Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Case report: The spectrum of SMPD1 pathogenic variants in Hungary.

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Acid sphingomyelinase deficiency is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated SMPD1 variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine SMPD1 variants are present in this cohort, including 3 SMPD1 variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.

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.

Disease Activity Is Associated with Obesity in Newly Diagnosed Pediatric Patients with Ulcerative Colitis.

Malnutrition and inflammatory bowel disease (IBD) are interrelated conditions. Our aim was to assess the prevalence of malnutrition, to compare anthropometric parameters in the evaluation of nutritional status in pediatric IBD, and to investigate the association between anthropometric parameters and disease activity indices (AI). Pediatric patients with newly diagnosed IBD recorded between 2010 and 2016 in the Hungarian Pediatric IBD Registry were included in this cross-sectional study. Body weight, body mass index (BMI), weight-for-height, and ideal body weight percent (IBW%) were analyzed. Pearson linear and non-linear correlations and polynomial regression analyses were performed to assess correlation between nutritional status and AI. p-values < 0.05 were considered significant. Anthropometric data of 1027 children with IBD (Crohn's disease (CD): 699; ulcerative colitis (UC): 328; mean age 13.7 years) were analyzed. IBW% identified more obese patients than BMI both in CD (7.02% vs. 2.28%) and UC (12.17% vs. 5.48%). Significant negative correlation was found among anthropometric parameters and AI in CD. In contrast, polynomial regression analysis revealed a U-shaped correlation curve between IBW% and AI in UC. Our findings show that obesity has a bimodal association with disease activity in pediatric UC. Furthermore, IBW% was more useful to identify obese pediatric patients with IBD.

The Covert Surge: Murine Bile Acid Levels Are Associated With Pruritus in Pediatric Autoimmune Sclerosing Cholangitis.

Objectives: The exact etiology of pruritus in chronic cholestasis is unknown. Pruritus intensity does not correlate with common biochemical indices and there is a lack of biomarkers guiding diagnosis and treatment. We explored profiles of bile acids (BA) and muricholic acids (MCA) as well as autotaxin (ATX) antigen levels as potential circulating biomarkers of pruritus in pediatric patients. Methods: In 27 pediatric cholestatic patients [autoimmune sclerosing cholangitis (ASC) n = 20 (with pruritus n = 6, without pruritus n = 14); progressive familial intrahepatic cholestasis (PFIC) n = 7 (with pruritus n = 5, without pruritus n = 2)] and 23 age-matched controls pruritus was assessed by a visual analog scale of pruritus (PVAS). We obtained profiles of serum human BA including MCA using a mass-spectrometry assay and ATX antigen levels with a commercial ELISA. Results: PFIC and ASC patients exhibited significantly higher BA-, and MCA levels, than healthy controls, but only PFIC patients showed elevated ATX antigen levels higher [median: 1,650 ng/ml, interquartile rang (IQR): 776.9-3,742] compared to controls (median: 315.9 ng/ml, IQR: 251.1-417.2; PFIC p = 0.0003). ASC patients with pruritus showed only a minor increase in total BA (tBA) levels (median: 76.5 µmol/L, IQR: 54.7-205), but strikingly higher T-conjugated BA (median: 16.4 µmol/L, IQR: 8.9-41.4) and total MCA (tMCA) (median: 1.15 µmol/L, IQR: 0.77-2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 µmol/L, IQR: 16.2-80.8; p < 0.0408; T-conjugated BA median: 1.3 µmol/L, IQR: 0.8-4.9; p = 0.0023; tMCA median: 0.30 µmol/L, IQR: 0.13-0.64, p = 0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. Different from PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8-1,203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2-485.6). In ASC patients, tBA, tMCA, and ATX antigen levels did not correlate with pruritus severity. Conclusion: Despite the same underlying disease, pediatric ASC patients with pruritus exhibit significantly altered BA profiles and MCA levels compared to ASC patients without pruritus. ATX antigen levels seem to have little diagnostic or prognostic meaning in ASC patients. An increased ATX activity alone seems not to be causal for pruritus genesis in ASC patients. Clinical Trial Registration: [www.drks.de], identifier [DRKS00026913].

Incidence, Impact and Treatment of Ongoing CMV Infection in Patients with Biliary Atresia in Four European Centres.

