Signature of chronic hepatitis B virus infection in nails and hair.

BACKGROUND: Hepatitis B virus (HBV) is detected in extrahepatic tissues of individuals with HBV infection. Whether nails and hair contain HBV has been unknown. METHODS: We examined two patient groups: those with chronic HBV infection alone (n = 71), and those with both chronic HBV and hepatitis delta virus (HDV) infections (n = 15). HBV DNA in the patients' fingernails and hair were measured by real-time PCR. Hepatitis B surface antigen (HBsAg) of fingernails was evaluated by an enzyme immunoassay. HDV RNA in fingernails was measured by real-time PCR. Immunochemical staining was performed on nails. We used chimeric mice with humanized livers to evaluate the infectivity of nails. RESULTS: Of the 71 pairs of HBV-alone nail and hair samples, 70 (99%) nail and 60 (85%) hair samples were positive for ß-actin DNA. Of those 70 nail samples, 65 (93%) were HBV DNA-positive. Of the 60 hair samples, 49 (82%) were HBV DNA-positive. The serum HBV DNA level of the nail HBV DNA-positive patients was significantly higher than that of the nail HBV DNA-negative patients (p < 0.001). The hair HBV DNA-positive patients' serum HBV DNA level was significantly higher compared to the hair HBV DNA-negative patients (p < 0.001). The nail HBV DNA level was significantly higher than the hair HBV DNA level (p < 0.001). The nails and hair HBV DNA levels were correlated (r = 0.325, p < 0.05). A phylogenetic tree analysis of the complete genome sequence of HBV isolated from nails and hair identified the infection source. Of the 64 nail samples, 38 (59%) were HBsAg-positive. All 15 pairs of chronic HBV/HDV infection nail and hair samples were ß-actin DNA-positive. However, nail HBV DNA was detected in two patients (13%). None of the 15 patients were positive for hair HBV DNA. Nail HDV RNA was detected in three patients (20%). Of the 15 patients, eight (53%) were nail HBsAg-positive. HBsAg and hepatitis delta (HD) antigen were detected in the nails by immunochemical staining. Chimeric mice were not infected with PBS containing HBsAg and HBV DNA elucidated from nails. CONCLUSIONS: Nails and hair were the reservoir of HBV DNA. Moreover, nails can contain HBsAg, HDV RNA, and HD antigen.

Hepatitis B virus DNA in the fingernails and hair of children with acute hepatitis B.

Hepatitis B virus (HBV) DNA is detectable in the nails and hair of patients with chronic HBV infection. However, it remains unclear whether HBV DNA can be detectable in the nails and hair of patients with acute HBV infection. We encountered two cases of children with acute HBV infection. HBV DNA in the nails and hair from the two children was evaluated by real-time PCR. To clarify the characteristics of HBV DNA, full-length HBV genome sequencing and phylogenetic tree analysis were performed. The levels of serum HBV DNA in children of cases 1 and 2 at day 0 were 7.6 Log IU/mL and 7.4 Log IU/mL, respectively. Nail HBV DNA was detected in both children (case 1: 4.6 Log IU/mL at day 0, case 2: 5.5 Log IU/mL at day 14). Moreover, hair HBV DNA was detectable in case 2 (4.0 Log IU/mL at day 14). Serum HBV DNA became undetectable within approximately 3-4 months after the first hospital visit. After the resolution of HBV viremia, nail and hair HBV DNA became undetectable. The sequence analysis of serum, nail and hair HBV DNA showed the same HBV genotype in each case (case1: genotype C, case 2: genotype A). In case 1, 3 nucleotides were different in the full-genome HBV sequence between the serum and nails. In case 2, the full-genome HBV sequences were identical among the serum, nails and hair. In conclusion, HBV DNA was detectable in nails and hair of children with acute HBV infection.

Clinical features of pediatric eosinophilic gastroenteritis.

