Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection.

Autoantibodies to smooth muscle (SMA) and nuclear components (ANA) arise in the natural course of chronic infection with hepatitis C virus. In view of the growing evidence for 'molecular mimicry' as a mechanism of autoimmunity we investigated whether cross-reactive immune reactions between host smooth muscle/nuclear components and HCV antigens may contribute to the formation of SMA and ANA in chronic HCV infection. Computer-assisted protein database search methods were used to identify three smooth muscle (smoothelin698-717, myosin1035-1054, vimentin69-88) and three nuclear (matrin722-741, histone H2A11-30, replication protein A133-152) host antigens with the highest local sequence similarity to the HCV polyprotein and 20-mer peptides corresponding to these regions were constructed. Sera from 51 children with chronic HCV infection [median age: 8 (2-16); 27 boys], 26 SMA positive and five ANA positive, were tested for reactivity to the synthesized HCV peptides and their human homologues by enzyme linked immunosorbent assay (ELISA). Sera from patients with HBV infection and chronic liver disease of different aetiologies were used as controls. 'Double reactivity' to HCV peptides and smooth muscle/nuclear homologues was associated strongly with HCV infection (P < 0.001 for both). Humoral cross-reactivity was established as the basis for double recognition by competition ELISA. Double-reactivity to smooth muscle and HCV peptide antigens correlated with SMA positivity by indirect immunofluouresence (P = 0.05). Of 15 patients double-reactive to myosin1035-1054 and its HCV homologue, 13 recognized whole myosin by immunoblot. These results suggest that ANA and SMA in chronic HCV infection may arise, at least in part, as a consequence of cross-reactive immune responses to HCV and host smooth muscle/nuclear antigens.

Low virological response to interferon in children with chronic hepatitis C.

BACKGROUND/AIMS: Children with chronic hepatitis C were recently found to have higher rates of sustained response to interferon compared to adults. The aim of this study was to verify the response to interferon using frequent viremia measurements. METHODS: Sera from 25 children (13 males; mean age 7.9 years) with chronic hepatitis C, treated with recombinant alpha-2b interferon for 12 months, were tested for liver function tests and viremia levels for a median of 27.5 months. Autoantibodies were evaluated during and after interferon. RESULTS: Fifteen patients completed 12 months of interferon; treatment was stopped in 10 other patients. In 11 (44%) patients viremia was undetectable already at the second administration of interferon; one of them remained viremia-free up to the end of follow-up and had persistently normal alanine-aminotransferase levels (complete sustained responder). A complete sustained response was observed only in one other patient, who normalized alanine aminotransferase and cleared viremia from the 3rd month of therapy. Three patients with persistent viremia normalized alanine-aminotransferase from the 3rd week of therapy up to the end of follow-up (biochemical sustained responders). Viremia was undetectable during treatment in four patients, who stopped interferon because of worsening in hypertransaminasemia. Three of these four patients were anti-liver-kidney microsomal type 1-positive. CONCLUSIONS: In this study the response rate to interferon was very low and viremia and transaminase findings were often discordant.

Chronic cryptogenic hepatitis in childhood is unrelated to hepatitis G virus.

OBJECTIVES: The aim of this study was to define the features of chronic cryptogenic hepatitis (CCH) in childhood and to investigate whether it is related to hepatitis G virus infection. METHODS: Forty-six children (24 males; age range, 1.5 to 17 years) with CCH were studied. CCH was diagnosed when serum alanine aminotransferase concentrations were more than 1.5 times normal for longer than 6 months without any apparent cause of liver disease. RESULTS: No patient had acute symptomatic onset or had received a blood transfusion. Three had undergone minor surgical procedures. All appeared to be healthy during follow-up (median, 4.2 years; range, 1 to 10 years). Hypertransaminasemia was the only aberrant liver function test. Elevated serum alanine aminotransferase values alternated with normal values in 40 children (86.9%). Five children (10.8%) had a spontaneous sustained (>12 months) remission of hypertransaminasemia. Twelve (26%) had laboratory signs of autoimmunity, but none fulfilled the criteria for autoimmune hepatitis. Of 20 children who underwent liver biopsy, 13 (65%) had minimal chronic hepatitis, 4 (20%) had mild chronic hepatitis and 3 (15%) had moderate chronic hepatitis. Serum hepatitis G virus RNA was detected in 2 girls (4%) whose risk factor was a hepatitis G virus-infected mother and a minor surgical procedure, respectively. In 12 families at least 1 other member had chronic liver disease. CONCLUSIONS: Childhood CCH seems to be a symptomless disease characterized by isolated hypertransaminasemia with onset during the first 4 years of life and mild to moderate histologic liver lesions. Although the frequency of spontaneous remissions is low, childhood CCH seems, in the short run, to be a nonprogressive disease. Hepatitis G virus does not play a major role in CCH.