Cytomegalovirus (CMV) infection has been suggested to be of importance for the development and outcome of biliary atresia (BA). However, most data are only available from single centre studies. We retrospectively collected data on rates, outcomes, and treatments for ongoing CMV infection at the time of Kasai portoenterostomy (KPE) from four different tertiary centres in Europe. The rate of ongoing CMV infection varied between 10-32% in the four centres. CMV positive patients were significantly older and had higher levels of several liver biochemistries at the time of KPE (p < 0.05 for all comparisons). In the largest centre, CMV infection was more common in non-Caucasians, and CMV infected patients had poorer long-term survival with native liver than CMV negative patients (p = 0.0001). In contrast, survival with native liver in the subgroup of CMV infected patients who had received antiviral treatment was similar to the CMV negative group. We conclude that ongoing CMV infection at the time of KPE occurs in a significant proportion of BA patients and that these patients seem to differ from CMV negative patients regarding age and biochemistry at the time of KPE as well as long-term survival with native liver. The latter difference may be reduced by antiviral treatment, but randomized, controlled trials are needed before such treatment can be recommended routinely.

Evolution of liver transplant waiting list in Hungary between 1995 and 2019. / Májvárólista 1995-2019: a hazai adatok nemzetközi összehasonlítása.

Összefoglaló. Bevezetés: A májtranszplantációs program részeként 1995 óta létezik folyamatosan vezetett várólista Magyarországon. Célkituzés: A legfontosabb várólista-paraméterek megállapítása és nemzetközi összehasonlítása. Módszer: A szerzok az 1995. január 1. és 2019. december 31. között elso májátültetés céljából várólistára helyezett betegek adatait elemezték. Eredmények: Összesen 1722 beteget helyeztek várólistára, 1608 felnottet, 114 gyermeket. A férfiak aránya 51,2%, az átlagéletkor 45,6 év. Az évente regisztrált új jelöltek száma 25 év során közel az ötszörösére emelkedett. A listára helyezés leggyakoribb indikációja a víruseredetu cirrhosis volt (n = 451). Ezt követte a cholestaticus (n = 314) és az alkoholos májbetegség (n = 264). Rosszindulatú daganat, 82%-ban hepatocellularis carcinoma miatt 215 beteget regisztráltak. Krónikus betegségekben az átlagos Model for End-Stage Liver Disease pontszám a regisztráláskor 13,5 volt. A 2018. december 31-ig listára helyezettek (n = 1618) 61%-a részesült májátültetésben, 24%-a várakozás közben meghalt, 7%-a a mutétre alkalmatlanná vált. A mutét elotti medián várakozási ido 248 nap volt a krónikus és 2 nap az akut betegek listáján. A transzplantált tumoros betegek (n = 132) szignifikánsan rövidebb ideig vártak mutétre (medián 115,5 nap), mint a többi krónikus beteg (n = 803, medián 282 nap). Az Eurotransplanthoz való csatlakozás utáni idoszakban (2013. július 1. és 2018. december 31. között) a transzplantációs arány növekedett (67%), a várólista-halálozás (meghaltak + mutétre alkalmatlanná váltak) 24%-ra csökkent. Megbeszélés: A várólista folyamatos bovülése hozzájárult a hazai májátültetési program fejlodéséhez. A hazai várólista diagnózis szerinti összetétele a mások által közöltekkel nagyrészt egyezik. A transzplantáltak aránya a nemzetközi átlagnak megfelelo. A várólista-halálozás és a mutét elotti várakozási ido a magyarországinál alacsonyabb donációs aktivitású vagy jelentosen nagyobb várólistával rendelkezo országokéhoz hasonló. Következtetés: Várólista-paramétereink javításához a transzplantációk számának további növelése szükséges. Orv Hetil. 2022; 163(8): 301-311. INTRODUCTION: The Hungarian liver transplant program including waiting list started in 1995. OBJECTIVE: Evaluation of the wait-list parameters and comparing them with those in the literature. METHOD: Data of patients listed for primary liver transplantation between 1995 and 2019 were analyzed. RESULTS: A total of 1722 recipient candidates were registered on the liver transplant waiting list: 1608 adults (51.2% men) with mean age of 45.6 year and 114 patients aged <18 year. Virus-induced cirrhosis was the leading indication of listing (n = 451) and cholestatic liver diseases (n = 314) and alcoholic cirrhosis (n = 264) thereafter. The mean Model for End-Stage Liver Disease score was 13.5 for those with chronic disease. 61% of 1618 patients listed before December 31, 2018 underwent liver transplantation and 31% were removed from the wait-list for death or clinical deterioration. After joining Eurotransplant (period of 01. 07. 2013-31. 12. 2018), the transplant rate was 67%, the waiting list removal due to death/too sick for operation decreased to 24%. The median waiting time till transplantation was 248 days for those on elective and 2 days on acute list. Patients grafted with malignancy (n = 132) waited significantly shorter time than those with chronic non-malignant liver disease (median 115.5 versus 282 days). DISCUSSION: The composition of our waiting list by primary liver disease was similar to that of countries with large burden of hepatitis C. Transplant rate was average, wait-list mortality and waiting time were in line with those observed in low-donation countries or in the case of large volume waiting list. CONCLUSION: Listing of increasing the number of patients contributed to evolution of our liver transplant program. To improve our parameters, increasing transplant activity is warranted. Orv Hetil. 2022; 163(8): 301-311.