BACKGROUND: No study has analyzed more than100 cases of eosinophilic gastroenteritis (EGE) in children in a single center. We aimed to describe the clinical features of pediatric EGE. METHODS: This retrospective study was conducted at a single center. Between April 2007 and December 2017, 860 children between the ages of 1 year and 15 years underwent endoscopy for gastrointestinal symptoms of unknown cause. Among them, 109 (12.7%) were diagnosed with EGE according to the diagnostic criteria for EGE developed by the research group of the Ministry of Health, Labour and Welfare of Japan for eosinophilic gastrointestinal disorder in 2015. We investigated their symptoms, comorbidities, endoscopic findings, pathological findings, treatments, and outcomes. RESULTS: Seventy-one boys (65.1%) and 38 girls (34.9%) were diagnosed with EGE. The median age at diagnosis was 11 years (range, 1-15 years). The chief complaints were abdominal pain in 83 (76.1%) and diarrhea in 26 (23.9%). Upper and lower gastrointestinal endoscopies showed normal findings in 32 patients (29.4%). The most common treatment was a combination of elimination of foods suspected of causing EGE and anti-allergic agents in 50 cases (45.9%). The outcomes were symptom disappearance in 43 patients (39.4%) and symptom improvement in 53 patients (48.6%). CONCLUSIONS: For gastrointestinal symptoms of unknown cause in children, EGE should be considered as a differential diagnosis. Although the symptoms and endoscopic findings are nonspecific, cracked mucosa may be a specific endoscopic finding for pediatric EGE. An elimination diet and/or anti-allergic drugs were effective in most patients with pediatric EGE.

Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis.

We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.

[Use of a somatostatin analog to improve a patient's condition and the subsequent diagnosis of pancreatic VIPoma:a case report].

A 68-year-old woman with an 11-day history of sudden abdominal pain and severe watery diarrhea was transferred to our hospital due to an exacerbation of renal function despite hydration. After treatment for dehydration and acidemia was provided in our intensive care unit, patient's renal function improved. Contrast-enhanced abdominal computed tomography was finally performed, revealing a hypervascular pancreatic mass with multiple hepatic masses. This imaging finding along with her clinical symptoms indicated watery diarrhea hypokalemia achlorhydria (WDHA) syndrome caused by a pancreatic VIPoma. Somatostatin analog was administered immediately leading to the improvement of her diarrhea and her general condition. As a result, endoscopic ultrasonography-guided fine-needle aspiration could be performed. Consequently, she was diagnosed with a pancreatic neuroendocrine tumor. She then underwent surgical resection of the pancreatic tumor and liver metastasis. As revealed in the immunohistochemical analysis of the excised tumor tissue, VIP was highly expressed, resulting in the final diagnosis of pancreatic VIPoma. Therefore, the immediate use of a somatostatin analog is crucial for improving the patient's general condition and achieving a definitive diagnosis pathologically when a patient is suspected of having a pancreatic VIPoma.

Loss of fibrocystin promotes interleukin-8-dependent proliferation and CTGF production of biliary epithelium.

BACKGROUND & AIMS: Congenital hepatic fibrosis (CHF) is a genetic liver disease resulting in abnormal proliferation of cholangiocytes and progressive hepatic fibrosis. CHF is caused by mutations in the PKHD1 gene and the subsequent dysfunction of the protein it encodes, fibrocystin. However, the underlying molecular mechanism of CHF, which is quite different from liver cirrhosis, remains unclear. This study investigated the molecular mechanism of CHF pathophysiology using a genetically engineered human induced pluripotent stem (iPS) cell model to aid the discovery of novel therapeutic agents for CHF. METHODS: PKHD1-knockout (PKHD1-KO) and heterozygously mutated PKHD1 iPS clones were established by RNA-guided genome editing using the CRISPR/Cas9 system. The iPS clones were differentiated into cholangiocyte-like cells in cysts (cholangiocytic cysts [CCs]) in a 3D-culture system. RESULTS: The CCs were composed of a monolayer of cholangiocyte-like cells. The proliferation of PKHD1-KO CCs was significantly increased by interleukin-8 (IL-8) secreted in an autocrine manner. IL-8 production was significantly elevated in PKHD1-KO CCs due to mitogen-activated protein kinase pathway activation caused by fibrocystin deficiency. The production of connective tissue growth factor (CTGF) was also increased in PKHD1-KO CCs in an IL-8-dependent manner. Furthermore, validation analysis demonstrated that both the serum IL-8 level and the expression of IL-8 and CTGF in the liver samples were significantly increased in patients with CHF, consistent with our in vitro human iPS-disease model of CHF. CONCLUSIONS: Loss of fibrocystin function promotes IL-8-dependent proliferation of, and CTGF production by, human cholangiocytes, suggesting that IL-8 and CTGF are essential for the pathogenesis of CHF. IL-8 and CTGF are candidate molecular targets for the treatment of CHF. LAY SUMMARY: Congenital hepatic fibrosis (CHF) is a genetic liver disease caused by mutations of the PKHD1 gene. Dysfunction of the protein it encodes, fibrocystin, is closely associated with CHF pathogenesis. Using an in vitro human induced pluripotent stem cell model and patient samples, we showed that the loss of fibrocystin function promotes proliferation of cholangiocytes and the production of connective tissue growth factor (CTGF) in an interleukin 8 (IL-8)-dependent manner. These results suggest that IL-8 and CTGF are essential for the pathogenesis of CHF.

