Objective:To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3).Methods:This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity.Results:Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment.Conclusions:Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.

Objective:To evaluate the efficacy and safety of direct antiviral drugs based on sofosbuvir in the treatment of chronic hepatitis C in children.Methods:Data of children diagnosed with chronic hepatitis C from May 2017 to December 2019 and received sofosbuvir (SOF, body weight ≥ 17 kg 200 mg/d, <17 kg 150 mg/d)/ledipasvir (LDV, body mass ≥ 17 kg 45 mg/d, <17 kg 33.75 mg/d) or velpatasvir (VEL, body weight ≥ 17 kg 50 mg/d), were collected. The patients were treated with ribavirin (RBV, 15 mg/kg·d) for 12 weeks and followed up for 12 weeks. The main outcome measures were sustained virological response (SVR) at 12 weeks follow-up after drug discontinuation, and the occurrence of adverse events during the treatment period was observed to evaluate the safety of the drug.Results:HCV RNA turned negative in 10 of the 13 children (76.92%), within 2 weeks after antiviral treatment, in 2 cases (15.38%) HCV RNA turned negative in 2-4 weeks, in 1 case (7.69%) RBV was added when HCV RNA did not turn negative in 8 weeks, but turned negative at 10 weeks. At 12 and 24 weeks after discontinuation of antiviral drugs (SVR12), HCV RNA continued to be negative, and at 24 weeks (SVR24), it was also negative. Adverse reactions: headache occurred in 2 cases (15.38%), fatigue in 3 cases (23.08%), no serious adverse reactions occurred in any of the patients.Conclusions:The efficacy and safety of direct antiviral drugs based on SOF in the treatment of children with chronic hepatitis C were good.

Drug-induced liver injury (DILI) is a common disease in children with non-infectious liver di-seases, but there is no specific diagnostic method.Genetic-metabolic liver disease is a rare disease with low social recognition and requiring special examination to be diagnosed.The clinical manifestations of the 2 diseases are similar and complex, so it is easy to misdiagnose genetic-metabolic liver disease as DILI.In clinical practice, it is necessary to raise the awareness of excluding genetic-metabolic liver diseases in the diagnosis of DILI, so as to avoid misdiagnosis.

Objective: To investigate the curative effect of antiviral therapy and related factors influencing the curative affect in children with immune-tolerant phase chronic hepatitis B. Methods: From May 2014 to April 2015, 46 children with chronic hepatitis B, aged 1 to 16 years with immune-tolerant phase were enrolled as the treatment group. All cases in the treated group either received interferon alpha (3-5 MIU/m², once daily) in lamivudine combination (if HBV DNA decreased < 2 log₁₀) or repeatedly received interferon-alpha alone (if HBV DNA decreased >2 log₁₀) for 12 weeks. Interferon was discontinued at 72 weeks and followed-up period was continued with lamivudine for 24 weeks. At the same time, data of 23 cases of untreated children with immune-tolerant phase chronic hepatitis B were collected as the control group. The treatment group and the control group were divided into two age groups: 1-7 years old and 7-15 years old. Data measurements were compared using t-test, analysis of variance and single factor analysis methods, and the count data were analyzed by χ ² test. Multiple logistic regression analysis was used to analyze the effects of different factors on response. Results: (1) There were 22 cases aged 1-7 years in the treatment group (47.8%) and 12 cases aged 1-7 years in the control group (52.2%). The cases of mother-to-child transmission (MTCT) in treatment and control group were 34 (73.9%) and 17 (73.9%), while children with normal baseline ALT in the treatment and control group were 18 (39.1%) and 10 (43.5%). (2) At the end of follow-up, 15 cases in the treatment group (32.6%) had HBeAg serological conversion. Among them, nine (19.6%) cases had HBsAg clearance or HB-Ag seroconversion with anti-HBs, and one (2.2%) case had HBsAg clearance, but both HBeAg and anti-HBe were positive. In the control group, one case had HBV DNA lower than the lower limit of detection level, and one case had HBeAg seroconversion without HBsAg clearance. (3) At the end of follow-up, the seroconversion rates of HBeAg in patients aged 1 to 7 years and patients aged 7 to 15 years were 45.5% and 20.8%, respectively (P = 0.078) and the clearance rates of HBsAg were 36.4% and 8.3% (P = 0.023). The serum conversion rates of normal and abnormal baseline alanine aminotransferase levels were 5.6% and 50.0% (P = 0.005), and the clearance rates of HBsAg were 5.6% and 32.1% (P = 0.077), respectively. There was no statistically significant difference in gender, mother-to-child transmission, HBV DNA genotyping and baseline HBsAg level in antiviral efficacy among children (P > 0.05). (4) HBsAg and HBeAg clearance occurred in 100% of patients at the end of follow-up who had HBsAg < 3 000 IU/ml at 24 weeks of treatment. (5) Multivariate logistic regression analysis showed that serum HBeAg conversion rate had relation with non-MTCT transmission and abnormal baseline alanine aminotransferase. Furthermore, HBsAg clearance rate was associated with the age of children. Conclusion Sequential combination of interferon and lamivudine with a prolonged course can improve the HBV DNA negative conversion rate, HBeAg seroconversion rate, HBsAg loss rate and mild ALT abnormalities at baseline in children under the age of 7 years with immune-tolerant phase chronic hepatitis B.

