Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. METHODS: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 µg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 µmol/L [SD 115] with odevixibat vs 246 µmol/L [121] with placebo) to the average of weeks 20 and 24 (149 µmol/L [102] vs 271 µmol/L [167]; LS mean change -90 µmol/L [95% CI -133 to -48] with odevixibat vs 22 µmol/L [-35 to 80] with placebo; difference in LS mean change -113 µmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING: Albireo Pharma, an Ipsen company.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Familial Mediterranean Fever Mutation Analysis in Pediatric Patients With Inflammatory Bowel Disease: A Multicenter Study.

BACKGROUND: The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously. METHODS: Children with IBD (334 ulcerative colitis (UC), 224 Crohn's disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined. RESULTS: A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/ heterozygous) in patients with UC (P < .05). There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007). CONCLUSION: Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Complementary Roles of Cadaveric and Living Donor Liver Transplantation in Acute Liver Failure.

BACKGROUND: Living donor liver transplantation may complement cadaveric transplantation in acute liver failure (ALF) patients. METHODS: Between 2008 and 2017, 89 patients were treated for ALF; 15 patients (17%) recovered with intensive care treatment; 31 (35%) died without transplant. The records of the remaining 43 patients (median (range) age: 14 (1-62)) who underwent transplantation were evaluated. RESULTS: The etiologic factors were toxic agents (10; mushrooms: 8; herbs: 2), hepatitis viruses (7; A: 1; B: 6), Wilson's disease (7), autoimmune hepatitis (4), and Budd-Chiari syndrome (2); 13 cases were idiopathic. Cadaveric organs (whole, split, reduced) were transplanted to 32 patients; 11 patients underwent living donor transplantation. One patient (2%) died of septic shock on the second postoperative day. Bacterial infection was the most common early (< 3 months) complication in the remaining patients (31/42; 74%), followed by delirium (5/42; 12%) and acute rejection requiring steroid pulse (5/42; 12%). Seven other patients died during median (range) follow-up of 94 (14-142) months: various infections (5), leukemia (1), and acute myocardial infarction (1). The 1-, 5-, and 10-year survival rates were 100%, 96%, and 92% in children and 94%, 82%, and 65% in adults respectively. CONCLUSIONS: Cadaveric organ sharing and transplantation from living donors when appropriate yield a high survival rate, despite high early morbidity, in ALF patients whose conditions deteriorate despite intensive care treatment. Efforts to eliminate preventable causes of acute liver failure will lead to more efficient use of health care resources.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Long-term outcomes of six patients after partial internal biliary diversion for progressive familial intrahepatic cholestasis.

BACKGROUND: Partial internal biliary diversion (PIBD) is an alternative approach for the treatment of devastating pruritus in patients with progressive familial intrahepatic cholestasis (PFIC). In these patients quality of life can be improved and progression of liver disease can be delayed while waiting for liver transplantation. The aim of our study was to evaluate six patients with PFIC who have undergone PIBD in long-term follow-up. METHODS: Retrospective review of the records of six patients who underwent PIBD for PFIC between 2008 and 2010 was conducted to evaluate age, growth, clinical and laboratory studies for long-term outcome. RESULTS: Serum postoperative bile acid levels were reduced from a mean 340.1µmol/L (range 851-105) preoperatively to a mean of 96.3µmol/L at postoperative fifth year. The difference between pre- and postoperative bile acid levels was statistically significant (p=0.018). AST decreased from 79.1U/L (range 43-150U/L) to 64.6U/L (range 18-172U/L), ALT decreased from 102.8U/L (range 35-270U/L) to 84.6U/L and total bilirubin decreased from 2.9µmol/L (range 0.35-6.4µmol/L) to 1.53µmol/L (range 0.3-2.4). Again, the decrease in total bilirubin levels was significant (p=0.043). Pruritus was diminished from a mean of +4 (range 4-4) preoperatively to a mean of +2 (4-0). One patient who underwent liver transplantation owing to relapsing pruritus died from postoperative sepsis in the early postoperative period at the fifth year after PBID. Five symptom-free patients have not required liver transplantation at a mean period of 6.1±0.83years (5.1-7.0years) follow-up. CONCLUSION: PBID is an effective surgical procedure in the long-term and can delay the need for liver transplantation in children with PFIC by reducing jaundice and pruritus.

