Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

Gastroesophageal reflux with children requiring adenotonsillectomy.

BACKGROUND: Our aim is to determine the incidence of reflux in children older than 3 years requiring adenotonsillectomy and relationship between GER and diagnostic tests. METHODS: Forty-four patients, who were listed for adenoidectomy/tonsillectomy at Pediatric Ear Nose Throat department due to severe hypertrophy, were evaluated for accompanying GER (Group 1). GER was diagnosed as having at least one positive GER test result (including esophagitis or pH monitoring). Twenty children without reflux symptoms were used as healthy control group (Group 2) and LPR was held. RESULTS: Reflux was detected in 32 children requiring adenotonsillectomy (72.7%). LPR score was negative in all patients in Group 2. There was no correlation between pH monitoring and histopathological evaluation of esophagus. There was a correlation between the LPR score and histological esophagitis in the proximal esophagus. CONCLUSIONS: GER was high in patients with adenotonsillary hypertrophy. LPR score and the history of patients are as effective as invasive techniques like pH monitorization and endoscopy in determining GER disease.

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.

A rare cause of refractory ascites in a child: familial Mediterranean fever.

Familial Mediterranean fever (FMF) is hereditary episodic febrile syndrome characterized by acute attacks of fever and serosal inflammation, generally lasting 1-3 days and resolves spontaneously. Apart from abdominal pain, patients may present with variety of abdominal manifestations such as acute peritonitis, mechanical intestinal obstruction, diarrhea, bowel infarction, amyloidosis and small amounts of peritoneal fluid during the acute attacks. A 6-year-old boy was admitted with massive ascites. After extensive laboratory investigations, no causative agent could be identified. On subsequent days, he developed fever and skin eruptions. Acute-phase reactants were increased. A second tomography revealed cystic fluid collection near the anterior side of spleen that invades the stomach. An exploratory was performed and histopathological examination of the all resected specimens revealed mix inflammatory cell infiltrate associated with severe myofibroblast proliferation suggesting chronic inflammatory process on the mesenteric region. A diagnosis of FMF was suspected based on the clinical, laboratory and histopathological findings, and a trial of colchicine therapy initiated. Ascites and other serosal inflammations improved within 1 week without any recurrence during the next 12-month period on colchicine treatment. Atypical presentations of FMF have been increasingly reported. Pediatricians should keep FMF in mind in the differential diagnosis of massive ascites especially in regions where hereditary inflammatory disease are common.

Infections developing in patients undergoing liver transplantation: Recipients of living donors may be more prone to bacterial/fungal infections.

BACKGROUND/AIMS: Despite surgical advances in liver transplantation and effective prophylactic strategies, posttransplant infections are the most important cause of morbidity and mortality. Diagnosis and management of infections because of developing immunosuppression is difficult and adversely affects mortality. This study aimed to review bacterial and fungal infections in patients after liver transplantation and to reveal the resistance rates. MATERIALS AND METHODS: A total of 107 patients who underwent liver transplantation between January 2017 and February 2018 were evaluated retrospectively with regard to demographic characteristics, causes of transplantation, conditions that may lead to infection, postoperative infections, pathogens, and resistance patterns. RESULTS: Of the 107 patients who underwent liver transplantation, 48 (44.8%) had an infection. Bacterial infections were detected in 41% of the patients, and fungal infections were found in 13%. When we compared living and cadaveric transplants in terms of infection development, these rates were found to be 53% and 33%, respectively (p=0.034). No statistically significant results could be obtained when evaluating conditions such as sex, presence of underlying primary disease, Model for End-Stage Liver Disease MELD score, diabetes status, total parenteral nutrition, and risk factors for infection. CONCLUSION: After liver transplantation, infections are often seen in the first month of the postoperative period. Knowing the most common pathogens and resistance states in this process reduces infection-related deaths by providing appropriate treatment regimens at the right time.

Long-term effect of gluten-free diet on growth velocity in Turkish children with celiac disease.

We sought to analyze the long-term growth in children with celiac disease (CD) as well as the association of height and weight SD score at the end of 4 years with the demographic and clinical presentation at initial admission. Thirty-four children with CD were enrolled in the study and followed for at least 4 years. Patients were divided into three groups (Group 1: patients 10 years, at the time of diagnosis). Patients' charts were reviewed for demographic and clinical features at initial admission. Anthropometric measurements at initial admission, at 6th months, and 1st, 2nd, 3rd, and 4th years were recorded. Gluten-free diet led to rapid increase in weight SD and height SD score in patients

A rare complication of central catheter in an infant with intestinal failure.

