Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection.

Assessment of liver disease in cystic fibrosis.

Liver disease in cystic fibrosis has many causes, with biliary fibrosis due to abnormal CFTR protein predominating. Assessment requires aetiology to be defined. Biliary fibrosis may progress to cirrhosis and portal hypertension, which although initially asymptomatic, may cause varices and splenomegaly. Monitoring progression includes clinical and ultrasound assessment with endoscopic assessment of varices for those at risk. Extrapolated primarily from longitudinal assessment of viral hepatitis in adults, non-invasive elastography has a potential role. Evidence is lacking to support intervention strategies, but ursodeoxycholic acid and ligation of varices are widely applied. Indication and timing of liver transplantation are not clearly defined. Multidisciplinary approach is needed to tailor assessment and guide management.

Guidelines on the management of abnormal liver blood tests.

These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.

Liver Failure in Early Infancy: Aetiology, Presentation, and Outcome.

OBJECTIVE: Acute liver failure (ALF) in early infancy is rare and challenging to recognize and manage. We aim to describe the presentation and outcome of infants with ALF according to their final aetiology to elucidate features to facilitate early recognition leading to prompt diagnosis and management. METHODS: All infants presenting within 120 days from birth with liver failure were included in a retrospective review over a 19-year period. The aetiology, clinical features, presenting investigations, and outcome were collected. RESULTS: Seventy-eight young infants presented with ALF. The aetiology was established in 94% and included metabolic disease (36%), hypoxic-ischaemic (HI) insult (19%), infection (17%), neonatal haemochromatosis (9%), and infiltrative disease (9%). Infections, infiltrative disease, and acute HI insult usually resulted in higher transaminases and international normalized ratio, whereas neonatal haemochromatosis and tyrosinaemia were characterized by lower or near normal transaminases. Overall jaundice was not visible in 24% of infants at presentation. Forty-five (58%) infants were alive at discharge from hospital. Survival at 1 year was 53% and survival with native liver 50%. Later deaths occurred in infants with mitochondrial disease. Six infants received a liver transplant and 4 subsequently died from their underlying disease. CONCLUSION: ALF should be considered in any young infant with a coagulopathy as transaminases and/or bilirubin levels can be near normal at presentation. Better intensive care and the judicious use of liver transplantation may have contributed to the improved outcomes for this group compared with previous decades.

Management of chronic hepatitis B infection.

The spectrum of chronic hepatitis B infection in children ranges from asymptomatic carriage with minimal disease, to progression to cirrhosis and risk of hepatocellular carcinoma in adulthood. Identifying those who will benefit from treatment is a challenge. Interferon-based therapies have limited efficacy, while prolonged use of nucleos(t)ide analogues may promote resistance. New antiviral agents have improved barriers to resistance, but long-term outcome is not yet known. Untreated infection, however, may in some, lead to natural seroconversion and reduce risk of further disease. Hepatitis B e antigen-positive infection is the most common scenario in chronically infected children, with e antigen-negative hepatitis rarely encountered. This paper reviews the clinical guidelines published in 2013 by the National Institute for Health and Care Excellence (NICE) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and focuses on the guidance for treatment in e antigen-positive children. The most significant difference is the lower threshold for starting treatment recommended by NICE guidelines. The need for regular evaluation of each child, in the light of new evidence and new drugs as they emerge, must remain the focus of each clinician involved in the care of children with hepatitis B virus infection.

Epidemiology and clinical features of childhood chronic hepatitis B infection diagnosed in England.

