Joanna Pawłowska

Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disorder characterized by episodes of intrahepatic cholestasis with varying durations and spontaneous resolutions. This article presents the use of nasobiliary drainage (NBD) in inducing remission of BRIC in our patients. We also...

The aim of the study was to find associations between the levels of liver injury serum markers and the selected liver, peripheral leukocytes, and plasma immune characteristics in biliary atresia (BA) children. Twenty‐five newly diagnosed BA children aged 4–30 weeks and 12 age‐matched controls were included (for leukocytes characteristics) and 19 BA children and 11 controls (for liver studies). The frequencies of T helper 1 (Th1), Th2, Th17, Th17.1 cells as well as numbers of regulatory T (Treg), B cell subsets, and matrix metalloproteinase −2 and −9 (MMP‐2 and MMP‐9) expressing leukocytes in the whole blood were evaluated by flow cytometry. Plasma concentrations of tissue inhibitors of metalloproteinase (TIMP)−1, −2, MMP‐9, interleukin‐17A (IL‐17A) and IL‐6 were assessed by enzyme‐linked immunosorbent assay (ELISA). The leukocyte and liver expression of the retinoic acid receptor‐related orphan nuclear receptor gamma ( RORγT ), fork‐head winged helix transcription factor P3 ( FoxP3 ), transforming growth factor beta ( TGF-β ), interleukin‐17A ( IL-17A ), IL-6 , IL-1β , IL-21 , interleukin 1 receptor antagonist ( IL-1Ra) , MMP-2 , MMP-9 , MMP-12 (liver only), TIMP-1 , TIMP-2 , T‐box transcription factor expressed in T cells, also called TBX21 ( T-bet ), GATA‐binding protein 3 ( GATA3 ), and C‐type lectin ( CD161 ) mRNA were determined by real time RT‐PCR (reverse‐transcription polymerase chain reaction). The BA patients were characterized by increased frequencies of peripheral “suppressor” glycoprotein‐A repetitions predominant protein (GARP) ⁺ latency‐associated peptide (LAP) ⁺ Treg and activated Treg cells as well as MMP‐2 and MMP‐9 bearing lymphocytes, elevated plasma TIMP‐1 levels, increased leukocyte expression of MMP-9 , TIMP-1 , TIMP-2 , IL-6 , and TGF-β , and decreased leukocyte expression of IL‐21 and T‐bet, increased liver expression of FoxP3 , TIMP-1 , and decreased liver expression of IL-1β and MMP-2 . The following correlations were found between serum markers of liver injury and leukocyte and liver immune characteristics: (a) hemoglobin (Hb) levels correlated negatively with frequency of peripheral “suppressor” GARP ⁺ LAP ⁺ Tregs; (b) aspartate aminotransferase (AST) levels correlated positively with frequency of the peripheral Th17.1 subset and expression of leukocyte FoxP3 , (c) gamma glutamyltransferase (GGT) levels correlated positively with the peripheral memory B cells frequencies, the leukocyte IL-6 and TIMP-1 gene expression, (d) alanine aminotransferase (ALT) serum levels correlated positively with the naïve B cell frequency and liver TIMP-2 expression, (e) total bilirubin (Bil) levels correlated positively with the leukocyte MMP-9 , the plasma IL‐6 levels, and the liver TIMP-2 gene expression, (f) direct Bil levels positively correlated with the liver IL-6 and TIMP-2 expression, (g) international normalized ratio of prothrombin time (PT/INR) concentrations correlated positively with the peripheral Th17.1 subset frequency and the leukocyte MMP-9 but negatively with the liver FoxP3 expression. There were numerous strong positive correlations between the BA liver genes known to be involved in upregulation of IL‐17 axis and MMPs/TIMPs expression. No prevailing leukocyte or liver single markers were uniquely associated with serum liver injury indices. BA immune profile is very complex with no single characteristics that would distinguish it from other liver inflammatory diseases.

Background: Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long‐term experience of the pediatric transplant center.Materials and Methods: Between 1990 and 2022, 104 children aged 7 days–17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period).Results: A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno‐venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow‐up.Conclusions: Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children.

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.

The pathogenesis of biliary atresia (BA) is still not clear. The aim of this study was to evaluate the expression of selected immunological parameters in liver tissue in BA children based on CMV/EBV infection status. Eight of thirty-one children with newly diagnosed BA were included in this prospective study and assigned to two groups (I with active infection, II without active or past infection). All studies were performed on surgical liver biopsies. To visualize CD8+ T cells and CD56 expression, immunohistochemical staining was performed. The viral genetic material in the studied groups was not found, but CMV infection significantly affected the number of CD8+ lymphocytes in both the portal area and the bile ducts. The average number of CD8+ cells per mm² of portal area in Groups I and II was 335 and 200 (p = 0.002). The average number of these cellsthat infiltrated the epithelium of the bile duct per mm² in Group I and II was 0.73 and 0.37 (p = 0.0003), respectively. Expression of CD56 in the bile ducts corresponded to the intensity of the inflammatory infiltrate of CD8+ cells. Our results suggest that active CMV infection induces an increased infiltration of CD8+ lymphocytes, which could play a role in BA immunopathogenesis. Increased CD56 expression can be a sign of a newly formed bile structure often without lumen, suggesting inhibition of the maturation process in BA.

Transaldolase deficiency (TALDO; OMIM 606003) is a rare inborn autosomal-recessive error of the pentose phosphate pathway. It is an early-onset multisystem disease with dysmorphic features, anaemia, coagulopathy, thrombocytopenia, tubulopathy, hepatosplenomegaly and end-stage liver disease. We present a case of two Polish brothers, born to consanguineous parents, with early-onset TALDO. The dominant feature of disease was an early severe liver injury, with subsequent renal tubulopathy. Nodular liver fibrosis developed in the course of the underlying disease. The older brother presented stable liver function, however, he was qualified for deceased donor liver transplantation (DDLT) because of a liver tumour and suspicion of hepatocarcinoma. The boy was transplanted at the age of 14. The younger brother was qualified for DDLT due to end-stage liver disease and transplanted at the age of 11. Currently, both our patients are alive and in a good condition with normal graft function 23 and 20 months after DDLT respectively. Liver transplantation can be a therapeutic option in TALDO and should be considered in patients with coexisting severe chronic and end-stage liver disease. Long term follow-up is necessary to assess the impact of liver transplantation for quality of life, survival time and the course of the disease.

Pawlowska J, et al. Pediatr Gastroenterol Hepatol Nutr. 2021 Mar;24(2):119-126. https://doi.org/10.5223/pghn.2021.24.2.119

Background.: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. Objective.: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver–derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. Methods.: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti–human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. Results.: The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. Conclusions.: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.