Long-term interferon-alpha treatment of children with chronic hepatitis delta: a multicentre study.

We assessed the efficacy of prolonged interferon-alpha (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN-alpha 2b (5 MU m-2, then 3 MU m-2 three times weekly for 12 (medium-term group MTG) or 24 months (long-term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow-up. Six of the eight hepatitis B e antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN-alpha treatment in children with chronic type D hepatitis has a transient effect, and long-term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological response.

Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.

Seventy-six children aged 1-13 years who were known to be positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months and who had biopsy-proven chronic hepatitis have been followed longitudinally for 1-12 years (mean, 5 years). Twenty-three of them are now young adults. Eight patients had acute type B hepatitis 12-24 months before entering the study, while 68 patients came to observation during a chronic phase. At the beginning of follow-up, all 76 children were positive in serum for hepatitis B virus DNA, and 44 (58%) had chronic active hepatitis, associated with cirrhosis in two cases. During follow-up, 23 (30%) patients remained hepatitis B e antigen-positive, most with unchanged biochemical and histological features. The other 53 (70%) cases seroconverted to hepatitis B e antibody and cleared hepatitis B virus DNA from serum, including 7 of 8 (87%) patients with acute hepatitis at presentation. After seroconversion, alanine aminotransferase levels normalized in all patients and remained normal in 49 patients (92.5%) throughout a mean observation period of 3 years. Five of these children, including 2 of 7 (29%) with previous acute hepatitis, eventually cleared hepatitis B surface antigen from their sera. Finally, 4 (7.5%) patients experienced a mild increase of alanine aminotransferase levels several months after seroconversion in the absence of hepatitis B virus replication or of delta virus superinfection. Clinical and virological parameters did not significantly differ between patients with or without acute onset; however, seroconversion occurred earlier, and the rate of hepatitis B surface antigen clearance was greater in the former than in the latter group. The present data indicate that approximately two thirds of children with hepatitis B e antigen- and hepatitis B virus DNA-positive chronic hepatitis clear hepatitis B virus DNA from their sera before reaching adulthood. After termination of viral replication, most patients achieve a sustained biochemical remission, suggesting the disappearance of disease activity. Reactivation of virus replication after hepatitis B e antibody seroconversion has never been observed in this series, although mild alanine aminotransferase level abnormalities could be detected in a minority of cases.

Long-term evolution of chronic hepatitis B in children with antibody to hepatitis B e antigen.

The aim of this study was to evaluate the long-term outcome of chronic hepatitis B in 27 children who had increased alanine aminotransferase activity and antibody to hepatitis B e antigen in serum from the time of their first clinical observation. Initial histologic changes were consistent with chronic active hepatitis in 13 cases (three with associated cirrhosis) and with persistent or lobular hepatitis in the remaining cases. On the basis of virologic testing, three groups of patients were identified: (1) two children had hepatitis delta antigen in the liver and anti-delta antibody in serum, and both had severe hepatitis; (2) 10 children had hepatitis B virus DNA in serum, and 60% of them had active hepatitis; (3) 15 patients had no hepatitis B virus DNA, and 33% of them had active hepatitis. During a follow-up period of 12 months to 12 years (mean +/- SD: 6.1 +/- 2.4 years), the disease remained active in both children with anti-delta antibody, but they had no major complaints. In all eight patients who could be followed in group 2, test results became negative for hepatitis B virus DNA and alanine aminotransferase activity normalized within 4 years; biochemical remission was delayed in three patients with higher hepatitis B virus DNA levels on entry, and one of these patients had a severe exacerbation of disease activity before remission. In group 3, a total of 10 patients (71%) achieved biochemical remission within 1 year, and two within 26 months; only two patients, who were transfused at birth, had long-lasting liver damage. These results indicate a trend to early remission of liver disease in children with chronic hepatitis B with antibody to hepatitis B e antigen without delta virus infection. Antiviral therapy aimed at accelerating the termination of hepatitis B virus replication may be indicated only in those with higher levels of hepatitis B virus DNA.

Different expression of HLA class I antigens in liver of children with chronic hepatitis B, evaluated by immunohistochemical method.

Studies on the quantitative expression of the Major Histocompatibility Complex (MCH) in hepatocytes chronically infected by Hepatitis B Virus (HBV) report that an increased expression of these antigens could be related to a good immunological response. In the present work we analyze the expression of the MCH antigens in cryostatic sections of liver biopsies taken from subjects (19 children) with various forms of HBsAg positive chronic hepatitis. A high expression of HLA class I antigens and a high degree of hepatocyte necrosis was evident in Chronic Active Hepatitis (CAH) and Chronic Lobular Hepatitis (CLH). On the contrary, subjects with histological diagnosis of Chronic Persistent Hepatitis (CPH) showed a low expression of such antigens. There was however, the difference that in subjects with high hepatic cytolysis and high expression of HLA class I antigens, serum HBV-DNA was clearly present in almost all the cases with CAH, but not detectable in all cases with CLH. The expression of HLA class II antigens and of Beta2 microglobulin was the same in all 19 cases. All cases with HBV-DNA positivity with high class I antigen expression had active hepatitis which seems to suggest that all attempts at viral clearance on the part of the immune system have been in vain. We hope our paper will be an additional parameter for evaluating the course of hepatitis during Interferon treatment.