OBJECTIVE: To report the successful percutaneous transcatheter removal of a snapped intracardiac fragment of the central vein catheter in an infant. CLINICAL PRESENTATION AND INTERVENTION: A 3-month-old infant with short bowel syndrome who required long-term parenteral nutrition via portacath central catheter was hospitalized. Two months after the insertion of the second catheter, the distal tip of the catheter snapped and became tangled in the heart. The catheter fragment was removed by a percutaneous femoral vein approach using a 10-mm diameter snare-loop catheter (Amplatz). The procedure was performed under fluoroscopy; the fragment was removed after being released into the right ventricle by pulling the proximal tip with a pigtail catheter. No complications were observed and the patient was transported back to the intensive unit in stable condition. CONCLUSION: Central catheter-related complications may cause difficulties in patients with short bowel syndrome prior to intestinal transplantation. The percutaneous retrieval of the fragmented catheter using a snare-loop catheter is a safe and reliable technique and may be used instead of surgery especially in small infants.

Efficacy and safety of long-term thiopurine maintenance treatment for ulcerative colitis in Turkey: A single-center experience.

BACKGROUND/AIMS: Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC). MATERIALS AND METHODS: Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus. RESULTS: Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush. CONCLUSION: Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.

Post-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey.

BACKGROUND/AIMS: A liver transplant is the preferred treatment for patients with end-stage liver disease, as it usually results in longterm survival. However, due to the use of chronic immunosuppressive therapy, which is necessary to prevent rejection, de novo cancer is a major risk after transplantation. The aim of this study was to assess the incidence of post-transplant malignancies in children after liver transplantations. MATERIALS AND METHODS: The study group consisted of 206 liver transplant recipients, with no history of cancer, including hepatocellular carcinoma, in two liver transplantation centers in Turkey between 1997 and 2015. Data were obtained from patient's data chart. RESULTS: In the study group, de novo cancer was diagnosed in 13 of the 206 patients. Post-transplant lymphoproliferative disease (PTLD) occurred in seven (53.8%) patients and other malignancies in six of the 13 patients. The types of PTLD were as follows: B-cell origin (n=2), Epstein-Barr virus (EBV)-related (n=2), T-cell origin (n=1), and Hodgkin's lymphoma (n=2). EBV DNA was isolated from seven patients, three of whom developed PTLD. The others developed Kaposi's sarcomas, Burkitt's lymphomas, cutaneous large-cell lymphomas, Hodgkin's lymphomas, and liver sarcomas. CONCLUSION: After transplantation, immunosuppressive treatment is unavoidable, increasing the risk of malignancies. However, a close follow-up and periodic screening can reduce cancer-related mortality and morbidity.

Results of 1001 liver transplantations in 23 years: Ege University experience.

BACKGROUND/AIMS: Liver transplantation (LT) is now the standard of care for most end-stage liver diseases. Over the next 30 years, advances in medicine and technology will greatly improve the survival rates of patients after this procedure. The aim of the present study was to analyze retrospectively the results of 1001 patients withLT. MATERIALS AND METHODS: Medical reports of 989 patients were analyzed retrospectively. Data were obtained from the patient's data chart. Descriptive statistics were used to describe continuous variables (mean, median, and standard deviation). RESULTS: A total of 1001 LTs for 989 recipients were performed at Ege University Organ Transplantation and Research Center between 1994 and 2017. Therewere 639 male and 350 female recipients. Among 1001 LTs, there were 438 deceased donors and 563 living donors. The age interval of the patients was 4 months to 71 years old. The median Model for End-Stage Liver Disease score was 20. There were 12 deceased liver donors using the split method. There were 12 cases subject to retransplantation. In living donor LT grafts, 423 right lobes, 46 left lobes, and 94 left lateral sectors were used. In the first monitoring,the total annual mortality rate was 130 cases (13%). The mortality rate in retransplantation was found to be 66%. A 1-year survival rate of 87% was generally stablished. CONCLUSION: LThas been improving consistently over the last two decades. Ege University is one of the biggest liver transplant centers in Turkey for both technical and educational perspective.

The influence of marginal zinc deficient diet on post-vaccination immune response against hepatitis B in rats.