Deep sequencing of hepatitis B surface antigen gene in the preserved umbilical cords in immunoprophylaxis failure against mother-to-child HBV transmission.

BACKGROUND: Vaccine escape mutants (VEMs) are one of the causes of breakthrough infections in the mother-to-child transmission of hepatitis B virus (HBV). We hypothesized that VEMs existing as minor populations in the maternal blood are associated with breakthrough infections in children. We sought to determine whether VEMs exist as minor populations in the preserved umbilical cords of children with breakthrough infections. CASE PRESENTATION: Two families (Family 1: three children, Family 2: two children) were enrolled. Despite immunoprophylaxis, a breakthrough infection occurred in two Family 1 children and two Family 2 children. Preserved umbilical cords, serum, and nails were used for the HBV DNA analysis. To detect VEMs, we performed direct and deep sequencing of hepatitis B surface antigen gene. The direct sequencing showed that there were no VEMs in the serum of the children or mother of Family 1 and family 2, but it identified a G145A mutant in the nails of the mother of Family 2. In Family 1, deep sequencing detected a T143S mutant as a minor population (1.7-2.0%) in the umbilical cords and serum of all three children and in the serum of the mother. A T126A mutant was also detected in the umbilical cord (9.2%) and serum (7.0%) of the first-born child of Family 1. In Family 2, the deep sequencing showed no VEMs in the umbilical cords, but it detected D144A (2.5%) and G145A (11.2%) mutants in the serum of the 2nd-born child. CONCLUSIONS: VEMs were present as minor populations in the preserved umbilical cords of children with breakthrough infections. The VEMs did not become major populations after the breakthrough infections. The evolution of VEMs from a minor form to a major form might not be a prerequisite for breakthrough infections in mother-to-child transmission.

Long-term outcomes of pediatric-onset primary sclerosing cholangitis: A single-center experience in Japan.

AIM: Primary sclerosing cholangitis (PSC) is very rare in Japan. Although a large-scale cohort study of 781 pediatric-onset PSC patients in Europe and North America showed that the 5-year survival with native liver was 88%, the long-term outcomes of pediatric-onset PSC in Japan are unknown. Here, we evaluated the clinical outcomes of pediatric-onset PSC in Japan. METHODS: We carried out a retrospective cohort study with a medical records review of pediatric PSC patients diagnosed between 1986 and 2017 at a single center. The PSC diagnoses were based on cholangiography, liver histology, and biochemical findings. The patients' survival was analyzed using the Kaplan-Meier method. Prognostic factors were determined by univariate and multivariate analyses using the Cox proportional hazards regression model. RESULTS: We identified 39 pediatric-onset PSC patients (22 boys, 17 girls). The median age at diagnosis was 9 years (interquartile range 6.0-13.5 years). The median follow-up period was 5.5 years (interquartile range 3.4-8.7 years). The phenotypes of PSC-autoimmune hepatitis, PSC-inflammatory bowel disease, and small-duct PSC were diagnosed in 13 (33.3%), 36 out of 38 (94.8%), and three (7.7%) patients, respectively. The 5-year liver transplantation-free survival of the whole cohort was 93.5%. Nine patients underwent liver transplantation, and four of these nine cases resulted in death. Both the univariate and multivariate analyses showed that the phenotype of "PSC-autoimmune hepatitis overlap" was an independent poor prognostic factor. CONCLUSIONS: The overall survival of pediatric-onset PSC in Japan was comparable to those in Western countries. The phenotype of PSC-autoimmune hepatitis was identified as a prognostic factor associated with a poorer long-term outcome.