Arthrogryposis­renal dysfunction­cholestasis syndrome / Arthrogryposis-renalis diszfunkció-cholestasis szindróma.

Összefoglaló. Az arthrogryposis-renalis diszfunkció-cholestasis (ARC) szindróma igen rossz prognózisú autoszomális recesszív kórkép. A három vezeto tünethez társulhat központi idegrendszeri érintettség, siketség, cardiovascularis anomália (pitvari és kamrai sövényhiány), thrombocytafunkció-zavar, rekurrens szepszisek, ichthyosis, valamint súlyfejlodésben való elmaradás. A háromnapos újszülöttet neuromuscularis betegség gyanúja miatt vettük át a szülészeti intézménybol. Fizikális vizsgálat során pes equinovarust és hypotrophiás küllemet tapasztaltunk. Kéthetes korában súlyos tubulopathia, valamint cholestasis igazolódott normális gamma-glutamil-transzferáz-szint mellett. A perifériás vérkenet vizsgálata során abnormális morfológiájú thrombocyták ábrázolódtak. Súlygyarapodást komplex felépített enteralis és parenteralis táplálás segítségével sem sikerült elérni. Három hónapos korára a gyermek súlya 15%-kal a születési súlya alatt volt. A kórkép szövodményeként ismétlodo bakteriális véráramfertozés súlyosbította az állapotát. Az újszülött klinikai képe az ARC-szindrómának felelt meg. A kóroki gének szekvenálása során a VPS33B-génben homozigóta c.498+1G>T variáns igazolódott, mely igazolja a betegség fennállását. Orv Hetil. 2022; 163(2): 74-78. Summary. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive multisystem disorder that typically presents with arthrogryposis, renal tubular leak and neonatal cholestatic jaundice. It can be accompanied by nervous system abnormalities, deafness, structural cardiac defects, abnormal platelet morphology, recurrent sepsis, ichthyosis and failure to thrive. The three-day-old neonate was admitted for a suspected neuromuscular disorder. On examination, clubfoot, jaundice and hypotonia were found. Laboratory evaluation revealed tubulopathy and cholestasis with normal gamma-glutamyl transferase level. Peripheral blood smear evaluation revealed abnormally giant platelets. Despite the combined enteral and parenteral nutrition, the infant experienced severe failure to thrive. The phenotype of the presented neonate is consistent with ARC syndrome. Sequencing of the causal genes revealed a homozygous consensus splice site VPS33B mutation (c.498+1G>T), confirming the clinical diagnosis. Orv Hetil. 2022; 163(2): 74-78.

Importance of donor-specific antibodies in the long-term outcome of liver-transplanted children / A donorspecifikus antitestek szerepének vizsgálata a gyermekkori májtranszplantációk hosszú távú kimenetelében.

