in 18 cases, signs of hepatic failure in 13 cases. In all patients various impairments of hepatocellular synthesis were detectable, especially during the period preceding the development of hepatic insufficiency. The mean time to cirrhosis was 5 years. The average duration of the follow up was 3 years and 4 months: during the follow up 6 patients improved, 5 patients showed no clinical or functional modifications of their hepatic disease, 3 patients worsened and 8 died. In order to perform suitable treatment of liver cirrhosis the need of early diagnosis and etiological definition should be emphasized.

[Reactivation of virus replication during immunosuppressive therapy in children with chronic hepatitis B]. / Riattivazione della replicazione virale in corso di terapia immunosoppressiva in bambini affetti da epatite cronica tipo B.

The aim of the present work is to assess whether reactivation of viral replication occurred in children affected by chronic hepatitis undergoing long term immunosuppressive therapy. 123 serum samples belonging to 25 children were retrospectively evaluated for HBV-DNA and HBeAg. Sera were collected prior to and during the protocol treatment (steroids alone or with azathioprine). Presence of HBV-DNA was evaluated by means of molecular hybridization technique, using a radiolabelled probe of cloned HBV-DNA. Sera (100 1) were denatured and transferred into nylon membrane (spot) then prehybridized and hybridized. After washing in stringent conditions, the filter was exposed in autoradiographic cassette with Kodak film XOmat5. Positivity was semiquantitatively evaluated by blackening of the spot. Increase or appearance of HBV-DNA was observed in the sera from 24/25 pts. HBeAg became positive in 4/5 pts previously negative. Obtained data shows reactivation of viral replication during immunosuppressive therapy. Data are especially significant in those cases in which such activity has apparently ceased or not been detected; HBV may be considered as a latent virus.

Hepatitis B virus (HBV)-DNA-positive hepatocellular carcinoma following hepatitis B virus infection in a child.

Integrated hepatitis B virus (HBV) DNA sequences were found in neoplastic liver tissue of a hepatitis B surface antigen (HBsAg)-negative child who had previously suffered from HBsAg-positive chronic active hepatitis and was anti-HBs and anti-hepatitis B core (HBc) positive at the time of tumor development. Reintegration pattern was consistent with the presence of a single integration site of the HBV genome into cellular DNA, and clonal proliferation of such infected cells. A normal liver, tested in the same experiment with the same amount of total DNA, was negative for viral DNA sequences. These findings support the possible oncogenic role of HBV in the development of liver cancer, not only in adults, but also in children, even in patients who are negative for HBsAg at the time of tumor diagnosis.

Liver cirrhosis associated with chronic hepatitis B virus infection in childhood.

We evaluated the prevalence and the clinical features of liver cirrhosis associated with chronic hepatitis B virus (HBV) infection in a prospective study of 292 consecutive children who were chronic HBsAg carriers with increased aminotransferase activity. Liver histologic changes at presentation were consistent with cirrhosis in 10 (3.4%) patients (100% boys, mean age 4.0 +/- 3.3 years). In none of the remaining children, including 166 with histologic evidence of chronic active hepatitis, did the condition progress to cirrhosis during an observation period of 1 to 10 years. This lack of progression suggests that cirrhosis is an early complication of chronic HBV disease in some patients. A higher prevalence of delta infection and increased incidence of blood transfusions were observed in patients with cirrhosis, supporting the hypothesis that superinfection with delta or non-A, non-B agents may play a synergistic role. Eight of 10 patients had histologic features of disease activity at presentation, although only two had symptoms. During follow-up, persistence of disease activity was observed only in the three delta antigen-positive patients. None of the patients with inactive cirrhosis have developed signs of liver failure or portal hypertension.

Correlation between e/anti e system and evolution of B virus chronic hepatitis in pediatric patients.

The authors have performed a longitudinal study of 118 children affected with B virus chronic hepatitis. Our first observation revealed 92 children with HBeAg positive (26 CPH, 66 CAH), 22 children with anti HBe positive (6CPH, 15 CAH, 1 cirrhosis), 4 children (CAH) with e/anti-e negative. A correlation between the severity of clinical forms and the behaviour of the e/anti-e system was not observed. Seroconversion was observed during the follow up period in 37 of 92 subjects in an average time of 59.83 +/- 32 months, time rather prolonged in patients under immunosuppressive therapy. To compare the clinical progress and the evolution of CPH and CAH respectively, always with regard to the e/anti-e system, statistically significant differences did not result. Only anti HBe positive recovered subjects, inclusive of seroconverted patients and those anti HBe from the first observation, showed significant results to the statistical analysis. Still, seroconversion corresponds frequently to a stable improvement of hepatitis. On the contrary evolution into cirrhosis was observed in 5 patients that had anti HBe antibodies.

A long-term study of hepatitis B virus-related antigens and immunological parameters in children with chronic hepatitis.

Forty-two children with HBsAg positive chronic hepatitis who received immunosuppressive therapy underwent multiple liver biopsies over periods ranging from one to five years. The presence of HBsAg, HBcAg, deltaAg, antinuclear antibodies and immune complexes was studied using immunofluorescent techniques. The data were correlated with the clinical status of the patients. The presence of HBsAg, HBcAg and deltaAg remained unchanged throughout the study in most positive patients. All 30 HBcAg positive cases were still positive at the end of the study. One of the negative cases became positive. Eight of the ten delta antigen positive cases showed no change. Intrahepatic immunoglobulins, immune complexes and antinuclear antibodies showed a decrease in positivity in a significant number of patients. Fifteen of the 36 patients positive for intrahepatic immunoglobulins became negative during the study, as did 12 of the 29 immune complex positive subjects and 22 of the 33 antinuclear antibody-positive cases. The persistence of HBV antigens seems to be independent of the clinical course. On the other hand, the persistence of positive immunological indices corresponds to a less favourable outcome.

[True hepatic Wilson's disease]. / Malattia di Wilson epatica pura.

Fourteen cases of Wilson's disease, 9 of which in pure hepatic form are presented. Earliest clinical sign of liver disease was hepatosplenomegaly with altered indexes of hepatic function. The disease was found in 4 couples of brothers and sisters of families reported. For all cases diagnosis was based on the values of ceruloplasmin, serum copper, basal urine copper and urine copper after D-penicillamine. Furthermore in 8 cases very increased copper concentration in the liver was demonstrated. D-penicillamine therapy produced hepatic improvement in 8 cases, 6 of which affected by only hepatic form and the treatment was fairly tolerated. In 1 case this therapy caused nephrotic syndrome it was replaced with Trien-2HCL. Wilson's disease in its pure hepatic form must be considered in the differential diagnosis of liver diseases in pediatric age, especially when markers of viral hepatitis are absent. The identification of pure hepatic form provides early diagnosis of Wilson's disease, basic requirement for an effective therapy.