Modified by the Innovative Drugs and Strategies-Pattern of Selected Indications for Pediatric Liver Transplantation.

BACKGROUND: Liver transplantation (LTx) constitutes a major life-saving routine treatment for children with end-stage liver disease. However, the analysis of LTx registries in children provides much information about changes in the indication profiles in the recent years. METHODS: The article provides a comprehensive review about the successes, hopes, and challenges related to changing indications for LTx in children based on the literature review and our own experience. Retrospective review of the indications for LTx at a tertiary referral pediatric hospital was also presented. RESULTS AND CONCLUSIONS: In the context of the new therapies that have emerged, the need for LTx has decreased in patients with chronic hepatitis B and C infection and tyrosinemia type 1. In primary hyperoxaluria type 1, new RNAi-based therapy has eliminated the requirement for LTx (both isolated or combined). There is a hope that introduction of ileal bile acid transporter (IBAT) blockers reduces the need for LTx in patients with Alagille syndrome or progressive familial intrahepatic cholestasis. The number of children qualified for LTx with urea cycle disorders (UCDs) as a prophylaxis of neurodevelopmental impairment is increasing.

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Relationship between Bone Mineral Density and Selected Parameters of Calcium-Phosphate Economy with Dietary Management and Metabolic Control in Polish Pediatric Patients with Classical Homocystinuria-A Preliminary Study.

BACKGROUND: Classical homocystinuria (HCU) is an inborn defect of methionine metabolism caused by a deficiency of the enzyme cystathionine ß-synthase (CBS). The main symptoms of classical homocystinuria are lens subluxation, bone lesions, vascular disease and developmental delay/intellectual disability. The treatment method for HCU is a methionine-poor diet supplemented with amino acid preparations. The aim of the study was to examine the relationship of dietary factors, metabolic compensation and selected skeletal parameters in patients with HCU. METHODS: Bone mineral density measurements (DXA) were performed in pediatric patients with HCU, and blood levels of selected amino acids, minerals and vitamins, as well as dietary nutritional value, were analyzed. RESULTS: A total of 11 patients with HCU whose median age was 9.3 years were enrolled in the study. The median DXA total body less head of HCU patients was -0.4 z-score, and the lumbar spine was -1.4 z-score. Despite supplementation, calcium intake was below the age norm. Average vitamin D3 intake was in line with recommendations, but 36% of patients had reduced blood levels. Bone mineral density depended on blood levels of 25-hydroxyvitamin D, homocysteine and methionine, as well as on BMI, age and intake of natural protein (R2 = 98.5%, p = 0.015; R2 = 86.7%, p = 0.0049) and protein from an amino acid preparation (r = 0.69, p = 0.026). CONCLUSION: The results of the study indicate the need for regular densitometry in patients with HCU and also the use of additional calcium and vitamin D3 supplementation. It is also necessary to perform a comprehensive analysis of the diet and metabolic controls.

DCDC2-Related Ciliopathy: Report of Six Polish Patients, Novel DCDC2 Variant, and Literature Review of Reported Cases.

INTRODUCTION: The increasing usage of NGS technology has enabled the discovery of new causal genes in ciliopathies, including the DCDC2 gene. The aim of our study was to present the clinical, pathological and molecular report of six patients (from three unrelated families) with DCDC2 biallelic pathogenic variants. A detailed overview of the reported patients with DCDC2-related disease was provided. MATERIAL AND METHODS: A retrospective chart review of the clinical, biochemical, pathological (liver histology) and molecular features of the study group was performed. The database PubMed (MEDLINE) was searched for relevant studies. RESULTS: All the patients presented with cholestatic jaundice and elevated GGT; the mean age was 2 months. The initial liver biopsy was performed in four children at a mean age of 3 months (age range: 2-5 months). In all of them, features of cholestasis, portal fibrosis and mild portal inflammation were observed; in three of them ductular proliferation was observed. One patient had undergone liver transplantation (LTx) at 8 years of age. At hepatectomy, a biliary-pattern cirrhosis was observed. Only one patient presented with features of renal disease. Whole exome sequencing was performed in all patients at the last follow-up visit (mean age 10 years). Three different variants (one novel) in the DCDC2 gene were identified in the study group. With our six patients, a total of 34 patients with DCDC2-related hepatic ciliopathy were identified. The main clinical presentation of DCDC2-related ciliopathy was liver disease in the form of neonatal sclerosing cholangitis. The predominance of early and severe liver disease associated with no or mildly expressed kidney involvement was observed. CONCLUSIONS: Our findings expand the molecular spectrum of pathogenic DCDC2 variants, provide a more accurate picture of the phenotypic expression associated with molecular changes in this gene and confirm a loss of functional behaviour as the mechanism of disease.