Pediatric liver transplantation for neonatal-onset Niemann-Pick disease type C: Japanese multicenter experience.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive inherited disease characterized by lysosomal accumulation of free cholesterol in macrophages within multiple organs. Infantile-onset NPC often presents with jaundice and hepatosplenomegaly from birth, but these symptoms usually improve during early childhood, and it rarely progresses to liver failure. We report three cases from different hospitals in Japan; the patients developed neonatal-onset NPC, and liver transplantation (LT) was performed as a life-saving procedure. LT was performed at 19 days, 59 days, and 4 months of age, respectively. The last patient was diagnosed with NPC before LT, while the first two patients were diagnosed with neonatal hemochromatosis at LT. In these two patients, the diagnosis of NPC was made more than a year after LT. Even though oral administration of miglustat was started soon after the diagnosis of NPC, all patients showed neurological regression and required artificial respiratory support. All patients survived more than one year after LT; however, one patient died due to tracheal hemorrhage at 4.5 years of age, and another one patient was suspected as recurrence of NPC in liver graft. In conclusion, while LT may be a temporary life-saving measure in patients with neonatal-onset NPC leading to liver failure, the outcome is poor especially due to neurological symptoms. A preoperative diagnosis is thus critical.

Liver Cirrhosis and/or Hepatocellular Carcinoma Occurring Late After the Fontan Procedure　- A Nationwide Survey in Japan.

BACKGROUND: Fontan-associated liver disease (FALD) is an important late complication involving liver dysfunction, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC), in patients undergoing the Fontan procedure. However, the prevalence, clinical manifestation, and methods of diagnosis of FALD are still not well established.Methods and Results:This study comprised 2 nationwide surveys in Japan. First, the prevalence of LC and/or HCC in patients undergoing the Fontan procedure was determined. Second, clinical manifestations in patients with LC and/or HCC were analyzed, along with data from blood tests, echocardiography, and right heart catheterization. In the 1st survey, of the 2,700 patients who underwent the Fontan procedure, 31 were diagnosed with LC and/or HCC (1.15%), and 5 died due to liver diseases (mortality: 0.19%). In the 2nd survey, data were collected from 17 patients (12 with LC, 2 with HCC, and 3 with LC+HCC. Of these 17 patients, 5 died (mortality: 29.4%). The mean age at diagnosis of LC and HCC was 23 and 31 years, respectively. Computed tomography followed by ultrasound was most frequently used for diagnosis. Blood tests revealed low platelet counts, increased hemoglobin, aspartate aminotransferase, γ-guanosine triphosphate, and total bilirubin levels, and an elevated international normalized ratio of prothrombin time. CONCLUSIONS: LC and/or HCC in patients undergoing the Fontan procedure were not rare late complications and were associated with high mortality rates.

Usefulness of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in children with primary sclerosing cholangitis.

BACKGROUND: Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) is a novel serum marker of hepatic fibrosis in adults with chronic hepatitis C. However, it remains unclear whether serum WFA+ -M2BP levels are associated with the progression of liver histology in primary sclerosing cholangitis (PSC). METHODS: Twenty-eight children and adolescents with pediatric-onset PSC (male : female patient ratio, 20:8; median age at diagnosis, 9 years) were enrolled in this study. The relation between serum WFA+ -M2BP levels and clinical characteristics was retrospectively evaluated. Moreover, receiver operating characteristic (ROC) analysis was used to determine whether serum WFA+ -M2BP levels could be a reliable marker to identify PSC patients with advanced liver histology. RESULTS: According to the Ludwig classification of liver histological stage, 28 patients were classified into the four stages. The WFA+ -M2BP level, aspartate aminotransferase (AST) to platelet ratio index (APRI), and hyaluronic acid correlated significantly with liver histological stage. Moreover, WFA+ -M2BP showed a significant positive correlation (P < 0.05) with autoimmune hepatitis overlap, AST, alanine aminotransferase (ALT), γ-glutamyltransferase, total bilirubin, immunoglobulin G, APRI, and hyaluronic acid. A ROC analysis was undertaken to distinguish the patients with advanced stage disease (stage 3-4) from those with early stage disease (stage 0-2). It showed that WFA+ -M2BP yielded the highest area under the ROC curve value (0.898) among four surrogate makers (APRI, 0.850; Fibrosis-4 index, 0.806; and AST/ALT ratio, 0.802). Moreover, WFA+ -M2BP yielded the highest sensitivity, specificity, positive predictive value, and negative predictive value among the four markers. CONCLUSIONS: Serum WFA+ -M2BP levels are useful to identify patients with advanced liver histology in pediatric PSC.