Összefoglaló. Bevezetés: A gyermekkori májtranszplantációk hosszú távú kimenetelének javítása érdekében az immunológiai mechanizmusok kerültek a kutatások középpontjába. A donorspecifikus antitesteknek (DSA-k) fontos szerepük van a graft túlélésében a szervtranszplantációk után, a májtranszplantáció esetén azonban ez még vitatott. Célkituzés: Tanulmányunk célja májtranszplantált gyermekeknél a DSA-k meghatározása, valamint a DSA-k jelenléte és a graft állapota közötti összefüggés vizsgálata volt. Módszer: A Semmelweis Egyetem I. Sz. Gyermekgyógyászati Klinikáján gondozott 54 májtranszplantált gyermek vérmintájából történt a humán leukocytaantigén (HLA) elleni antitestek meghatározása. Vizsgáltuk, hogy a laboratóriumi vérvizsgálat eredményei - szérumbilirubin (összes, direkt), alkalikus foszfatáz (ALP), transzaminázok, gamma-glutamil-transzferáz (GGT), immunglobulin-G (IgG) -, az aszpartát-aminotranszferáz/thrombocyta hányadosindex (APRI) és a 4 tényezon alapuló fibrosisindex (FIB4) tekintetében van-e eltérés a DSA-pozitív, illetve a HLA-immunizált betegek esetén a nem immunizált csoporthoz képest. Eredmények: A vizsgált paraméterekben nem találtunk szignifikáns különbségeket a DSA-pozitív, a HLA-immunizált és a nem immunizált betegek csoportjai között. Következtetés: Bár a jelen vizsgálatban nem volt szignifikáns különbség a vizsgált paraméterek esetén, de ez a kis esetszámból is adódhat. A DSA-knak a graftfibrosis kialakulásában való szerepe tisztázására több páciens vizsgálata szükséges, ezért megkezdtük az összes páciensnél a DSA- és HLA- (donor, recipiens) meghatározást, valamint ennek a klinikai gyakorlatunkba való beépítését. Orv Hetil. 2021; 162(47): 1897-1901. INTRODUCTION: To improve the long-term survival of liver-transplanted children, immunological mechanisms became the main interest of researchers. Donor-specific antibodies (DSAs) play a significant role in graft survival after solid organ transplantation, although their role in liver transplantation is controversial. OBJECTIVE: The aim of our study was to determine the presence of DSAs in liver-transplanted children and to examine their effect on graft's condition. METHOD: The determination of anti-human leukocyte antigen (HLA) antibodies was performed using the blood samples of 54 liver-transplanted children. We analysed the difference between the results of the laboratory blood examination - serum bilirubin (all, direct), alkaline-phosphatase (ALP), transaminases, gamma-glutamyl transferase (GGT), immunoglobulin-G (IgG) -, aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB4) according to DSA and HLA immunization. RESULTS: We did not find any significant difference in the examined parameters regarding DSA and HLA immunization. CONCLUSION: Although this study was not able to provide significant difference in the examined parameters, this can be explained with the low number of cases. To clarify the significance of DSA in graft fibrosis, we need a larger dataset. We started regular DSA and HLA (donor and recipient) determination during follow-up in liver-transplanted children. Orv Hetil. 2021; 162(47): 1897-1901.

Adherence to the Porto Criteria Based on the Hungarian Nationwide Pediatric Inflammatory Bowel Disease Registry (HUPIR).

Objectives: According to the Porto criteria, upper endoscopy and ileocolonoscopy with histology for patients with pediatric inflammatory bowel disease (pIBD) are recommended with small bowel imaging (SBI). We aimed to evaluate the adherence to the Porto criteria and biopsy sampling practice and to evaluate the diagnostic yield of magnetic resonance enterography (MRE) first time in a nationwide pIBD inception cohort. Methods: Newly diagnosed pIBD cases (ages 0-18 years) are registered in the prospective, nationwide Hungarian Paediatric IBD Registry (HUPIR). We analyzed the diagnostic workup of patients recorded between the 1st of January 2007 and the 31st of December 2016. Results: Data for diagnostic workup was available in 1,523 cases. Forty percent of the cases had complied with the Porto criteria. Adherence to the Porto criteria increased significantly from 20 to 57% (p < 0.0001) between 2007 and 2016. The most frequent reason for the incomplete diagnostic work-up was the lack of small bowel imaging (59%). In 2007, 8% of cases had a biopsy from all segments, and this rate reached 51% by 2016 (p < 0.0001). We analyzed the diagnostic yield of MRE in 113 patients (10.1%), who did not have any characteristic lesion for Crohn's disease. The MRE was positive for the small bowel in 44 cases (39%). Conclusions: Adherence to the Porto criteria increased significantly during the 10-year period. This is the first study that reports multiple biopsy sampling as the less accepted recommendation. The diagnostic yield of MRE in patients without characteristic lesion for Crohn's disease is 39%.

De novo inflammatory bowel disease in children after solid organ transplantation / Szolidszerv-transzplantáció után kialakuló de novo gyulladásos bélbetegség gyermekkorban.