BACKGROUND: This study aimed to estimate the prevalence of childhood chronic hepatitis B (CHB) infection diagnosed in England using capture-recapture analysis of 2 independent data sources and to describe the clinical and epidemiological characteristics, management, complications and outcome of children with CHB. METHODS: Pediatric specialists were contacted to report all CHB cases in children aged <16 years and complete a standardized questionnaire. Capture-recapture analysis of cases diagnosed during 2001-2009 using 2 independent data sources was performed to estimate the prevalence of childhood CHB. RESULTS: Capture-recapture analysis estimated 448 diagnosed CHB cases (prevalence, 4.6/100,000) in England, of whom only 44% had been referred for specialist follow up. Clinical information for 325 cases under specialist care revealed that half the cases (n = 164, 50%) had been born overseas, mainly Sub-Saharan Africa and Eastern Europe, whereas half the UK-born children were either Pakistani (25%) or Chinese (25%). Most children (n = 216, 66%) were asymptomatic, with only 60 (18.5%) ever receiving any antiviral therapy, although 2 developed cirrhosis in childhood and 1 hepatocellular carcinoma. Horizontal transmission among UK-born children was identified in only 3 children born since 2001, when universal antenatal hepatitis B virus screening was introduced. Most children born to antenatally diagnosed hepatitis B virus-positive mothers (49/51, 96%) had received at least 1 hepatitis B vaccine dose after birth. CONCLUSIONS: In England, the prevalence of diagnosed childhood CHB is low, although the potential number of undiagnosed cases is difficult to estimate. Further efforts are required to strengthen the current antenatal screening program and newly diagnosed cases should be referred for specialist follow up.

Renal function evaluated by measured GFR during follow-up in pediatric liver transplant recipients.

Calcineurin inhibitors form the mainstay of immunosuppression in pediatric liver transplantation, but may cause significant nephrotoxicity. We evaluated renal function in liver transplant recipients treated with a tacrolimus-based immunosuppressive regimen. GFR was measured using 99 mTc-DTPA in patients pretransplant and annually thereafter. GFR calculated by Schwartz formula was compared with the measured values. Sixty patients who underwent 69 transplants were followed for at least one yr post-transplant (median three yr). In children over two yr of age at transplant GFR fell significantly from pretransplant (140 mL/min/1.73 m(2)) to one yr post-transplant (112 mL/min/1.73 m(2)) (p = 0.01) but thereafter there was no significant decline. In younger children the picture was confounded by maturation of renal function, but again there was no significant fall to five yr post-transplant. Although 13 (22%) patients developed renal dysfunction post-transplant, none required renal replacement therapy. cGFR correlated poorly with measured values (r = 0.21). Use of a tacrolimus-based immunosuppressive regimen is associated with an initial decline in GFR, though this picture is confounded in younger children by normal maturation of renal function. There is no further significant fall in GFR in the medium-term. The Schwartz formula is inaccurate in determining GFR in this patient group.

Management strategies for hepatitis C virus infection in children.

Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. Progression to cirrhosis and hepatocellular carcinoma occurs in 20% of infected adults. The natural history following childhood infection is less well defined, although cirrhosis in children is described. Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother. Transmission to offspring occurs in approximately 5%. Most children with HCV infection are asymptomatic. Diagnosis is made by testing those at risk for HCV RNA by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) by enzyme immunoassay (EIA). The clinical impact of HCV infection is assessed by monitoring symptoms and signs, blood testing of liver enzymes, ultrasound imaging, and by liver biopsy. Improved efficacy and tolerability of treatment strategies in adults have had a significant impact on the management of children with HCV infection. The emphasis is now on promoting awareness, early diagnosis, and treatment. Treatment strategies have evolved from monotherapy with interferon alfa (IFNalpha), to combination therapy with ribavirin. Pegylated IFNalpha is superior to conventional IFNalpha, and forms the basis of current recommendations. The genotype of HCV influences treatment efficacy. Treatment is generally well tolerated in children, although adverse effects are common. Preparation and support throughout treatment for the whole family is needed. A proportion of children with HCV infection have co-morbidity, including viral co-infection or hematologic disease. Although treatment may be contraindicated, risks and benefits must be considered before denying treatment. Anemia is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis, and may be aggravated by treatment. Children with thalassemia may have iron overload, and transfusion requirements may increase during treatment. Further refinements of combination therapy and development of new drugs are in progress. Vaccine candidates are undergoing phase I and II treatment trials.

Histologic oddities at the porta hepatis in biliary atresia.