Clinical features of pediatric autoimmune hepatitis in Japan: A nationwide survey.

AIM: The purpose of this study was to determine the characteristics of children with autoimmune hepatitis (AIH) in Japan. METHODS: Questionnaires that asked about patients newly diagnosed with AIH from 2009 to 2013 were sent to hospitals certified as training facilities for pediatrics in January 2015. RESULTS: A total of 35 patients were enrolled. The median age at diagnosis was 10 years (range, 3 months-15 years), and the male-to-female ratio was 2:3. Female patients were more prevalent among those older than 10 years and male patients were more prevalent in those younger than 10 years. Fifteen patients had jaundice as a subjective symptom, and 5 had hepatic coma grade II. Liver histology classified 20 as chronic hepatitis, 8 as acute hepatitis, and 4 as cirrhosis. Liver histology was not described in 4 patients. Among the 35 patients, 32 were treated with corticosteroids and 29 were initially treated with methylprednisolone pulse therapy. Corticosteroid therapy was effective in 27 patients and ineffective in 1 patient. Plasma exchange with continuous i.v. infusion of cyclosporine A was given to 7 patients with acute hepatitis. Of these, 4 patients presented with fulminant hepatitis and received high-flow, continuous hemodiafiltration. CONCLUSIONS: This survey clarified that the clinical profile of pediatric AIH in Japan is not only different from that of adult AIH in Japan but is also different from that of pediatric AIH in other countries.

Acute liver dysfunction not resulting from hepatitis virus in immunocompetent children.

BACKGROUND: The aim of the present study was to clarify the roles of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) in immunocompetent children with acute liver dysfunction not resulting from hepatitis virus. METHODS: Sixty-eight children (median age, 3 years) hospitalized as a result of acute liver dysfunction were enrolled in this study. Hepatitis A, B, and C were excluded. The prevalence of CMV, EBV, and HHV-6 and viral DNA load in whole blood was prospectively evaluated on multiplex real-time polymerase chain reaction (PCR). RESULTS: Of the 68 children with acute liver dysfunction, multiplex real-time PCR was positive in 30 (44%). CMV, EBV, and HHV-6 DNA were detected in 13 (19%), 14 (21%), and seven (10%), respectively. Serum CMV immunoglobulin (Ig)G/IgM and EBV viral capsid antigen IgG/IgM were measured in 40 (CMV DNA positive, n = 10; negative, n = 30) and 45 (EBV DNA positive, n = 14; negative, n = 31) of the 68 children, respectively. Eighteen percent (CMV, 7/40) and 9% (EBV, 4/45) were positive for both PCR and viral-specific IgM. There was no significant difference in CMV and EBV viral load between IgM-positive and -negative children with viremia. CONCLUSIONS: CMV, EBV, and HHV-6 DNA were frequently detected in immunocompetent children with acute liver dysfunction, but primary CMV and EBV infection were confirmed in 10-20% of the children with acute liver dysfunction. The combination of PCR assay and serology is necessary to make a diagnosis of acute liver dysfunction due to primary CMV, EBV and/or HHV-6 infection in immunocompetent children.

Feasibility and safety of bowel cleansing using low-volume polyethylene glycol with ascorbic acid before pediatric colonoscopy: A pilot study.

