Although thrombocytopenia is a frequent complication that develops after liver transplantation, immune thrombocytopenia rarely occurs post-transplant. We present an 8-year-old boy who experienced 2 immune thrombocytopenia episodes that occurred 72 and 93 months after liver transplant while the patient was on tacrolimus therapy. The patient, who had primary diagnosis being deoxyguanosine kinase deficiency, received a liver transplant from his father at 1 year of age. Parents were first-degree relatives. In both episodes, the patient was admitted because of diffuse petechial lesions that developed 7 to 14 days after upper respiratory tract infection. Laboratory findings were unremarkable except for low platelet count (13 × 109/L and 6 × 109/L) and increased immature megakaryocytes in the bone marrow. The first episode responded to a mega-level dose of methylprednisolone; platelet count remained stable at >150 × 109/L until immune thrombocytopenia recurred 21 months later. The second episode was resistant to standard treatment modalities, including steroid, intravenous immunoglobulin G, and rituximab administration but responded to eltrombopag (starting at 25 mg/day and gradually increased to 75 mg/day) as a bridging regimen for partial splenic embolization and as maintenance therapy for 45 days. Platelet count has remained normal and stable over 3 years. In our literature review, we found 9 children who developed immune thrombocytopenia after liver transplant. In our patient, with response to eltrombopag as a bridging regimen for partial splenic embolization and maintenance therapy and primary liver pathology showing deoxyguanosine kinase deficiency, the posttransplant period before diagnosis of immune thrombocytopenia was longer than periods reported in the literature. These factors make our case unique. Our case highlights the need for clinicians to be aware of posttransplant immune thrombocytopenia, which can develop despite ongoing immunosuppressive therapy, and to differentiate this entity from other causes of thrombocytopenia.

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to liver sinusoidal endothelial cells (LSECs) and transendothelial migration (TEM) are crucial in the inflammatory process. Under lipotoxic stress, LSECs develop a proinflammatory phenotype known as endotheliopathy. However, mediators of endotheliopathy remain unclear. Methods: Primary mouse LSECs isolated from C57BL/6J mice fed chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH resulting from a choline-deficient high-fat diet (CDHFD) or FFC diet were also treated with two structurally distinct GSK3 inhibitors (LY2090314 and elraglusib [9-ING-41]). Results: Integrated pathway analysis of the mouse LSEC proteome and transcriptome indicated that leukocyte TEM and focal adhesion were the major pathways altered in MASH. Kinome profiling of the LSEC phosphoproteome identified glycogen synthase kinase (GSK)-3β as the major kinase hub in MASH. GSK3β-activating phosphorylation was increased in primary human LSECs treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependent mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through the LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC- and CDHFD-fed mice, respectively. Immunophenotyping using cytometry by mass cytometry by time of flight of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib showed reduced infiltration of proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells. Conclusion: GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and could serve as a potential therapeutic strategy for treating human MASH. Impact and Implications: LSECs under lipotoxic stress in MASH develop a proinflammatory phenotype known as endotheliopathy, with obscure mediators and functional outcomes. The current study identified GSK3 as the major driver of LSEC endotheliopathy, examined its pathogenic role in myeloid cell-associated liver inflammation, and defined the therapeutic efficacy of pharmacological GSK3 inhibitors in murine MASH. This study provides preclinical data for the future investigation of GSK3 pharmacological inhibitors in human MASH. The results of this study are important to hepatologists, vascular biologists, and investigators studying the mechanisms of inflammatory liver disease and MASH, as well as those interested in drug development.

Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

BACKGROUND:Pediatric acute liver failure (PALF) with undetermined etiology is associated with higher liver transplantation and lower spontaneous recovery (transplant-free) rates. The diagnostic odyssey in PALF cases hinders appropriate management and follow-up after liver transplantation. Advances in whole exome sequencing analysis have already been successful at identifying new genetic causes of PALF. CASE PRESENTATION:We report a 17-year-old girl who underwent liver transplantation at the age of 7 months due to acute liver failure and presented later with abnormal neurological manifestations, that is, gait disturbances, dysarthria, and mental retardation that led us to the diagnosis of SCYL1 deficiency. CONCLUSION:PALF cases should be screened for possible underlying genetic disorders. Genetic studies and reanalysis of whole-genome sequencing data may help identify new cases and clarify the genotype-phenotype correlation. SCYL1 deficiency should be suspected in PALF patients who develop neurological involvement after LT. Early diagnosis is vital for proper management of ALF crises in SCYL1 deficiency patients. Despite the reported favorable outcomes of ALF crises in SCYL1 deficiency, liver transplantation decision should be discussed on a case-by-case basis.