Transplantation for Large Liver Tumors in the Setting of Abernethy Malformation.

In this study, we report our experiences on the role of transplantation in 2 patients with large liver tumors in the setting of Abernethy malformation. Patient 1 was a 17-year-old boy who was referred for hepatic masses and recurrent hepatic encephalopathy episodes. Computed tomography and magnetic resonance imaging showed 2 large tumors (4 and 8 cm) in the liver. The portal vein drained directly into the vena cava. Core biopsy of the larger mass revealed fibrosis and regenerative hyperplasia. There were hyperintense signals in the T1-weighted images in the globus pallidus. The Stanford-Binet intelligence scale showed moderate mental retardation (IQ 39); however, the patient showed good ability for caring for himself. His cognitive defect was ascribed partially to chronic encephalopathy. The patient received a right hepatic lobe from his older brother. The congenital portacaval shunt was disconnected to provide inflow to the graft. Pathologic examination of the explanted liver revealed no evidence of malignancy. His IQ improved to 75 at 29 months posttransplant. The hyperintensity of the globus pallidus on magnetic resonance imaging disappeared. The patient has maintained a normal life during 9 years of follow-up. Patient 2 was a 17-year-old girl who was referred for multiple hepatic masses; she had no symptoms at admission. Magnetic resonance imaging showed type 1 Abernethy malformation and multiple hepatic masses (largest was 10 cm), which appeared to be hyperplastic lesions. Because malignancy could not be definitely excluded, she received a right lobe without the middle hepatic vein from her uncle. Pathologic examination of the explanted liver showed localized nodular hyperplasia; there was no evidence of malignancy. She has maintained normal life activities during 3 years of follow-up. Liver transplant is a curative treatment option for patients with large liver tumors, replacing the hepatic parenchyma in the setting of Abernethy malformation.

Copper, zinc and iron levels in infants and their mothers during the first year of life: a prospective study.

BACKGROUND: Essential micronutrients are important for maintenance of life. Deficiency of micronutrients is more likely to be encountered in children, and women studies are required to investigate the status of micronutrients in children and women. This study aimed to longitudinally evaluate changes in zinc, copper, and iron levels in breastfed infants and their mothers during the first year of life. METHODS: Serum and hair samples were obtained from 35 healthy breastfed infants (51% males, 49% females) and their mothers 2, 6, and 12 months after delivery. All of the samples were assessed using an atomic absorption spectrophotometer. Serum iron levels were determined by a Roche/Hitachi/Modular analyzer. Statistical analyses were performed using SPSS-PC (Version 21.00) software. RESULTS: Hair zinc (p < 0.05) and serum iron (p < 0.001) levels of infants were significantly decreased towards the end of the first year. Infants' serum copper levels were increased towards the end of the first year. Maternal serum and hair copper levels and serum iron levels were significantly decreased towards the end of the first year. There were no significant correlations between dietary zinc, copper, iron intake, and trace element levels of infants and their mothers. CONCLUSIONS: Infants' hair zinc levels, maternal and infants' hair copper levels, and infants' and maternal serum iron levels declined towards the end of the first year. Infants need more zinc after 6 months of age. Infants' and mothers' daily iron intake was less than the recommended intake.

Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

Pediatric liver transplant: a single-center study of 100 consecutive patients.