Chronic hepatitis in childhood: the spectrum of the disease.

During a multicentre study of chronic hepatitis in childhood diagnosed by biopsy, the spectrum of the disease has been evaluated in 196 consecutive patients, including 157 from Northern Italy and 39 from Southern Italy. Only 31% of patients in the former group and 27% in the latter were symptomatic when first seen: the majority of cases being seen after familial screenings for hepatitis B virus (HBV) markers or during intercurrent infections, thus suggesting that the frequency of chronic hepatitis in childhood might be largely underestimated in our area. In Southern and Northern Italy 83% of symptomatic and 95% of asymptomatic patients were hepatitis B surface antigen (HBsAg) positive in serum; only 15 (8.3%) of these children were born to mothers known to be HBsAg positive at delivery, but a high circulation of HBV was found in their families: in fact more than 65% of household contacts in Northern Italy and more than 90% in Southern Italy had serological evidence of past or ongoing HBV infection. These data indicate that, although familial screenings for HBV could have enhanced the percentage of HBsAg positive asymptomatic cases, chronic hepatitis in Italian children is mainly caused by HBV infection acquired in the familial setting through horizontal transmission. Such findings also emphasise the importance of mass vaccination of infants as the most effective means to prevent chronic type B hepatitis in childhood in our area. Among HBsAg positive children 55% had histological features of chronic active hepatitis and 85% were hepatitis Be antigen (HBeAg) positive in serum. Anti-HBe positive hepatitis was significantly more frequent in Southern than in Northern Italy in parallel with the significantly higher prevalence (17%) of hepatitis delta virus infection in that area. Of the 16 HBsAg negative cases included in the study three had autoimmune hepatitis, three Wilson's disease, one alpha1 antitrypsin deficiency, and nine had cryptogenic hepatitis, often associated to mild liver lesions resembling those seen in our adult patients with chronic non-A, non-B hepatitis unrelated to percutaneous exposure.

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.

[Comparison between immunofluorescent aspects of chronic HBsAG+, HBAG-hepatitis and some cases of chronic toxic-dismetabolic liver diseases]. / Confronto fra gli aspetti all'immunofluorescenza di epatiti croniche HBsAG+, HBsAG- e alcuni casi di epatopatia cronica su base tossico-dismetabolica.

In the study the aspects noticed on hepatic biopsies by I.F. in HBsAg+ and HBsAg- chronic hepatitis and in some cases of hepatitis on dismetabolic basis in Wilson's disease are compared. Great differences occurred between HBsAg+, HBsAg- and the Hepatitis in Wilson disease. In fact in the first case reactivity is often present due to immunological phenomena (presence of IgG immunocomplexes and autoantibodies) while in Wilson's disease these aspects are not found confirming the hypothesis that in the latter case is a question of an exclusively toxic damage.

Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment.

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.

[Evaluation of functional periodicity of the pituitary gland by harmonic analysis.--IV) Circadian prolactin secretion in women with breast cancer]. / Valutazione della periodicita'funzionale dell'ipofisi mediante analisi armonica.--IV) La secrezione circadiana della prolattina in donne affette da carcinoma mammario.

Secretory periodicity of prolactin (PRL) is preserved in women with breast cancer in spontaneous or surgical menopause. Hormone titres occurring during the day may be occasionally significantly higher in respect to the ones observe in normal controls at the same hours. The periodicity features calculated by the Fourier's method show however normal indices, namely mesor (mean PRL titres in the 24 hours) phase, amplitude and frequency of oscillations.

[Evaluation of functional periodicity of the pituitary gland by harmonic analysis.--III Circadian prolactin secretion in subjects with prolactin-secreting adenoma]. / Valutazione della periodicita' funzionale dell'ipofisi mediante analisi armonica.--III) La secrezione circadiana di prolattina in soccetti con adenoma prolattino-secermente.

The 24-hour periodicity of PRL secretion in 7 prolactinoma subjects of both sexes has been studied by means of the Fourier's harmonic analysis. In all cases elevated PRL titres have been found, that did not show the physiological changes due to sleep and wake. In most of the cases could not be demonstrated either a significant secretory periodicity or secretory episodes occurred with a frequency higher than in the control groups. Such secretory features may depend on changes in the neoplastic cells' receptors for regulating neurotransmitters.