BACKGROUND AND AIM: To assess the feasibility and safety of same-day regimen of low-volume polyethylene glycol solution with ascorbic acid for bowel cleansing before colonoscopy in children. METHODS: Data on children who received polyethylene glycol solution with ascorbic acid for bowel cleansing in our department were retrospectively analyzed. On the day before the procedure, patients ate a low-residue diet and received sodium picosulfate in the evening. The following day, patients took polyethylene glycol solution with ascorbic acid in the morning; the procedure was carried out in the afternoon. Dosages of sodium picosulfate and polyethylene glycol solution with ascorbic acid were adjusted based on bodyweight. Bowel cleansing efficacy was rated on a scale of 1-5 by the colonoscopist. RESULTS: Between July 2013 and November 2014, polyethylene glycol solution with ascorbic acid was used in 112 cases (96 patients; male : female 73:39; median age 10.9 years, range 4-19 years). Ninety-one cases (81%) were able to orally ingest the prescribed amount of polyethylene glycol solution with ascorbic acid. Satisfactory bowel cleansing (cleansing grade ≥3) was attained in 87% on intention-to-treat analysis and 85% on per-protocol analysis. Cleansing grade was significantly better in children who ingested polyethylene glycol solution with ascorbic acid within 60 min (P < 0.05). There were no serious adverse events. CONCLUSION: Same-day regimen of polyethylene glycol solution with ascorbic acid is effective and safe for bowel cleansing in children.

Chronic hepatitis without hepatic steatosis caused by citrin deficiency in a child.

Citrin deficiency manifests as both neonatal intrahepatic cholestasis (NICCD) during early infancy and adult-onset type II citrullinemia during adulthood. Hepatic steatosis is most frequently observed in patients with citrin deficiency. Thus, non-alcoholic fatty liver disease that is unrelated to being overweight is considered one of the clinical features of citrin deficiency in children and adults. However, it remains unknown whether citrin deficiency is a cause of chronic hepatitis in the absence of fatty changes to the liver that occur during childhood. We encountered an 8-year-old girl who showed no clinical features of NICCD during infancy and had persistently elevated transaminase levels for several years. Liver biopsy showed widening of the portal tracts with intense mononuclear cell infiltration and mild fibrosis but no fatty changes. However, she had peculiar dietary habits similar to those that have been observed in many patients with citrin deficiency. In addition, a slightly elevated plasma citrulline level and a high pancreatic secretory trypsin inhibitor level were detected by blood examination, and she was diagnosed with citrin deficiency. Analysis of the SLC25A13 gene revealed the presence of the compound heterozygous mutations 851del4 and IVS13 + 1G > A. Thus, citrin deficiency should be included in the differential diagnosis of chronic hepatitis in children, even in the absence of hepatic steatosis.

Transmission route and genotype of chronic hepatitis B virus infection in children in Japan between 1976 and 2010: A retrospective, multicenter study.

AIM: The aim of this study was to clarify the trends of the infectious source of chronic hepatitis B virus (HBV) infection and the HBV genotype in the Japanese pediatric population over the last three decades. METHODS: The present study was a retrospective, nationwide, multicenter study. Patients who were under 20 years of age when diagnosed with chronic HBV infection were eligible for enrollment in this study. A total of 430 patients (male/female, 256/174; age at the time of writing, 1-37 years; median age, 14 years; birth year, 1976-2010) from 11 hospitals were evaluated. RESULTS: The incidence of chronic HBV infection from 1976 to 1980, 1981-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2005 and 2006-2010 was 56, 52, 34, 37, 81, 92 and 78, respectively. Of the 430 patients, 304 (71%), 61 (14%), 11 (3%) and 54 (13%) were infected via mother-to-child transmission, close contact, blood transfusion and unknown source, respectively. After the introduction of perinatal immunoprophylaxis, the rate of mother-to-child transmission increased from 62% during the 1991-1995 period to 86% during the 2006-2010 period. The distributions of genotypes A, B, C, D and F were 3%, 9%, 86%, 2% and 1%, respectively. No obvious change was observed in the distribution of genotypes. Genotype C was significantly associated with mother-to-child transmission. CONCLUSION: Mother-to-child transmission remains the primary source of chronic HBV infection after the introduction of immunoprophylaxis. Taking measures to prevent immunoprophylaxis failure is essential to reduce pediatric chronic HBV infection in Japan.

Neonatal liver failure owing to gestational alloimmune liver disease without iron overload.