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.

Case Report: Adenosine kinase deficiency diagnosed 10 years after liver transplantation: Novel phenotypic insights.

Adenosine kinase (ADK) deficiency is a rare inborn error of methionine and adenosine metabolism. So far, a total of 27 patients with ADK deficiency have been reported. Here, we describe the first Polish patient diagnosed with ADK deficiency, aiming to highlight the clinical presentation of disease, emphasize diagnostic difficulties, and report the long-term follow-up. Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine. A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy. The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency. Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine.

Disturbance of lipid homeostasis in lysosomal lipase deficiency ­ pathomechanism, diagnosis and treatment / Zaburzenie homeostazy lipidowej w deficycie lizosomalnej lipazy ­ patomechanizm, diagnostyka i leczenie.

Lysosomal acid lipase (LAL) plays a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes. LAL deficiency is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. In the case of LAL deficiency, cholesteryl esters and triglycerides accumulate within the lysosomes. The up-regulation of endogenous cholesterol production, increased synthesis of apolipoprotein B (ApoB) and increased production of very-low-density lipoprotein cholesterol (VLDL-C) is observed. The diagnosis is easy due to the currently available method of testing the enzyme activity in a dry blood spot. Molecular analysis is necessary to verify the clinical and biochemical diagnosis and to analyze the genotype-phenotype correlation. Sebelipase alfa is a recombinant human lysosomal lipase intended for use in enzyme replacement therapy in patients with LAL deficiency.

Transferrin gene polymorphisms alter the transferrin focusing pattern, making congenital disorder of glycosylation diagnosis difficult.

BACKGROUND: Several transferrin gene polymorphisms are known to result in a shifted IEF pattern. The aim of this study was to characterize the transferrin gene polymorphisms observed in patients from one referral center. MATERIALS AND METHODS: Patients with solely increased pentasialo-Tf were selected. The whole exome sequencing was done from probands (patients) and from DNA available from their parents. RESULTS: Two various polymorphisms in the transferrin gene: c.2012G>A, p.Gly671Glu and c.1027C>T, p.Arg343Trp, were found. CONCLUSIONS: Two transferrin gene polymorphisms: c.2012G>A, p.(Gly671Glu) and c.1027C>T, p.(Arg343Trp) solely correspond to an elevated pentasialo-Tf.

Skeletal and Bone Mineral Density Features, Genetic Profile in Congenital Disorders of Glycosylation: Review.

Congenital disorders of glycosylation (CDGs) are a heterogeneous group of disorders with impaired glycosylation of proteins and lipids. These conditions have multisystemic clinical manifestations, resulting in gradually progressive complications including skeletal involvement and reduced bone mineral density. Contrary to PMM2-CDG, all remaining CDG, including ALG12-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, PGM3-CDG, CSGALNACT1-CDG, SLC35D1-CDG and TMEM-165, are characterized by well-defined skeletal dysplasia. In some of them, prenatal-onset severe skeletal dysplasia is observed associated with early death. Osteoporosis or osteopenia are frequently observed in all CDG types and are more pronounced in adults. Hormonal dysfunction, limited mobility and inadequate diet are common risk factors for reduced bone mineral density. Skeletal involvement in CDGs is underestimated and, thus, should always be carefully investigated and managed to prevent fractures and chronic pain. With the advent of new therapeutic developments for CDGs, the severity of skeletal complications may be reduced. This review focuses on possible mechanisms of skeletal manifestations, risk factors for osteoporosis, and bone markers in reported paediatric and adult CDG patients.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

Congenital disorders of glycosylation in children - Histopathological and ultrastructural changes in the liver.