PURPOSE: Highly unusual histologic findings at the porta hepatis in 3 infants who underwent Kasai portoenterostomy for biliary atresia are reported. METHODS: Portoenterostomy was performed using a standard operative technique. Serial transverse sections of the excised portal plate were examined by light microscopy along with sections from the distal extrahepatic biliary remnants, gallbladder, and liver biopsy. RESULTS: Of 61 consecutive infants who underwent Kasai portoenterostomy for biliary atresia, 3 were found to have highly unusual histologic features at the porta hepatis. All had type 3 biliary atresia. Two had hilar biliary ductules lined in part by squamous epithelium, and the third had a focus of mature hyaline cartilage surrounded by perichondrium adjacent to biliary ductules. In each case, these unusual histologic features were localized to the porta hepatis in the region of the transected portal plate. CONCLUSIONS: The presence of hyaline cartilage at the portal plate is likely to be an expression of defective morphogenesis, thus supporting the concept of disordered embryogenesis in the etiology of biliary atresia. Squamous epithelium within biliary ductules might also reflect a similar mechanism but could alternatively be an unusual metaplastic response to inflammation at this site.

A national sample of individuals who acquired hepatitis C virus infections in childhood or adolescence: risk factors for advanced disease.

OBJECTIVES: To describe hepatitis C virus (HCV)-related liver disease in a national cohort of patients who acquired their infections in childhood or adolescence and to assess risk factors for progressive disease and response to antiviral therapy. PATIENTS AND METHODS: Demographic, laboratory, and clinical outcome data on 246 individuals who acquired HCV infection before the age of 16 years were extracted from the UK HCV National Register database. Logistic regression analysis was used to investigate the independent effects of sex, age, duration and route of infection, and comorbidity on histological stage of liver disease. RESULTS: Median ages at enrollment and follow-up were 14.0 years (range, 2.2-29.6 years) and 19.2 years (range, 2.3-35.5 years), respectively. Mean duration of infection at enrollment was 8.5 years (standard deviation [SD], 3.3 years), and mean duration of follow-up was 4.5 years (SD, 4.5 years). Fifty-nine (24%) had persistently abnormal liver aminotransferase levels; 22% reported physical signs and symptoms of liver disease. Among 123 individuals with liver biopsies, 117 (95%) had abnormal histological findings. Ninety-eight individuals had biopsies referred for independent blind scoring; median Ishak grade and stage scores were 3 and 1, respectively. Presence of comorbidities (odds ratio [OR], 7.19; 95% CI, 2.00-26.17; P = 0.003) and female sex (OR, 0.31; 95% CI, 0.10-1.00; P = 0.05) were independently associated with histological stage scores greater than the median. A total of 110 individuals received antiviral therapy; 47% achieved a sustained response. CONCLUSIONS: HCV-related liver disease in those who acquired the infection in childhood or adolescence was mild for most, although comorbidity and female sex were associated with more advanced disease. Antiviral therapy in childhood or adolescence successfully eradicates the virus for many patients.

Kasai portoenterostomy: 12-year experience with a novel adjuvant therapy regimen.

AIM: The role of adjuvant therapy with corticosteroids and choleretics after Kasai portoenterostomy for biliary atresia (BA) remains uncertain. Experience with a novel postoperative adjuvant therapy regimen is reported. METHODS: Between 1994 and 2006, 71 infants with BA were referred. Four died from uncorrectable congenital heart disease/cardiorespiratory failure without undergoing portoenterostomy, 7 underwent primary liver transplantation (3 referred > or = 19 weeks of age), and 60 underwent portoenterostomy at a median of 51 (10-104) days. Of these, 55 (92%) had type 3 BA and 6 had the BA splenic malformation syndrome. Fifty (83%) received the following adjuvant therapy beginning on postoperative day 5: oral dexamethasone 0.3 mg/kg bd for 5 days, 0.2 mg/kg bd for 5 days, and 0.1 mg/kg bd for 5 days together with oral ursodeoxycholic acid 5 mg/kg bd and phenobarbitone 5 mg/kg nocte, both of which were continued for 1 year. All infants received routine perioperative prophylactic antibiotics. RESULTS: Overall, 42 of 60 (70%) infants cleared their jaundice (bilirubin < 20 micromol/L): 38 of 50 (76%) with the dexamethasone/ursodeoxycholic acid regimen compared with 4 of 10 (40%) not receiving this adjuvant treatment. There were 4 late deaths after portoenterostomy: 2 from associated congenital disorders and 2 after liver transplantation. Of the remaining 56 children, 39 (70%) are currently alive with their native liver at a median follow-up of 3.3 years and 17 are alive after liver transplantation. Surgical complications occurred in 3 after portoenterostomy: adhesive bowel obstruction (2) and an anastomotic leak. One infant had gastrointestinal bleeding that may have been related to dexamethasone, but this resolved with ranitidine. There were no perioperative septic complications. CONCLUSION: In this series, adjuvant postoperative treatment with a short course of oral dexamethasone and longer-term ursodeoxycholic acid significantly improved the outcome after Kasai portoenterostomy.