AIM: To evaluate in vitro T lymphocyte proliferation and specific antibody response to hepatitis B vaccination in two groups of rats fed with normal and marginal zinc content. METHODS: Twenty-two Wistar-Albino rats were randomly assigned into two groups and were fed with constant diet. Zinc was suplemented 10mg/kg dry weight in group I (marginal zinc content) (n=14) and 30mg/kg dry weight in group II (n=8). Hepatitis B vaccine (Engerix B, 4mug) was administered intramuscularly after 8 weeks on feeding and a booster dose was applied 4 weeks after the first injection. Rats were killed 3 weeks after the second injection. Peripheral blood mononuclear cells were stimulated in vitro by PHA (2.5mug/ml) and hepatitis B surface antigen (2.5, 5, 10mug/ml). Proliferation was evaluated by ELISA (celltiter-96 aqueous one solution cell proliferation assay). Serum zinc, anti-HBs titer and zinc per dry liver weight were also measured. Two groups were compared with respect to antigen specific antibody and lymphocyte proliferation responses. Proliferation response to HbsAg were expressed as net percent increase (pci) in lymphocyte proliferation from the baseline activity. RESULTS: Rats' mean body weight and weight gain per month were similar. Median serum zinc was 39 (23-75) and 76(64-115)mug/dl of groups I and II rats, respectively (p<0.05), while there was no difference in liver zinc content between the two groups (37mug/g dry weight versus 32mug/g dry weight). Median anti-HBs levels of groups I and II were 741 (0-10,000)IU/l, 5791 (558-10,000)IU/l, respectively (p<0.05). In lymphocyte proliferation assays, mean net pci with HbsAg of 5 and 10mug/ml were 9.4% and 11.3% in group I rats; while they were 25.3% and 26.1% in group II rats (p<0.01 and p<0.01, respectively). CONCLUSION: In vitro cell-mediated immune response and in vivo specific antibody response to hepatitis B vaccine was decreased in rats fed a diet with marginal zinc content. These observations have shown that marginal Zn deficiency might influence the efficacy of hepatitis B vaccination in humans.

Autoimmune hepatitis and long-term disease course in children in Turkey, a single-center experience.

INTRODUCTION: The aim of this study is to determine clinic and laboratory features, treatment protocols, treatment responses, and long term follow-up of children with autoimmune hepatitis (AIH) in a region of Turkey followed at Ege University. MATERIALS AND METHODS: The records of 47 children with AIH between 1998 and 2012 were retrospectively analyzed for clinical profiles, treatment response, relapse rate, and long-term side effects. RESULTS: The median age of the children was 10±4.1 years (55.3% females). A total of 29 patients presented with chronic hepatitis (61.7%). According to the autoantibody profiles, 40 (85.1%) and seven (14.9%) cases were classified as type 1 and type 2, respectively. Presentation with acute hepatitis and chronic hepatitis was significantly higher in type 1 disease. Laboratory findings at presentation was found similar among races as well as AIH types (P>0.05). The prednisolone was used for remission induction in 37 patients; 86.4% (n: 32) achieved a complete response, 2.7% (n: 1) achieved a partial response, and four patients (10.8%) showed no response. Maintenance was attained by low-dose steroid plus thiopurine and relapse in steroid responders (n: 32) was 9.4% (n: 3) at 8, 12, and 48 months. A total of 36% (n: 24) had neither acute nor chronic treatment side effects. Bone marrow suppression was observed in five patients and hyperglycemia was observed in one patient (10.6 and 2.1%), respectively. CONCLUSION: AIH type 1 prevails in children in a region of Turkey during the second decade of life. Low-dose corticosteroids combined with azathioprine are found.

Validity and reliability study of the pediatric Rome III questionnaire for Turkish children and adolescents.