Introduction: Glycogen storage diseases (GSDs) are inherited metabolic disorders result from impaired glycogen storage, glycogen or glucose breakdown. Liver transplantation (LT) is considered as a treatment option for patients with glycogen storage diseases present with hepatic malignancy, liver failure or metabolic decompensation. GSD type Ia is associated with mutations in the G6PC gene due to deficiency of glucose-6-phosphotase, while glycogen storage disease type 9 results from phosphorylase kinase deficiency, an enzyme necessary for glycogen breakdown. Herein, we present our experience and transplantation outcomes in 7 pediatric patients with GSD who underwent LT. Methods: We retrospectively analyzed data from patients diagnosed with GSD who underwent LT between 1993-2021 years. Results: LT was performed in 6 patients with GSD type 1a and one patient with GSD type 9. Four patients had a family history of consanguinity (3 patients 1st degree, 1 patient 2nd degree). Mean age of diagnosis was 7.28 (1-24) months. Mean age of LT was 128.5 (13-216) months. Transplantation indications were hepatic adenoma (4/7), poor metabolic control (4/7) and cirrhosis (1/7). Extra-hepatic findings included proteinuria (4/7), Focal segmental glomerulosclerosis (1/7), proximal tubulopathy (4/7), nephrolithiasis (2/7), hyperlipidemia (7/7), delayed puberty (3/7), hypertension (2/7), short stature (6/7), epilepsy (2/7) and osteoporosis (4/7). One patient with GSD1a underwent cataract surgery. Three patients with GSD1a incidentally had the same G6PC gene mutations (c.247C>T). Three patients had normal cognitive functions and development (WISC-R Test). Two patients had mild where one patient had moderate mental retardation. One patient had %30 developmental delay (AGTE Test). Six patients underwent LT from living-related donors while one patient had cadaveric donor. Patients who underwent LT from live donors received left lateral segment. Explant liver pathology revealed variable numbers (1-12) of hepatic adenoma in 4 patients. Hepatocellular carcinoma (HCC) was detected in one patient. Serum lactate, uric acid and triglyceride levels normalized after LT. Tubulopathy resolved in one patient while epilepsy continued in two patients. Height SD scores were improved in 4 patients while remained unchanged in one patient after 5-year follow up. Acute graft rejection was detected in 4 patients. Mean follow up time was 80 (3-183) months. All patients are still alive and routinely followed up at our department. Conclusion: LT improved the quality of life in our GSD patients with metabolic decompensation and severe disease manifestations. Biochemical parameters (lactate, uric acid and triglyceride levels) normalized after transplantation. Our patients displayed improved height growth. LT should be considered in GSD patients with poor metabolic control despite dietary management, hepatic malignancy or progressive liver failure.

Introduction: Several studies suggest that chronic immunosuppressive treatment in pediatric liver transplant recipients may predispose to increased risk of acquiring SARS-CoV-19 infection, however, the severity of the infection and mortality rates remains unclear due to the lack of sufficient clinical data. Herein, we assessed the severity and clinical features following SARS-CoV-19 infection in our pediatric liver transplant recipient’s cohort. Methods: We assessed total of 118 pediatric liver transplant recipients between 1-18 years of age who had been followed between 01 March 2019 to December 2021. Demographic data, clinical and laboratory features were obtained from electronic medical record as well as the state health record system. The information regarding the severity of the symptoms, duration of hospitalization, and outcomes of the infection were obtained by telephone inquiries. Patients with COVID-19 infection prior liver transplantation, unknown hospitalization status or unconfirmed SARS-CoV infection were excluded. The demographic, clinical and laboratory features of the patients were analysed descriptively. Results: A total of 16 out of 118 (13.5%) pediatric liver transplant recipients were diagnosed with COVID-19 infection. Eleven (68.8%) patients were male with a median age of 14.8 (interquartile range, 8-16) years. The main presenting symptoms were as follows; fever in 8 (50%), cough in 6 (37.5%), sore throat in 4 (25%), runny nose in 5 (31.3%), myalgia in 3 (18.8%), and abdominal pain in 2 (12.5%) patients. None of the patients exhibited respiratory failure, arthralgia, smell and taste loss, or diarrhea. Out of 16 COVID-19 patients, 6 (37.5%) had complete blood count, biochemistry tests and coagulation profile. Four of them exhibited leukopenia and mildly elevated C-reactive protein. One patient required computed tomography of thorax due to respiratory distress which revealed the ground-glass opacity and minimal pleural effusion. Only 3 out of 16 patients required hospitalization with a mean 2.67-days length of stay. Two out of 16 patients received favipiravir and two patients required antibiotics treatment due to suspected pneumonia. No SARS-CoV-19 infection associated intensive care admission or death were observed in our study. Nine out of 16 patients with SARS-CoV-19 were unvaccinated due to following reasons: 8 patients were younger than 12 years as vaccination is not recommended in this age group by the current guidelines of the Turkish ministry of health, and 1 patient was recently tested positive for COVID-19 infection. Rest seven out of 16 patients had two doses of COVID-19 vaccination. Conclusion: In this study, pediatric LT patients with SARS-CoV-19 infection showed a wide range of clinical presentations while the outcomes of the infection were generally mild.