BACKGROUND: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and their attachment to proteins and lipids. Histologically, liver steatosis, fibrosis and cirrhosis have been reported in CDG. The aim of the study was to characterize the histopathological and ultrastructural liver changes in CDG patients hospitalized in our Institute, and to find the most characteristic features, as articles concerning the liver microscopic features in CDG are sparse. METHODS: Out of 32 CDG patients diagnosed and followed-up in our Institute, the liver biopsy was performed in 4 of them, including 2 with MPI-CDG, 1 with SRD5A3-CDG, and 1 with PGM1-CDG, as a part of diagnostic process. In one patient, diagnosed post mortem with PMM2-CDG, the histopathological study comprised liver autopsy samples. RESULTS: The most common histopathological liver finding was the presence of steatosis (4/5) of varying severity, the mixed macro- and microvesicular type as well as the foamy degeneration of hepatocytes. In two patients, liver steatosis was associated with fibrosis, stage 4 (cirrhosis) and 2 according to Batts and Ludwig classification, respectively. In two patients, besides steatosis, mild inflammatory infiltrates composed of lymphoid cells in portal tracts were observed. No correlation between the patient's age and histopathological features was observed. CONCLUSIONS: The histopathological changes in the liver of CDG patients are miscellaneous; thus, based on the microscopic examination only, we can not identify (even suspect) the exact CDG. The most common histopathologic finding in our cohort of CDG patients was the presence of liver steatosis (of various severity) and foamy degeneration of hepatocytes.

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.

Transferrin isoform analysis from dried blood spots and serum samples by gel isoelectric focusing for screening congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are a growing, heterogeneous group of genetic disorders caused by a defect in the glycoprotein synthesis. The first and still widely used method for routine CDG screening was isoelectric focusing (IEF) of serum transferrin. Dried blood spot (DBS) testing is commonly used in newborn screening procedures to detect inborn errors of metabolism. The aim of this study was to demonstrate the reliability of the IEF method in DBS testing. Dried blood spot testing can help in the postmortem diagnosis of CDG disorders when other material is unavailable. The patterns and concentrations of transferrin isoforms in serum and DBS are comparable, and slight differences do not affect interpretation of results.

Over 20-Year Follow-up of Patients with Hepatic Glycogen Storage Diseases: Single-Center Experience.

BACKGROUND: The published data on the long-term outcomes of glycogen storage disease (GSD) patients is sparse in the literature. The aim of this study was to analyze the long-term (over 20 years) follow-up of patients with hepatic types of GSD-I, III, VI, and IX-from childhood to adulthood, managed by one referral center. PATIENTS AND METHODS: Thirty adult patients with hepatic GSD were included in the study. A retrospective chart review of patients' medical records has been performed. RESULTS: During the long-term follow-up, the most frequent complications observed in a group of 14 GSD I patients were nephropathy with blood hypertension (10/14), hyperuricemia (8/14), and development of hepatocellular adenomas (HCA; 5/14). All individuals but four presented with normal height. Two patients with GSD Ib suffered from inflammatory bowel disease (IBD). Nine (64%) GSD I patients were in balanced metabolic condition at the age of 18. Regarding GSD III/VI/IX, the most frequent complication was short stature observed in 5 out of 16 patients. All patients but one with GSD VI were in balanced metabolic condition at the age of 18. CONCLUSION: The long-term outcomes of patients with GSD depend mainly on proper (adjusted to each type of GSD) dietary management and patient compliance. However, in GSD type I, even proper management does not eliminate all long-term complications in adulthood.

Liver involvement in NGLY1 congenital disorder of deglycosylation.

N-glycanase 1 deficiency is a congenital disorder of deglycosylation, which has been diagnosed in 27 patients, including 2 of them from Poland. The most characteristic symptoms include global developmental disability, hyperkinetic movement disorder, hypo-/alacrimia, and elevated serum transaminases. We reported on a patient in whom the liver biopsy done at the age of 3 years revealed the presence of steatosis, fibrosis, and an amorphous periodic acid-Schiff staining positive diastases-digested material in the cytoplasm.

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.

Sterol 27-Hydroxylase Deficiency as a Cause of Neonatal Cholestasis: Report of 2 Cases and Review of the Literature.