OBJECTIVES: Here, we present the outcomes of 100 consecutive pediatric liver transplant patients in our center. MATERIALS AND METHODS: Five hundred fifteen adult and pediatric liver transplants were performed at Organ Transplantation Center, Sisli Memorial Hospital, Istanbul, Turkey, between August 2006 and November 2012. Of these, the first 100 consecutive pediatric liver transplant patients were retrospectively analyzed. RESULTS: One hundred three liver transplants were performed in 100 children (mean age, 4.7 y; age range, 4.4 mo to 17.3 y; 53% female, 47% male; mean body weight, 17.2 kg; range, 4.5 to 75 kg). Biliary atresia (27%) and progressive familial intrahepatic cholestasis (18%) were the most common causes of liver disease. Of all the cases, 88.4% were living-donor liver transplants. Arterial reconstruction was performed under an operating microscope in most cases. Duct-to-duct biliary anastomoses were preferred in anatomically favorable cases. Mean hospital stay was 17.5 days. Median follow-up was 19.9 months (range, 6 to 66.1 mo). The main complication after surgery was infection (34%). Postoperative technical complications included hepatic arterial thrombosis (3.9%), portal venous thrombosis (6.8%), and biliary leak (6.8%). One-, 3-, and 5-year patient survivals were 89.8%, 89.8%, and 83.8%. There were no serious postoperative complications in the living donors. CONCLUSIONS: Living-donor liver transplant in pediatric patients is a safe alternative to deceased-donor transplant. It is becoming the most frequent treatment option for end-stage liver disease in pediatric patients in our center, given the paucity of pediatric deceased-donor organs.

Hepatoportal sclerosis in childhood: descriptive analysis of 12 patients.

Hepatoportal sclerosis (HPS) is defined as sclerosis of portal areas in the absence of cirrhosis. There is little information about HPS in children in the literature. The aim of this study was to describe the clinical presentation, associated disorders, laboratory characteristics and outcome of children who were diagnosed as HPS. This study included 12 children diagnosed as HPS by the Pathology Department between 2005 and 2011. Data were collected from the gastroenterology clinic charts retrospectively, including demographics, presentation characteristics, laboratory data and recent status of patients. Twelve patients were enrolled (6 girls, 6 boys). The median age of patients was 13.5 yr. Median age at the time of biopsy was 11 yr. Four patients had splenomegaly, 3 had esophageal varices, one had hepatopulmonary syndrome and had been transplanted. Smooth muscle antibody was found positive in 4 patients, without autoimmune hepatitis findings in liver biopsy. One patient had celiac disease and another patient had positive celiac disease serology but pathology findings. Another patient had Turner's syndrome. Mean follow-up time was 39 months (3.3 yr) after biopsy. Hepatoportal sclerosis does not necessarily present with portal hypertension in children.

Hepatitis C infection in childhood.

Hepatitis C infection in children has a different course than in adults, with higher rates of spontaneous clearance. Prenatal (vertical) transmission is the most common route of transmission in childhood. Only a high maternal viral load and HIV co-infection have been proven to increase the risk of infection in the offspring. There is thus no evidence to recommend abstinence from breastfeeding, or elective C-section to prevent transmission. Standard interferon, pegylated interferon and ribavirin are the only approved therapies in children. Severe liver disease is extremely rare in childhood, and described mainly in patients contaminated through blood transfusion.

Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.

Portal gastropathy and duodenopathy in children with extrahepatic and intrahepatic portal hypertension: endoscopic diagnosis and histologic scoring.

OBJECTIVES: The aim of the study was to determine the frequency of portal gastropathy (PG) and duodenopathy (PD) in children, to document the correlation of various clinical and laboratory parameters associated with portal hypertensive gastroduodenal lesions, to compare the endoscopic portal hypertensive lesions with different histologic findings, and to evaluate the use of a possible histologic scoring system. METHODS: All children undergoing endoscopic investigation for portal hypertension (PH) between January 2006 and November 2007 were analysed retrospectively. Clinical and demographical data and endoscopic and histologic findings were recorded. Histologic findings suggestive of PG and PD (capillary dilation, increased numbers of capillaries, histologic bleeding, and edema) were scored. RESULTS: Of 51 consecutive children (29 boys, mean age 10.1 ± 3.6 years [range 2.5-15.8 years]), 28 were cirrhotic. PG was diagnosed in 58.8% endoscopically. Children with cirrhotic PH had the highest rate of PG (64.3%), whereas those with extrahepatic or intrahepatic noncirrhotic PH were alike (50% and 54.5%, respectively). Baveno PG scores were higher in children with cirrhosis with higher Child-Pugh scores. Capillary dilation was the only histologic finding showing significant association with the endoscopic diagnosis. Only 9% had PD on endoscopy. None of the histologic findings correlated with endoscopic diagnosis of PD. CONCLUSIONS: PG and PD are seen in children with extrahepatic and intrahepatic PH at rates similar to those reported in adult studies. Baveno PG scores increased in parallel with Child-Pugh class in children with cirrhosis. Capillary dilation was the only histologic finding showing significant association with the endoscopic diagnosis of PG in this study.