Safety and immunogenicity of hepatitis A vaccine in infants: a candidate for inclusion in the childhood vaccination programme.

Forty-eight infants received a single dose (720 ELISA units = 0.5 ml) of inactivated hepatitis A vaccine at the fifth month of age with booster at the 11th month of age, together with the second and third doses of the vaccines compulsory under Italian law (diphtheria, tetanus, oral polio and hepatitis B). Overall, the seroconversion rate was 100%. The anti-HAV geometric mean titre (GMT) reached 3,021 mIU/ml in infants born to anti-HAV-negative mothers, but only 399 mIU/ml in infants born to anti-HAV-positive mothers. Hepatitis A vaccine was immunogenic, safe and well tolerated without significant side-effects. There seems to be no reason for not including it in childhood vaccination programmes particularly in low endemic HAV areas.

Autoantibody prevalence in children with liver disease due to chronic hepatitis C virus (HCV) infection.

HCV infection and interferon-alpha (IFN-alpha) therapy have been associated with autoimmunity. To assess whether chronic liver disease (CLD) due to HCV infection or its treatment with IFN-alpha cause autoimmune manifestations, the prevalence of tissue autoantibodies in 51 children with chronic HCV infection and 84 with other CLD was analysed by standard techniques. Sixty-five percent of patients with chronic HCV infection, 66% with chronic hepatitis B infection and 60% with Wilson's disease were positive for at least one autoantibody. In the 51 subjects with chronic HCV infection (29 treated with IFN-alpha, 22 untreated), tested on 165 occasions over a median of 9 months (range 5-42 months), autoantibodies to nuclei (ANA), smooth muscle (SMA), gastric parietal cell (GPC) and/or liver kidney microsomal type 1 (LKM-1) were similarly prevalent in treated and untreated patients (90% versus 68%, P = 0.12). Positivity for SMA was present in 67%, GPC in 32%, ANA in 10%, LKM-1 in 8% of cases. Treatment with IFN-alpha had to be suspended due to transaminase elevation in one SMA-positive, one ANA-positive but in three of four LKM-1-positive patients. Our results show that: (i) autoantibodies are common in viral-induced hepatitis and Wilson's disease; (ii) positivity for SMA, GPC, ANA is part of the natural course of chronic HCV infection, their prevalence being unaffected by IFN-alpha; and (iii) IFN-alpha should be used cautiously in the treatment of LKM-1/HCV-positive patients.

Side effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis.

BACKGROUND: Interferon (IFN) is standard therapy for chronic viral hepatitis in children. The aim of this study was to evaluate the side effects of alpha-interferon (IFN) in 94 consecutive children (58 males; age range, 3 to 14 years) affected by chronic viral hepatitis treated with different schedules ranging from 3 to 10 MU and from 3 to 12 months, and the impact of this therapy on health-related quality of life. METHODS: Side effects were evaluated with clinical and laboratory examinations and were recorded on a diary card. The health-related quality of life was evaluated with a modified version of the Sickness Impact Profile. RESULTS: All patients experienced at least one adverse reaction to IFN treatment; 80% had more than five side effects. There were no life-threatening reactions. Three children experienced severe reactions (febrile seizure, severe hypertransaminasemia and relapsing episodes of epistaxis, respectively) that required permanent IFN withdrawal. Another child had a febrile seizure requiring temporary IFN withdrawal. In seven children the neutrophil count fell below 1000/mm3 and promptly increased when IFN was temporarily discontinued. The remaining children had mild or moderate clinical and/or laboratory adverse reactions. Age, sex, viral etiology of chronic hepatitis and response to therapy were not significantly associated with the appearance of side effects. The pre-IFN health-related quality of life was good in all children; it deteriorated significantly during IFN therapy and returned to basal standards within 3 months after IFN withdrawal. No patient required suspension of IFN therapy because of worsening of health-related quality of life. CONCLUSION: Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.