BACKGROUND/AIMS: Questionnaire on Pediatric Gastrointestinal Symptoms: Rome III version (QPGS-RIII), originally developed in English, was adapted to different languages in order to widen its use. The aim of this study was to evaluate the validity and reliability of a questionnaire on the Pediatric QPGS-RIII parent-report form for children and self-report form for children and adolescents, which has been adapted into Turkish. MATERIALS AND METHODS: The study group comprised 7-18-year-old children/adolescents (n=690) who presented to Ege University School of Medicine, Department of Child Health and Diseases outpatient clinic. In the study, the validity and reliability of the QPGS-RIII Turkish version of the questionnaire was established. RESULTS: Confirmatory factor analysis (CFA) resulted in a 10-factor model satisfactory construct for the validity and in acceptable indices of goodness of fit. Standardized coefficients determined with CFA in the Turkish version of the instrument ranged between 0.15 and 0.87 in the 7-9-year-old children and between 0.13 and 0.98 in the 10-18-year-old children/adolescents. t-values of all the factor loadings were significant. In addition, the test-retest analyses were above 0.70, except for the abdominal migraine factor. CONCLUSION: Findings relating to the validity and reliability of the study indicated that the Turkish version of the instrument could be adequately used to assess functional gastrointestinal disorders (FGIDs) in Turkish children and adolescents. The Turkish version of the instrument is therefore recommended to be used in epidemiologic studies and in clinical trials to be conducted in a Turkish-speaking population.

Trigonocephaly and Wilson's disease in two siblings.

Trigonocephaly and Wilson's disease (WD) are two different entities. The former is a type of craniosynostosis that occurs because of fusion of the metopic suture and the latter, also called hepatolenticular degeneration, is caused by an accumulation of copper in tissues all over the body because of failure of copper excretion. No single gene has been identified for trigonocephaly whereas the ATP7B gene has been shown to be responsible for Wilson's disease. Here we present two siblings born to nonconsanguineous parents who both presented with trigonocephaly, Wilson's disease and facial dysmorphism. In addition, the female has renal agenesis and the male has a history of undescended testis. Karyotypes were normal and no mutation of the ATP7B gene has been identified in the patients or their parents.

Effect of long-term lamivudine in chronic hepatitis B virus-infected children.

OBJECTIVE: To evaluate, retrospectively, biochemical, serological and histological responses in chronic hepatitis B (CHB)-infected children who received combination therapy and continued with prolonged treatment with lamivudine (3TC). PATIENTS AND METHODS: CHB infection was defined as the presence of hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA in serum screened at 3-month intervals for at least 1 year, serum alanine aminotransferase (ALT) levels >1.5 times the normal limit and CHB with histological activity index (HAI) >5 by liver biopsy. A total of 99 children with CHB infection were treated with IFN-alpha (three times a week, 5 MU/m2) and 3TC (4 mg/kg/d) orally for 6 months. End of therapy response (CR) was defined as ALT normalization, HBV-DNA clearance and e seroconversion. Partial responders (PR) were defined as patients who had ALT normalization and HBV-DNA clearance, but who had not had e seroconversion. Forty-five children with PR at the end of the sixth month continued to receive 3TC alone thereafter. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. The response rate, side effects and the breakthrough infection rate were examined on prolonged 3TC treatment. Liver biopsy was held in 29 patients at median 32 (14-66) months of 3TC; pre- and post-treatment liver histology was compared. RESULTS: Pre- and post-treatment evaluation was carried out in 45 children [mean age: 11+/-4.2 years, 31 males (69%), 14 females (31%)] with PR at the end of the sixth month of combination therapy. The initial mean ALT values and HAI scores were 75.6+/-60 IU/l and 8+/-3.3, respectively. 3TC was continued for median 33 (14-66) months and CR was achieved in 15.6% (7/45) and 5.6% (2/36) at the end of first and second year, and 0% (none) at the end of third and fourth year, respectively. Breakthrough incidence was detected in six (13.3%) cases at 12 months and increased to 69.4% (n=25) and 82.4% (n=14) at the end of the second and third years, respectively. Patients with breakthrough continued to receive 3TC. Seroconversion and CR of the mutant virus was achieved in one patient (2.9%) at month 46 of treatment with 3TC. Liver biopsy was held in 29 cases at median 32 (14-66) months of 3TC. Pre- and post-treatment mean HAI scores were 8+/-3.3 and 3.9+/-2.1, respectively (P=0.000). Mean necrosing scores were not different at the beginning and end of therapy (P=1.0). Inflammation, bridging and fibrosis scores decreased to 0.8+/-0.6, 1.3+/-1.2 and 0.6+/-0.8, respectively (P=0.000, P=0.002, P=0.000). CONCLUSION: The long-term 3TC usage in children with PR does not induce complete response and is associated with high breakthrough incidence. However, histological improvement is achieved and/or sustained even in children with HBV DNA breakthrough.

Comparison of antiviral effect of lamivudine with interferon-alpha2a versus -alpha2b in children with chronic hepatitis B infection.