Human herpes virus type 8-associated Kaposi sarcoma in a pediatric liver transplant recipient.

Development of KS in pediatric liver transplant recipients is a rare entity and has dismal prognosis. Latent HHV-8 infection, immunosuppression, and genetic predisposition are possible etiological factors. Decreasing the dose or cessation of immunosuppressive drugs, switching to sirolimus with antiproliferative and antitumor properties, and different chemotherapeutic regimens are the current therapeutic strategies. We herein report a pediatric liver transplant recipient who developed generalized KS at post-transplant fifth month. The disease had an aggressive course despite the highly toxic chemotherapy. On the other hand, a prompt and durable response was provided by paclitaxel with tolerable side effects. The patient is now free of disease for at least 24 months and healthy with good graft function under sirolimus therapy as maintenance immunosuppression. Instead of highly toxic chemotherapy, paclitaxel can be used as therapeutic option in cases with generalized disease and in those who are unresponsive to conventional chemotherapy. However, new studies are needed to assess the efficacy of the paclitaxel therapy in KS in the liver transplant recipients.

The role of the non-invasive serum marker FibroTest-ActiTest in the prediction of histological stage of fibrosis and activity in children with naïve chronic hepatitis B infection.

The aim of this study was to investigate whether the non-invasive serum marker FibroTest-ActiTest (FT-AT) reliably predicts the histological stage of fibrosis and/or activity, and decreases the need for a liver biopsy. Twenty-five children with naïve chronic hepatitis B were analyzed for haptoglobin, alpha2-macroglobulin, apolipoprotein A1, bilirubin, gamma-glutamyl transferase, and alanine aminotransferase activity, and the FT-AT scores were computed. FT-AT scores were compared with histological data. FT predicted insignificant fibrosis in 14/23 (61%) patients at a cut-off level of 0.31. Nine patients (36%) had significant histological fibrosis, but none were predicted by FT. There was no correlation between FT scores and histological stage of fibrosis (r: -0.221, p = 0.228). All 4 patients with significant histological activity had corresponding significant activity in AT (100%). Fifteen out of the 19 patients (78.9%) with significant activity in AT had insignificant histological activity. At the cut-off level of 0.36, AT predicted insignificant activity in all 6 patients (100%). There was no correlation between AT scores and histological activity (r: 0.245, p = 0.237). According to histological data, 12 patients were candidates for treatment, but FT-AT did not predict 3 of them (25%). FT-AT does not appear ready for use in detecting either the stage of fibrosis or activity in children with chronic hepatitis B.

Valproic acid-associated vanishing bile duct syndrome.

Hepatotoxicity as a result of valproic acid therapy is well documented. Elevation in aminotransferase activities is rarely associated with symptoms. It sometimes manifests as acute liver failure. Here, we report a 8-year-old girl who was referred for unresolving jaundice and itching for 3 months. Past history revealed afebrile convulsion 5 months previously and beginning of valproic acid treatment. Valproic acid was discontinued after the development of jaundice. Physical examination revealed ichterus, xanthomas on extensor surfaces of extremities, and hepatomegaly without any sign of chronic liver disease. Total and direct bilirubin levels were 20.2 and 12.9 mg/dL, respectively. Enzyme activities indicating cholestasis were increased together with blood cholesterol. Tests for infectious and autoimmune, metabolic, and genetic disorders were not informative. Liver biopsy revealed portal inflammation, severe bile duct loss, and cholestasis. The patient was considered to have valproic acid-associated vanishing bile duct syndrome, which has not been reported previously.