Tsuyoshi Sogo

Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: Hepatic manifestation in wilson disease as a consequence of augmented oxidative stress

The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper that generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic antioxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5), and fulminant hepatic failure (group III, n = 5) and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in group II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-dependent superoxide dismutase (CuZn-SOD), and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase (GPx) activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD, and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.

Long-term outcome of chronic hepatitis B in adolescents or young adults in follow-up from childhood.

BACKGROUND It has not yet been defined whether children with chronic hepatitis B are likely to develop severe liver disease in the future. The purpose of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood. METHOD Fifty-two children in the age range of 0 to 15 years who were positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months were enrolled in this study. In the majority of the 52 children, hepatitis B virus infection was acquired by perinatal transmission. All 52 showed abnormal liver function test findings for more than 6 months before enrollment, and the subjects were followed up longitudinally for 3 to 22 years (mean, 11 years). They are now more than 15 years of age (15-27 years old). RESULTS During the follow-up period, 26 (50%) children had spontaneous seroconversion to anti-hepatitis B e. Serum levels of alanine aminotransferase normalized in these 26 children. In one child of these children, hepatocellular carcinoma developed at the age of 21 years, 16 years after seroconversion, although his liver function profiles remained normal. The other 26 children remained hepatitis B e antigen positive, most with unchanged biochemical features. Sixteen (62%) children among these 26 children were treated with interferon-alpha. Eleven (69%) children had seroconversion to anti-hepatitis B e within the first year after the cessation of therapy. Hepatocellular carcinoma developed in 1 of these 11 children at the age of 16 years, 6 years after interferon therapy. Thus, hepatocellular carcinoma developed in two children in an anti-hepatitis B e positive phase. CONCLUSION All children carrying hepatitis B surface antigen should be observed carefully to monitor the possible development of hepatocellular carcinoma, especially in the antihepatitis B e-positive phase after spontaneous seroconversion or even after interferon treatment.

Utility of Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children

Background and Aim: Although the diagnostic scoring system of autoimmune hepatitis (AIH) has been used, these criteria are intended mainly as research tools and are complicated to apply. To resolve these difficulties and allow quick diagnosis, a simplified scoring system was proposed in 2007. We retrospectively compared the simplified AIH scoring system with the 1999 revised original AIH scoring system in children. Patients and Methods: Twenty children (boys/girls 10/10, age 1–15 years, mean age ± SD 8.4 ± 4.4 years) who were diagnosed with AIH based on clinical, biochemical, immunological, and histological data were enrolled in this study. In addition, 36 children with non-AIH liver diseases (boys/girls 22/14, age 1–16 years, mean age ± SD 7.8 ± 4.4 years) were available for evaluation of both the simplified and the 1999 revised scoring system. Results: The sensitivity and specificity of the 1999 revised scoring system were 100% and 81%, respectively. In contrast, the sensitivity and specificity of the simplified scoring system were 55% and 86%, respectively. Of the 20 children with AIH, 9 (45%) were classified as not having AIH using the simplified scoring system. Of the 9 children, 2 and 7 were classified as having definite AIH and probable AIH using the 1999 revised scoring system, respectively. All 5 children with primary sclerosing cholangitis were graded as having AIH using the simplified AIH criteria and the 1999 revised criteria. Conclusions: Although the simplified AIH scoring system has low sensitivity for the diagnosis of AIH in children, the specificity of the simplified AIH scoring system is high. However, the simplified AIH scoring system could not differentiate between AIH and primary sclerosing cholangitis. Therefore, the simplified AIH scoring system does not seem to be a reliable diagnostic tool in children.

Source of transmission in children with chronic hepatitis B infection after the implementation of a strategy for prevention in those at high risk

Aim:  In order to clarify the sources of chronic HBV (hepatitis B virus) infection in children after the implementation of an “at‐risk” strategy in Japan, chronically infected children were assessed. In addition, chronically infected children born to HBsAg‐negative mothers and their family members were assessed to identify the sources of HBV transmission.

Hepatic copper concentration in children undergoing living related liver transplantation due to Wilsonian fulminant hepatic failure

Liver transplantation is indicated for Wilsons disease (WD) patients having the fulminant form and end‐stage liver failure. To evaluate whether living related liver transplantation (LRLT) can correct the copper metabolism in WD patients, we studied two children who underwent LRLT because of fulminant hepatic failure. They were 7 and 13 yrs old at the time LRLT was performed. Serum ceruloplasmin levels, serum copper levels, copper urine excretion, and hepatic copper concentrations were measured. Serum ceruloplasmin levels (16.7 ± 1.2 mg/dL) and serum copper levels (67.0 ± 1.4 μg/dL) were lower than the normal range after LRLT in case 1. In both patients, urinary copper excretion was reduced markedly after LRLT, but was not normalized (case 1, 191.2 ± 182.2 μg/d; case 2, 140.0 ± 156.7 μg/d). Hepatic copper concentrations were slightly elevated (case 1, 158.8 ± 44.6 μg/g dry weight; case 2, 147.0 μg/g dry weight) after LRLT in both cases, but did not exceed 250 μg/g dry weight. LRLT is a curative procedure in Wilsons disease presenting fulminant hepatic failure or advanced cirrhosis. However, this study indicates that the conditions of copper metabolism in WD patients undergoing LRLT are similar to those in heterozygous genetic carriers. Because the living related donors are the parents who carry the abnormal gene, LRLT cannot completely restore the copper balance in WD patients.