Introduction: Inborn errors of primary bile acid (BA) synthesis are rare autosomal recessive disorders responsible for 1-2% of cases of neonatal cholestasis. Among them, cerebrotendinous xanthomatosis (CTX) is caused by mutations in the CYP27A1 gene resulting in the impairment of sterol 27-hydroxylase enzyme activity. Patients and Methods: Here we present the study on two siblings with neonatal cholestasis diagnosed with sterol 27-hydroxylase deficiency. The clinical, biochemical, histological, and molecular presentation at the time of diagnosis and detailed follow-up were described. An extensive overview of the literature regarding patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis was also provided. Results: Patient 1 presented with cholestatic jaundice since 10 weeks of age and developed the end-stage liver disease requiring liver transplantation at 8 months of age but finally succumbed 3 years post-transplantation due to autoimmune hemolytic anemia and multiorgan failure development. Next-generation sequencing performed post mortem, revealed him to be homozygous for the known pathogenic splicing variant c.1184+1G>A in the CYP27A1 gene. Patient 2 (sibling) presented with cholestatic jaundice since the first day of life. Sanger sequencing of CYP27A1 revealed the same results. Chenodeoxycholic acid treatment was introduced just after diagnosis, at 4 months of age. Fourteen patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis were reported in the literature, in most of them presenting as a self-limiting disease. Conclusions: An early recognition and treatment initiation in CTX is essential.

Controlled attenuation parameter and liver stiffness measurements using transient elastography by FibroScan in Gaucher disease.

BACKGROUND: Liver involvement in Gaucher disease (GD) is a result of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) infiltration of macrophages. The long-term liver-related complications of GD could include liver fibrosis and cirrhosis. The aim of the study was to evaluate clinical utility and relevance of TE by FibroScan in GD patients by assessing two parameters: controlled attenuation parameter (CAP) and liver stiffness (LS), in regard of GD-related variables, type of GD, age of patients, enzymatic replacement therapy (ERT), and metabolic features. METHODS: 59 Polish patients (55 adults, 4 children) with GD (43 patients with type 1 and 16 patients with type 3) aged 7-86 years, underwent TE by FibroScan; elevated CAP was defined as >250 dB/m and elevated LS as >7 kPa. All patients, except five patients with type 1 GD (patients' refusal), were treated by ERT. RESULTS: Elevated CAP was present in 23% of GD1 patients and 19% of GD3 patients. Elevated LS was present in 21% of GD1 patients and 13% of GD3 patients. CAP was fairly, positively (ρ = 0.356) correlated with BMI. LS was fairly, positively (ρ = 0.4) correlated with patient's age, as well as the age at start of ERT (ρ = 0.326). CAP was strongly, negatively (ρ = -0.52) correlated with the age at start of ERT. LS and CAP were correlated (strongly, positively) only in GD3. CONCLUSIONS: TE by FibroScan could be considered as an additional method for evaluating GD patients for non-invasive assessment of CAP and LS. The investigation of serial TE measurements in untreated as well as treated GD patients is needed to better determine whether this technology should be added to recommendations for monitoring GD patients. TE by FibroScan could be performed in GD patients with increased BMI and especially those with metabolic syndrome as they have other important risks for liver disease. After our analysis we think these risks factors are independent of GD but still very important for their overall health.

Long-term follow-up in children with progressive familial intrahepatic cholestasis type 2 after partial external biliary diversion with focus on histopathological features.

Progressive familial intrahepatic cholestasis (PFIC) comprises a group of rare cholestatic liver disorders of childhood that could lead to liver cirrhosis. Nowadays, the partial biliary diversion procedure is still a therapeutic option in non-cirrhotic children with PFIC1 or PFIC2 after an ineffective ursodeoxycholic acid (UDCA) therapy. However, the relevant disadvantage of the partial external biliary diversion (PEBD) is that adolescent patients could not accept a permanent stoma. In some of them, despite of good clinical and biochemical results of this procedure, the ileal exclusion (IE) procedure had to be performed many years after PEBD. Our aims were to find the most characteristic early microscopic features of the disease as well as to compare changes in the liver biopsy specimens at the time of diagnosis and long-time (more than 10 years) after a surgical procedure. We examined retrospectively 8 liver biopsies from 4 PFIC2 patients comparing the results from the first biopsies done at the time of PFIC diagnosis and the second ones, done many years after PEBD. The characteristic lobular rosette formations of hepatocytes were found in all patients at the time of diagnosis. Cholestasis was observed in each patient, but only in two of them, centrally located bile plugs were found. The majority of hepatocytes showed degenerative changes from mild to severe degree. In the follow-up biopsies, cholestasis completely disappeared in 3 patients and decreased significantly in 1 other patient. Based on Batts and Ludwig fibrosis scoring system, the liver fibrosis had resolved in two out of three patients. The formation of lobular rosettes with centrally located bile plugs and degenerative changes of hepatocytes seem to be the most characteristic microscopic features in early liver biopsies in PFIC2 patients. Partial external biliary diversion significantly improved the clinical, anthropological, biochemical as well histological outcome of the patients.