Objective To review and analyze the clinical and pathological data of children with autoimmune hepatitis (AIH).Methods Medical records of 46 patients hospitalized in Pediatric Liver Diseases Treatment and Research Center,Fifth Medical Center,General Hospital of People's Liberation Army(PLA) from April 2012 to April 2018 were extracted.Medical data included type of AIH,clinical manifestations,biochemical parameters,liver biopsy results,and outcomes of treatment were analyzed retrospectively.Among 46 children,19 were males and 27 were females.The age of onset was 10.1 (1.4-18.0) years old.Chi-Square test,Rank sum test or t test were used for inter-group comparison.Results There were 32 (70％)AIH-Ⅰ cases and 14 (30％)AIH-Ⅱ cases (x2=12.565,P=0.000).Among the 46 patients,there were 5 modes of onest:17 cases (37％) had acute viral hepatitis-like presentation,2 cases (4％)had fulminant hepatic failure,9 cases (20％) had insidious onset,5 cases (11％) showed cirrhosis and portal hypertension,and 13 cases (28％) were incidentally found to be due to elevated hepatic aminotransferases.Comorbidities including primary sclerotic cholangitis (n=3),primary biliary cholangitis (n=1),systemic lupus erythematosus (n=1) and inflammatory bowel disease (n=2),were all seen in AIH-Ⅰ cases.The elevated biochemical parameters of these patients were as follows:alanine aminotransferase (n=46),aspartate transminase (n=46),total bilirubin (n=35) γ-glutamyl transpeptadase (n=39),γ-globulin (n=32) and IgG (n=33).The γ-globulin and IgG levels were significantly higher in AIH-Ⅰ patients than those with AIH-Ⅱ ((32±9)％ vs.(23±8)％,t=3.217,P=0.002,(27± 10) vs.(18±8)g/L,t=3.193,P=0.003,respectively).Thirty-nine patients received liver biopsy,among whom 22 (56％) with inflammation grade (G)≥3,26(67％) with fibrosis stage (S) ≥3,and 7 with hepatic cirrhosis (S4) according to pathological analysis.Typical histopathological changes of AIH included:36 cases of interfacial hepatitis (92％),23 cases of lymphocyte/plasma cell infiltration (59％),3 cases of rosette (8％).Forty patients received prednisolone monotherapy or combined with azathioprine after diagnosis.Complete remission was seen in 29 (72％) patients,partial remission in 10 (25％) patients and no response in 1 (3％) patient.Among complete remission patients,15 (52％) had relapse in the process of prednisolone reduction.Repeated liver biopsy performed in 8 patients after treatment showed that hepatic inflammation and fibrosis were both improved in 6 patients,only inflammation was alleviated without fibrosis improvement in 1 patient,and neither inflammation nor fibrosis was improved in 1 case.The length of follow-up was 3.3 (0.3-10.5) years,and none of the 39 prednisolone-responded cases discontinued treatment successfully.Adverse effect of long-term prednisolone therapy included bilateral cataract (n=6),spinal fracture accompanied with delayed bone age development (n=1).Conclusions AIH-Ⅰ is more common than AIH-Ⅱ in children,with diverse clinical characteristics.Most cases have progressive liver inflammation and fibrosis when diagnosed.Prednisolone monotherapy or combined with azathioprine could achieve both biochemical and pathological improvement,but relapse is inevitable during drug tapering,hence long-term treatment is essential.

The natural history of chronic hepatitis B is complex including immune-tolerant phase,immune clearance phase,inactive carrier phase and reactivation phase,among these phases,it has not yet reached a consensus on the definition of the immune-tolerant phase,because its key immune features are not entirely sure.However,the current diagnostic criteria of this phase require normal alanine aminotransferase (ALT) levels,positive hepatitis B s antigen and e antigen,high serum hepatitis B virus DNA (HBV-DNA),and slight or normal inflammation of liver histology.Antiviral therapy in this phase is currently not recommended in all guidelines,but in recent years,antiviral treatment of immune-tolerant children achieved efficacy in several study.Nonetheless before new findings are published,it would be important to closely and regular monitor serum ALT and HBV-DNA in the immune-tolerant children.