Although neonatal hemochromatosis (NH) is a well-known cause of liver failure during the neonatal period and iron deposition in extrahepatic tissues is considered essential in the diagnosis of NH, there is no consensus regarding the pathology or diagnostic criteria of NH. Recent studies of immunohistochemical assays have shown that the C5b-9 complex (the terminal membrane attack complement complex) is strongly expressed in the liver of NH cases, suggesting that a gestational alloimmune mechanism is the cause of liver injury. The patient was a low birthweight primiparous male born at 37 weeks of gestation by vaginal delivery. Blood tests 3 h after birth showed signs of liver failure, including high transferrin saturation, resembling the clinical characteristics of NH. However, magnetic resonance imaging and a lip biopsy showed no obvious iron deposition outside the liver. The patient was refractory to exchange transfusion and immunoglobulin therapy but was successfully treated by liver transplantation. Histologically, the explanted liver showed established cirrhosis, with large amounts of human C5b-9 in the residual hepatocytes, suggesting the alloimmune mechanism of liver injury was the cause of his liver failure. Liver failure caused by a gestational alloimmune mechanism should be considered in patients with antenatal liver failure, even without obvious extrahepatic siderosis.

Chronic hepatitis B virus infection in children and adolescents in Japan.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is an important event in patients with chronic hepatitis B virus (HBV) infection. This study aimed to clarify the outcome of long-term follow-up of chronic HBV infection and the factors affecting HBeAg seroconversion in children in Japan. METHODS: Patients who were first examined at our institution between 1980 and 2012, who were <20 years of age at the time of this initial visit, and who were positive for hepatitis B surface antigen for at least 6 months were identified retrospectively. Sex, age at diagnosis, HBV genotype, maximum serum alanine aminotransferase (ALT) level, occurrence of hepatitis flare-ups (yes/no), and transmission route were evaluated to identify the predictors of HBeAg seroconversion. RESULTS: A total of 205 children with chronic HBV were enrolled. Among them, 192 were positive for HBeAg upon diagnosis of chronic HBV infection. Out of this group, 95 (49%) achieved HBeAg seroconversion and 43 (21%) received treatment during the follow-up period. Only the maximum serum ALT level was significantly associated with the achievement of HBeAg seroconversion by multivariate analysis (P < 0.05). Kaplan-Meier analysis showed that the median times to HBeAg seroconversion (50% achievement of HBeAg seroconversion) of the treated and untreated children were 10.2 and 12.0 years, respectively. The cumulative proportion of HBeAg seroconversion was significantly higher in the treated children than in the untreated children (P = 0.02). CONCLUSIONS: A higher serum ALT level was a predictor for HBeAg seroconversion. Antiviral treatment could accelerate the achievement of HBeAg seroconversion in HBV-infected children.

Hepatitis B (HB) immunoglobulin plus HB vaccine for intrauterine HB virus infection.

BACKGROUND: Vaccination against hepatitis B virus (HBV) infection in infants born to hepatitis B surface antigen (HBsAg)-positive mothers using HB immunoglobulin (HBIG) and hepatitis B (HB) vaccine was launched in Japan in 1985. Infants testing positive for HBsAg at 1 month of age are considered to have prenatally acquired the infection and are usually excluded from the prevention program. Infants born to HB e antigen (HBeAg)-positive mothers are at a high risk of perinatally acquiring the infection. In this study, long-term outcome was evaluated in children with prenatal HBV infection who received the HBIG and HB vaccine in Japan. METHODS: Newborns of both HBsAg- and HBeAg-positive carrier mothers received HBIG within 48 h of birth and at 2 months of age. Subsequently, three doses of recombinant HB vaccine were given at 2, 3, and 5 months of age. Outcome was compared between the following two groups: infants who completed the vaccination program, even if they were HBsAg positive at 1 month of age (n = 15), and infants who did not (n = 51). RESULTS: Seroconversion from HBeAg to anti-HBe antibody (HBeAb) before 3 years of age was observed in five children (33%) who completed the vaccination program and in two (4%) who did not (P = 0.005). In 2/5 children who completed the vaccination program and achieved HBeAb seroconversion, seroconversion from HBsAg to anti-HBs antibody was also noted. CONCLUSION: This specific vaccination program for children with prenatal HBV infection has the potential to alter immune tolerance to HBV.