Successful conservative management of idiopathic fibrosing pancreatitis in children.

UNLABELLED: Idiopathic fibrosing pancreatitis, a rare cause of obstructive jaundice and abdominal pain in children, which has certain features in common with the emerging entity of autoimmune pancreatitis as described in adults, has frequently been managed surgically. We present our experience of successful conservative management of this condition in children. Three children (6-12 years; two girls, one boy) presented with a short history of abdominal pain followed by obstructive jaundice. Abdominal ultrasonographic examination in each case showed dilated intrahepatic and common bile ducts with a bulky pancreas, predominantly the head. These findings were confirmed by magnetic resonance imaging. In two cases, the diagnosis of fibrosing pancreatitis was made by exclusion after extensive investigation. The third case had a percutaneous ultrasound-guided pancreatic needle biopsy. Two patients were managed by supportive medical therapy alone, whilst the third, with symptomatic obstructive jaundice, underwent temporary endoscopic stenting of the common bile duct. Cases have been followed-up for 12-49 months. There was complete clinical and biochemical resolution of obstructive jaundice in all three cases. Plasma bilirubin concentrations decreased to normal within 3-8 weeks. Serial abdominal imaging showed a gradual resolution of biliary dilatation and abnormal pancreatic morphology with subsequent pancreatic atrophy. Two children developed steatorrhoea that responded to pancreatic enzyme supplements, and one patient developed diabetes mellitus. None of the cases needed invasive surgery for diagnosis or management. CONCLUSION: With careful radiological and biochemical assessment and monitoring, invasive surgery can be avoided in the management of fibrosing pancreatitis. The eventual outcome is no different from reported surgically treated cases.

Immediate extubation of children following liver transplantation is safe and may be beneficial.

BACKGROUND: Immediate tracheal extubation of selected adult patients after orthotopic liver transplant (OLT) is common practice. We hypothesized that selected children may be safely extubated immediately after OLT and avoid potentially deleterious effects of artificial ventilation and sedation. METHODS: After June 2002, we chose immediate extubation unless a specific contraindication was identified. Charts of all children undergoing OLT between June 2002 and February 2005 were reviewed to audit safety and outcome of this approach. Comparative data were obtained for children undergoing first elective OLT at other UK centers. RESULTS: Forty-six cadaveric liver transplants were performed in 40 patients: 26 of 34 (76%) elective transplants and 4 of 12 (33%) urgent transplants were extubated immediately after surgery. Eight of 14 (57%) children weighing less than 10 kg were successfully extubated. One child required reintubation after developing transfusion-related acute lung injury. There were no other events compromising patient or graft. Small recipient size, split/reduced grafts, preexisting respiratory disease, retransplantation, and acute liver failure did not individually preclude successful immediate extubation. After elective OLT, the mean duration of intensive care stay was significantly shorter in the extubated group than in those who were ventilated (2.5 vs. 6.1 days, P<0.01). All children receiving a liver transplant at other UK centers in 2003 were ventilated postoperatively. However, the median duration of intensive care stay (2 days) was the same as in our series. CONCLUSIONS: Immediate extubation of selected children after OLT is safe. It may enhance patient recovery, benefit graft physiology, and reduce intensive care requirement.