Objective Retrospectively study of the effects of interferon-α therapy on height and weight of children with chronic hepatitis B (CHB).Methods Total of 116 hospitalized cases of CHB children in Adolescent Liver Centre, 302 Military Hospital of China from January 2010 to December 2011 were respectively studied.Heights and weights of all the subjects at baseline, 24 weeks, 48 weeks, 72 weeks and 96 weeks of treatment, and 24 weeks, 48 weeks and 96 weeks of follow-up were measured.The weight Z score (WAZ), height Z score (HAZ) and body mass index (BMI) Z score of subjects with hepatic fibrosis (S) <3 and S≥3 were compared.The differences of HAZ and WAZ between baseline and treatment or follow-up in groups of subjects aged 1-6 years and 6-16 years were also compared.T test or rank sum test was used for comparison between groups.Results Among the study of all 116 patients studied, median baseline values of HAZ, WAZ and BMI Z score were 0.76, 0.38 and-0.04, respectively.For patients with hepatic fibrosis S<3, the median HAZ and WAZ were 0.83 and 0.32, respectively.For patients with hepatic fibrosis S≥3, the median HAZ and WAZ were 0.52 and 0.15, respectively.The differences were not statistically significant (both P>0.05).At 48 weeks of treatment, the median HAZ was 0.50, and the median WAZ was 0.20;after a follow-up period of 24 weeks, the median HAZ was-0.32, and the median WAZ was-0.18;after a follow-up period of 48 weeks, the median HAZ was 0.09 and the median WAZ was 0.06.All the above median values of HAZ and WAZ were significantly different from those at baseline (all P<0.05).The difference of HAZ at baseline and 96 weeks of treatment in group aged 6-16 years was significantly different from that in group aged 1-6 years (-0.74±0.69 vs-0.53±0.35, t=1.85, P<0.05).Also, the difference of WAZ at baseline and 96 weeks of treatment in group aged 6-16 years was significantly different from that in group aged 1-6 years (-0.69±0.41 vs-0.17±0.75, t=3.74, P<0.05).The difference of HAZ at baseline and 96 weeks after treatment in group aged 6-16 years was significantly different from that in groups aged 1-6 years (-1.12±0.81 vs-0.05±0.69, t=2.06, P=0.022).Conclusions Interferon-α treatment for children with chronic hepatitis B does have influence on their height and weight, which restores to some degree after the treatment finished.Physicians should pay more attention to the influence of interferon-α treatment on height and weight in children aged 6-16 years.

The antiviral treatment for children with chronic hepatitis B virus(HBV) infection should be started in the immune active phase.Interferon (IFN) is the drug of first choice in most cases,however,the individual treatment and management of adverse effects need to be considered.Currently,Nucleos (t)ide analogues (NAs) can be used as the first choice only for those special children who can't use IFN.Efficacy will be seriously affected once the emergence of viral resistance mutants to NAs.However,there is high risk of relapse after the NAs are discontinued.Compared with the mono therapy,the therapeutic strategy of interferon combined with NAs have obtained better effect and safety in children with chronic HBV infection.

Children with hepatitis C virus RNA positive were considered to start antiviral treatment.Alpha interferon or pegylated interferon plus ribavirin in children achieved satisfactory sustain virology response.Although there were many adverse events,some can be relieved by communicating with the guardian,bringing care to the patient and giving treatment.Clinical trials in children with hepatitis C by the direct-acting antiviral agents were in progress,safety and efficacy have no differences with the adult.There were still lots of work to do in view of the particularity of children.

For children with chronic hepatitis B (CHB), the antiviral therapy should be started in the immune active phase. There are two categories of antiviral drugs used for CHB: interferons (IFNs) and nucleos(t)ide analogues (NAs). In this paper, the current status of antiviral therapy of CHB in children is reviewed. It is pointed out that IFNs are the drug of first choice in antiviral therapy for children with CHB, and the individualized treatment and management of adverse events need to be considered. Some NAs can be given to those special children who cannot accept IFNs. However, there is a high risk of relapse after drug withdrawal. And the subsequent treatment will be seriously affected once the drug resistance is developed. It needs further investigation to improve the efficacy of antiviral therapy and reduce the adverse events and the drug resistance in the future.