AIM: To compare additive efficacy of combination therapy including interferon (IFN)-alpha2a+lamivudine (3TC) to IFN-alpha2b+3TC in children with chronic hepatitis B virus (HBV) infection. MATERIAL AND METHODS: Chronic hepatitis B infection was determined by presence of HBsAg, HBeAg and HBV DNA in serum screened at 3 months intervals for at least 1 year, serum alanine transaminase (ALT) levels more than 1.5-times the upper normal limit and chronic hepatitis with histological activity index (HAI) more than 6 by liver biopsy. Sixty-three children with chronic hepatitis B infection were treated randomly with thrice-weekly subcutaneous injections of 5 MU/m2 recombinant IFN-alpha2a (n=29) or recombinant IFN-alpha2b (n=34) with the same dose, intervals for 6 months. Patients also received 3TC (4 mg/kg/day, max 100 mg/day) orally daily combined with IFN and continued for 12 months. End of therapy response was defined as ALT normalization, HBV DNA clearance and HBe/anti-HBe seroconversion. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. Response rate, incidence of side effects and breakthrough infection were compared between IFN-alpha2a+3TC- and IFN-alpha2b+3TC-treated patients. RESULTS: Response rate was 44.8% (n=13) with IFN-alpha2a+3TC and 47.1% (n=16) with IFN-alpha2b+3TC (P=1.0). No significant difference was found in respect to the DNA clearance (P=0.32), anti-HBe (P=1.0), anti-HBs (P=0.09) seroconversion and response rates (P=1.0) between the groups. Breakthrough infection was detected in 1 (3.4%) case on IFN-alpha2a and none of the cases on IFN-alpha2b (P=0.46). All of the patients experienced flu-like symptoms, malaise and fatigue; however, side effect interfering with therapy was not encountered. CONCLUSION: No significant difference was found in response rates achieved by combination therapies based on IFN-alpha2a and IFN-alpha2b. Clinical efficacy of 3TC and two different IFN subtypes was found similar.

Therapeutic vaccination in the immunotolerant phase of children with chronic hepatitis B infection.

AIM: Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. Our aim was to investigate the efficacy of specific HBV vaccination as active immunotherapy in treating chronic hepatitis B (CHB) infection during the immunotolerant phase of children with normal aminotransferase values and high viral load. MATERIALS AND METHODS: Seventy-four patients never vaccinated before were randomly and prospectively recruited into two groups. Group 1 included 43 patients vaccinated with three standard injections of the GenHevac B vaccine at 30-day intervals. Group 2 contained 31 patients who did not receive any medication or vaccination (control group). Postvaccination serologic and virologic evaluation was performed 6 months after the first injection and at the end of the 12th month. Response to therapy was defined as loss of HBV DNA in serum and hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg), development of hepatitis B e antibody (anti-HBe). RESULTS: The mean baseline alanine aminotransferase (ALT) value in Group 1 was 33.0 +/- 9.6 IU/l, 34.6 +/- 13.9 IU/l at 6 months after first injection and 34.3 +/- 17.1 IU/l at end of 12 months (P > 0.05). In Group 1 the HBV DNA load at the start of immunization was 3571 +/- 1292 pg/ml; this value was 3220 +/- 1217 pg/ml at the 6th month and 2931 +/- 1292 pg/ml at the 12th month (P > 0.05). In Group 2 the mean ALT values at the beginning of therapy and at the 6th and 12th months were 32.6 +/- 7.8, 32.3 +/- 8.0 and 30.3 +/- 7.3 IU/l, respectively (P > 0.05), and the mean viral load HBV DNA values were 3909 +/- 1378, 3546 +/- 869 and 3106 +/- 718 pg/ml, respectively (P > 0.05). There was no statistically significant difference between Group 1 and Group 2 at the end of the 6th and 12th months in the mean ALT values and mean viral load of HBV DNA (P > 0.05). Except for one patient in each group, hepatitis B surface antigen and HBeAg clearance or hepatitis B surface antibody and anti-HBe seroconversion were not observed during follow-up (P > 0.05). CONCLUSION: In this multicentered study comparison of vaccinated and unvaccinated groups of immunotolerant children with CHB infection showed no difference in the clearance of HBV DNA or seroconversion from HBeAg to anti-HBe. Different immunization protocols should be considered for future investigations in the immunotolerant phase of children with CHB infection.