Penicillamine-related neurologic syndrome in a child affected by Wilson disease with hepatic presentation.

OBJECTIVES: To describe a case of penicillamine-related neurologic symptoms in a 9-year-old boy affected by asymptomatic Wilson disease with hepatic presentation; to compare this case with similar cases in adults; and to discuss the role of zinc therapy as an alternative treatment for patients who have an adverse reaction to penicillamine therapy. SETTING: Referral hospital. MAIN OUTCOME MEASURE: The occurrence of a neurologic syndrome that severely impaired a child's usual daily activities and his health-related quality of life after the institution of penicillamine therapy. RESULTS: Initial penicillamine therapy was chronologically related to the development of progressive neurologic deterioration in the absence of other causes of neurologic syndrome. The discontinuation of penicillamine therapy and the initiation of zinc therapy were followed by a prompt disappearance of neurologic symptoms and a return to neurologic baseline status. CONCLUSIONS: Penicillamine therapy, even in children affected by Wilson disease with hepatic presentation alone and without neurologic disease at the beginning of treatment, may trigger neurologic symptoms. Zinc therapy may be a satisfactory alternative.

Lymphoblastoid interferon alfa treatment in chronic hepatitis C.

Interferon is becoming the standard treatment in adults for chronic hepatitis C. Twenty one children with histologically proved chronic hepatitis C (10 boys, range 2.5-13 years), who were otherwise healthy, were enrolled in a randomised controlled study to test their response to interferon alfa. Eleven children were treated with lymphoblastoid interferon alfa (3 million units/m2) for 12 months; 10 children received no treatment. All had raised transaminases and positive antihepatitis C virus (HCV) antibodies and HCV-RNA. Alanine aminotransferase (ALT) serum levels became normal in five (45%) treated patients after a mean of three weeks (range 1-6 weeks) and no relapse had occurred by the end of follow up (30th month). Only one (10%) untreated patient had normal ALT serum levels from the 11th until the 30th month. Disappearance of serum HCV-RNA, persisting throughout the follow up period, was observed in the six children (five treated) whose ALT became normal. Biopsy specimens in treated patients showed a significant improvement in Knodell's score (median (SD) basal 9.0 (2.2); final 2.0 (0.4)). Interferon treatment was well tolerated in all. This study confirms the efficacy of interferon in children with chronic hepatitis C, not only by restoring normal ALT serum levels, but also viral clearance and histological amelioration of liver inflammation. Contrary to reports in adults no biochemical and virological relapses occurred in responder children.

Lack of intrafamilial transmission of hepatitis C virus in family members of children with chronic hepatitis c infection.

Intrafamilial transmission of hepatitis C virus (HCV) was studied in family members of 44 children with chronic hepatitis C infection (index cases). There were 22 males and the mean age of all patients was 9.5 years (range, 1.5 to 16 years). Eleven index patients were multitransfused because of thalassemia major. Aminotransferase serum concentrations and anti-HCV antibodies were evaluated in 77 parents (38 fathers) and 56 siblings (28 males; mean age, 11.2 years; range, 2.5 to 18 years). No sibling showed evidence of liver disease or HCV infection. Eight parents (14%) were found to be anti-HCV positive, but only one of them acquired HCV infection from an index case through an accidental needle stick injury. A nonsexual person-to-person transmission of HCV was conceivable only in a girl (index case) who had no risk factor other than the contact with anti-HCV-positive father. Vertical transmission played a role in five children (index cases) (three males) from five different mothers. Among the eight children belonging to these mothers, three did not show evidence of HCV infection although born after their HCV-infected siblings. Furthermore, we have not identified factors related to activity of disease or to duration of contact with index cases or to peculiar features of family members capable of favoring the spreading of HCV infection. Different from hepatitis b, pediatric age does not seem to represent a reservoir for HCV infection since the majority of children acquired HCV infection through parenteral routes and no HCV-infected child transmitted HCV infection horizontally.