Autoimmune hepatitis in childhood

Autoimmune hepatitis (AIH) is a generally progressive inflammatory liver disease of unknown etiology that occurs in adults and children. Although the peak age of incidence is in prepubertal girls, AIH has been diagnosed as early 6 months of age. Two types of AIH are recognized according to the nature of the autoantibody detected in children at the time of diagnosis. The diagnosis of AIH is based on histological abnormalities, characteristic clinical and biochemical findings, and abnormal levels of serum globulin due almost exclusively to markedly increased immunoglobulin G including various autoantibodies. A genetic predisposition is suggested by the increase frequency of human leukocyte antigen (HLA) haplotypes HLA‐B8/DR3, and allotypes DR3 and DR4. However, the incidence of these HLA types is different in each country.Proposed triggers of AIH that may initiate the inflammatory process include some viral infections and some drugs. There is much information about adults with AIH, however, little information on AIH in children, especially in Japanese children. To clarify the clinicohistological features of AIH in Japanese children, we analyzed the clinical, pathological features and response to treatment in 12 Japanese children with AIH. Furthermore, we discuss several problems for diagnosis and treatment for AIH in children.

Safety and utility of capsule endoscopy for infants and young children

AIM To assess the safety and utility of capsule endoscopy (CE) for children who are unable to swallow the capsule endoscope. METHODS The medical records of all of the children who underwent CE between 2010 and 2012 were retrospectively reviewed. The patients were divided into 2 groups: group A included patients who were unable to swallow the capsule endoscope, and group B included patients who were able to swallow it. For the patients who were unable to swallow the capsule endoscope, it was placed in the duodenum endoscopically. The small bowel transit time, endoscopic diagnosis and complications of the 2 groups were compared. RESULTS During the study period, 28 CE procedures were performed in 26 patients. Group A included 11 patients with a median age of 2 years (range 10 mo-9 years), and group B included 15 patients with a median age of 12 years (range 8 years-16 years). The lightest child in the study weighed 7.9 kg. The detection rates did not differ between the 2 groups. The median small bowel transit time was 401 min (range 264-734 min) in group A and 227 min (range 56-512 min) in group B (P = 0.0078). No serious complications, including capsule retention, occurred. No significant mucosal trauma occurred in the pharynx, esophagus, stomach or duodenum when the capsule was introduced using an endoscope. CONCLUSION CE is a safe and useful procedure for infants and young children who are unable to swallow the capsule endoscope.

Tears From Children With Chronic Hepatitis B Virus (HBV) Infection Are Infectious Vehicles of HBV Transmission: Experimental Transmission of HBV by Tears, Using Mice With Chimeric Human Livers

BACKGROUND Body fluids such as saliva, urine, sweat, and tears from hepatitis B virus (HBV) carriers are potential sources of HBV transmission. METHODS Thirty-nine children and 8 adults who were chronically infected with HBV were enrolled. Real-time polymerase chain reaction was used for the quantification of HBV DNA. RESULTS HBV DNA was detected in 73.7% of urine samples (14 of 19), 86.8% of saliva samples (33 of 38), 100% of tear samples (11 of 11), and 100% of sweat samples (9 of 9). Mean HBV DNA levels (±SD) in urine, saliva, tears, and sweat were 4.3 ± 1.1 log copies/mL, 5.9 ± 1.2 log copies/mL, 6.2 ± 0.7 log copies/mL, and 5.2 ± 0.6 log copies/mL, respectively. A statistically significant correlation was observed between the HBV DNA level in serum specimens and HBV DNA levels in saliva and tear specimens (r = 0.88; P < .001). Tear specimens from a child were injected intravenously into 2 human hepatocyte-transplanted chimeric mice. One week after inoculation, both chimeric mice had serum positive for HBV DNA. CONCLUSIONS The levels of HBV DNA in tear specimens from young children were high. Tears were confirmed to be infectious, using chimeric mice. Strict precautions should be taken against direct contact with body fluids from HBV carriers with high-level viremia.

Different outcomes of vertical transmission of hepatitis C virus in a twin pregnancy.

The risk of vertical transmission of hepatitis C virus (HCV) from mother to infant has been well documented, but the exact mode of transmission is still unclear. In a set of monochorionic diamniotic monozygous twins, only the second baby was infected with HCV from the mother who was positive for serum HCV‐RNA. The babies had an uncomplicated vaginal delivery 3 min apart and they were both bottle fed from the outset. The second baby developed clinical hepatitis that persisted to 30 months follow up. The intrauterine environment should have been identical for these twins, and therefore, the maternal HCV factors, including viral load are not the sole determining factors for mother‐to‐infant transmission of HCV.

Fulminant hepatitis B and acute hepatitis B due to intrafamilial transmission of HBV after chemotherapy for non-Hodgkin’s lymphoma in an HBV carrier

Hepatitis B virus (HBV) reactivation after chemotherapy has been investigated, but little is known about the risk of horizontal transmission from an immunocompromised host with HBV reactivation. We treated two children with fulminant hepatitis B and acute hepatitis B, respectively, whose grandmother, an HBV carrier, had been undergoing rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R+CHOP) therapy for lymphoma. The grandmother was also suffering from fulminant hepatitis when both children became ill. The complete HBV DNA sequences of the three family members were identical. The full genome sequence analysis of HBV provided strong evidence of intrafamilial transmission of HBV. Treatments that cause immunosuppression, such as R+CHOP therapy for lymphoma, can increase the levels of serum HBV DNA and the risk of intrafamilial HBV infection when given to HBV carriers. In conclusion, specific antiviral prophylaxis is indispensable for preventing horizontal transmission as well as reactivation of HBV in chemotherapy-treated HBV carriers.