Összefoglaló. A gyulladásos bélbetegség (inflammatory bowel disease, IBD) incidenciája folyamatosan no, etiológiája egyelore ismeretlen. Kezelésében gyakran alkalmazunk immunszuppresszív, illetve immunmoduláns szereket. Egyes esetekben azonban szolidszerv-transzplantációt követoen, folyamatos immunszuppresszív kezelés mellett is megfigyelheto de novo IBD kialakulása. Célunk az volt, hogy Klinikánk beteganyagából összesítsük azon eseteket, amelyekben szolid szerv (máj, vese, tüdo) transzplantációját követoen de novo IBD alakult ki. A transzplantációt megelozoen szklerotizáló cholangitis miatt gondozott betegeket kizártuk. A Klinikánkon gondozott, szolid szerv transzplantációján (179 máj, 197 vese, 29 tüdo) átesett betegek közül 4 (2 máj- és 2 vesetranszplantált) gyermeknél alakult ki de novo IBD. A transzplantációhoz vezeto alapbetegségek biliaris atresia, polycystás vese és Denys-Drash-szindróma voltak. A transzplantációt követo immunszuppresszív terápia mind a 4 esetben tartalmazott szisztémásszteroid- és takrolimuszkezelést, emellett 3 esetben mikofenolát-mofetil (MMF)-terápiát is. A kivizsgálást indikáló fobb tünetek a haematochesia, hasmenés, fáradékonyság és fogyás voltak. A családi anamnézis 1 esetben volt pozitív. A de novo IBD diagnózisának felállítását követoen mind a 4 betegnél az addigi immunszuppressziós terápia módosításra került. Összességében elmondható, hogy a szolidszerv-transzplantációt követo de novo IBD kialakulása ritka, etiológiája tisztázatlan. Az irodalom felveti az alkalmazott immunszuppresszív szerek (takrolimusz és MMF), illetve infekciók etiológiai szerepét, de az is felmerül, hogy a de novo IBD olyan önálló entitás, mely elkülönül a klasszikus IBD kategóriáitól. Klinikai szempontból fontos a tünetek hátterében álló betegség tisztázása, hiszen a prezentációs tüneteknek megfelelo, a differenciáldiagnosztika során felmerülo egyéb betegségek terápiája meroben eltér. A megfelelo terápia hozzájárulhat a transzplantált betegek morbiditásának és mortalitásának csökkentéséhez. Orv Hetil. 2021; 162(18): 720-726. Summary. The incidence of inflammatory bowel disease (IBD) is increasing, however, the aetiology is still unknown. The therapy consists of immunosuppressants and immunomodulators. In some cases, despite the continuous immunosuppressant therapy, de novo IBD develops. Our aim was to evaluate patients diagnosed with de novo IBD after solid organ (liver, kidney, or lung) transplantation. Patients treated with sclerosing cholangitis prior to liver transplantation were excluded. 4 patients (two kidney and two liver transplants) were diagnosed with de novo IBD. The underlying diseases leading to transplantation were biliary atresia, polycystic kidney, and Denys-Drash syndrome. All patients received systemic steroid and tacrolimus treatment, and 3 patients (2 kidney and 1 liver transplant) also received mycophenolate mofetil (MMF). The main symptoms indicative of de novo IBD were haematochezia, diarrhoea, fatigue, and weight loss. Family history for IBD was positive in 1 case. Following the diagnosis of IBD, immunosuppressive therapy was modified. Overall, the development of de novo IBD following solid organ transplantation is quite rare, and its aetiology is unknown. According to the literature, immunosuppressants (tacrolimus and MMF) and infections play a role in the pathomechanism, but it seems that de novo IBD is a separate entity from the classical IBD categories. From a clinical point of view, it is important to elucidate the underlying disease of the symptoms, as the treatment of other diseases that arise during differential diagnosis according to the presentation symptoms is very different. Appropriate therapy can help reduce morbidity and mortality in transplant patients. Orv Hetil. 2021; 162(18): 720-726.

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.

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.

Similarities and Differences in Allocation Policies for Pediatric Liver Transplantation Across the World.

OBJECTIVES: We aimed to investigate national allocation policies for pediatric liver transplantation (LT). METHOD: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. RESULTS: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. CONCLUSIONS: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

OBJECTIVES: Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children. METHODS: A total of 42 LT recipients (21 men, age 9.93 ±â€Š3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed. RESULTS: Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%. CONCLUSIONS: Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.

[Solid organ transplantation in childhood]. / Szervtranszplantáció gyermekkorban.

Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948-1956.

The Health Care Transition of Youth With Liver Disease Into the Adult Health System: Position Paper From ESPGHAN and EASL.

BACKGROUND: Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system. AIM: The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services. METHODS: Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique. RESULTS: We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients. CONCLUSIONS: Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.