Preoperative vascular imaging in pediatric liver transplantation.

BACKGROUND/PURPOSE: There is a considerable variation in the use of vascular imaging techniques in the preoperative assessment of children scheduled for liver transplantation. Duplex Doppler ultrasound scan (US), magnetic resonance angiography (MRA), and conventional angiography are used to varying extents. The authors compared the results of preoperative vascular imaging studies with operative findings to determine their accuracy and usefulness. METHODS: Results of preoperative vascular imaging in 37 consecutive children undergoing cadaveric liver transplantation were compared with operative findings. Those undergoing relatively elective transplantations were investigated by US and MRA (group 1), whereas those requiring urgent transplants were assessed only by US (group 2). RESULTS: The median age of the cohort (15 boys; 22 girls) was 4 years (19 days to 16 years) and the median weight was 17 kg (2.9 to 82 kg). In group 1 (n = 26), 20 children had a normal-caliber, patent portal vein at transplant and 6 had a narrow but patent portal vein requiring venous reconstruction in 4. The sensitivity and specificity of MRA in the detection of an abnormally narrow portal vein were 100% (6/6) and 95% (19/20), respectively. If reversed or absent flow in the portal vein on US was taken as an indication of a potentially abnormal vein, the sensitivity and specificity of Doppler US were 83% (5/6) and 95% (19/20), respectively. Magnetic resonance angiography revealed arterial anomalies in 4 children but failed to detect small accessory hepatic arteries in 5. The single patient with an aberrant vena cava was identified by MRA. In group 2 (n = 11), venous findings at operation and on US were concordant in 10 (91%) cases; one infant with reversed flow in the portal vein on US had a thrombosed vein at surgery. Magnetic resonance angiography was useful in 2 patient groups: those with reversed flow on Doppler US or suspected portal vein thrombosis in whom an abnormal portal vein was present in 86% (6/7) and infants with the biliary atresia splenic malformation syndrome who had multiple venous and arterial anomalies. CONCLUSIONS: A detailed Doppler examination of the hepatic vasculature by an experienced sonographer/radiologist provides sufficient vascular imaging for most children scheduled for cadaveric liver transplantation. Routine MRA is recommended in children with the biliary atresia splenic malformation syndrome and in those with abnormal duplex Doppler US findings. Although there are limited data in this study, MRA is also valuable in children with Budd-Chiari syndrome, liver tumors, or a previous portosystemic shunt.

Multidisciplinary management of surgical disorders of the pancreas in childhood.

OBJECTIVES: To describe the frequency and range of pancreatic disorders in children requiring surgical intervention and to highlight the importance of multidisciplinary management. METHODS: An audit of all children under 17 years of age referred with surgical disorders of the pancreas or pancreatitis to a regional pediatric gastroenterology unit in the United Kingdom during a 10-year period. A retrospective chart review of clinical features, pathology and outcome was undertaken. RESULTS: Surgical intervention was required for the following pancreatic disorders: persistent hyperinsulinemic hypoglycemia of infancy (n = 4), pancreatic tumors (n = 5), pancreaticobiliary malunion (n = 12), pancreatic trauma (n = 6) and pancreatitis (n = 10). The indications for surgery in acute pancreatitis were a persistent pseudocyst (n = 1) and treatment of an underlying cause of pancreatitis (n = 4); in chronic pancreatitis, surgery was used to treat symptomatic pancreatic duct strictures (n = 4). One child died of a progressive lymphoma but all others who underwent surgery are alive and well. All 33 children with acute pancreatitis, including four with pancreatic necrosis, survived. CONCLUSIONS: Surgery for pancreatic disorders in children is rarely required but may be necessary a) for definitive management of primary pancreatic pathology, b) to treat sequelae of acute or chronic pancreatitis and c) to treat an underlying cause of pancreatitis. There is a broad spectrum of potential pathologies. These patients are best managed by a multidisciplinary team approach.