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare disorder characterized by multiple small intestine ulcers. Patients with CEAS typically present with chronic anemia and gastrointestinal bleeding. Besides CEAS, SLCO2A1 mutations cause primary hypertrophic osteoarthropathy (PHO) which is considered as an extraintestinal manifestation in CEAS patients. Since CEAS and Crohn's disease are clinically indistinguishable, patients are often misdiagnosed with Crohn's disease. Herein, we describe a 4-year-old Turkish girl with CEAS due to homozygous pathogenic variant (c.656C > T) in SLCO2A1 with concomitant hereditary fructose intolerance (HFI) caused by homozygous pathogenic variant (c.1005C > G) in ALDOB. Prompt restriction of fructose, sucrose and sorbitol resulted in hepatomegaly regression and mild amelioration of patient's symptoms. Despite budesonide and azathioprine treatments, patient's protein losing enteropathy and chronic anemia did not improve. Although previous CEAS cases were reported from East Asian countries, it is likely to occur in people from other geographic areas. CEAS seems to be underdiagnosed and high index of suspicion is required for the diagnosis of this rare entity. Patients with prior diagnosis of Crohn's disease with no response to immunosuppressive treatment or anti-TNF therapy should be re-evaluated for possible CEAS diagnosis.

Non-cirrhotic portal hypertension (NCPH) is a rare clinical entity in children. Familial clusters of idiopathic non-cirrhotic portal hypertension (INCPH) were previously reported in cases with deoxyguanosine kinase (DGOUK) and potassium calcium-activated channel subfamily N member 3 (KCNN3) mutations. Herein, we report two siblings who had a novel mutation in mitochondrial tRNA methyltransferase 5 (TRMT5) gene and presented with hepatopulmonary syndrome and later diagnosed as INCPH. Autosomal recessive inheritance of this mutation may suggest a role of TRMT5 mutations in the development of NCPH. Screening of TRMT5 mutations could be considered when familial INCPH is suspected.

OBJECTIVES:Several studies suggest that chronic immunosuppression in pediatric liver transplant patients may affect the severity and mortality rates of SARS-CoV-2 infection.MATERIALS AND METHODS:We assessed a total of 118 pediatric liver transplant recipients for SARS-CoV-2 infection, aged 1 to 18 years, followed between March 2019 and January 2022. We compared the clinical characteristics and outcomes of SARS-CoV-2 infection in pediatric liver transplant patients to 187 non-liver transplant pediatric patients with SARSCoV-2 infection who had been diagnosed at our institution between March 15, 2020, and December 31, 2020. Demographic data, clinical features, and laboratory findings from the patients were retrospectively collected from hospital reports and telephone inquiries.RESULTS:A total of 20 liver transplant patients with SARS-CoV-2 infection were identified. Median age of liver transplant recipients with SARS-CoV-2 infection was higher than non-liver transplant pediatric patients with SARS-CoV-2 (14.8 [range, 7-16] vs 6.8 [range, 2-14] years; P = .016). There were no significant differences in mild and moderate disease courses of SARS-CoV-2 infection between liver transplant recipients and non-liver transplant pediatric patients (18 [90.0%] vs 133 [71.1%] patients [P = .188] and 2 [10%] vs 49 [26.2%] patients [P = .118], respectively). Fever was less frequently observed in liver transplant patients with SARS-CoV-2 infection compared with non-liver transplant patients (55.0% vs 80.2%; P = .015). We found no intergroup differences in sex (P = .342), hospitalization rate (P = .161), and overall clinical presentation.CONCLUSIONS:Despite the immunosuppression regimens, liver transplant patients in our series survived SARS-CoV-2 infection without serious sequelae and without graft rejection. Overall, liver transplant and non-liver transplant pediatric patients with SARSCoV-2 infection experienced a mild disease course.

Objective:Uric acid (UA), a known danger signal released from injured cells, is a valuable sign of inflammation. We aimed to evaluate the association of serum UA levels before the start of conditioning regimens with the risk of hepatic sinusoidal obstruction syndrome (SOS) development after hematopoietic stem cell transplantation (HSCT).Materials and Methods:Two hundred and twenty-two children who underwent allogeneic HSCT at the Pediatric BMT Unit of Hacettepe University between 2000 and 2014 were included in this retrospective study. Serum UA levels were measured before conditioning as an indicator of the pre-transplant inflammatory status of the patients. Patients with and without a diagnosis of SOS were compared regarding primary diagnosis, previously described risk factors for SOS, and pre-conditioning serum UA.Results:SOS was diagnosed in 42 patients who had higher pre-conditioning serum UA levels compared to those who did not. Pre-transplant serum creatinine, gamma-glutamyl transferase, bilirubin, ferritin, and C-reactive protein levels did not differ significantly among patients with and without SOS; however, serum albumin was lower in the patients who developed SOS. Receiver operating characteristic analysis revealed that a pre-conditioning UA level higher than 3.32 mg/dL was predictive of SOS. When applied to a multivariate model, only pre-conditioning UA and albumin levels remained significant risk factors for SOS (UA: odds ratio [OR], 2.54; 95% confidence interval [CI], 1.26-5.12, p=0.009; albumin: OR, 0.45, 95% CI, 0.22-0.95, p=0.037).Conclusion:Our results suggest that pre-conditioning serum UA is an independent risk factor for SOS, and it might be used as an early predictor of hepatic SOS together with previously described clinical and laboratory parameters.