Gestational Alloimmune Liver Disease Research Articles

Neonatal Hemochromatosis Secondary to an Inborn Error of Metabolism (Mitochondrial Disorder): Post- mortem Diagnosis in the Fetus of a Young Primipara

Abstract Introduction/Objective Neonatal hemochromatosis (NH), an extremely rare congenital phenotype of acute hepatic failure with hepatic and extrahepatic siderosis, is primarily (98%) caused by gestational alloimmune liver disease (GALD) and, rarely (2%), by infection, metabolic disorders, bile acid defects, and mitochondrial hepatopathy. This report presents an extremely rare case of NH caused by an inborn error of metabolism (suspected mitochondrial dysfunction). This low-birth-weight female was born with acute liver failure, metabolic acidosis, multisystem failure, and progressive lactate acidosis, and expired on day 7. On autopsy, liver was less than 50% of normal size and without nodularity. Microscopic architecture was preserved with erythropoiesis, canalicular bile plugs, microvesicular steatosis (oil red O stain) and abundant coarsely granular siderosis (iron stain). GALD was unlikely because of the absence of the typical hepatocytic injury, fibrosis or biliary destruction, and the negative immunohistochemistry for MAC (C5b-C9). Extrahepatic siderosis was demonstrated in thyroid follicles, thymic Hassall corpuscles, myocardium, and adenohypophysis. Sanger sequencing and deletion testing of mitochondrial genome on a maternal buccal biopsy identified a homoplasmic variant (m.15482 T>C p.(S246P) in maternal MT-CYB gene but without molecular diagnosis of a mitochondrial DNA disorder. Infant plasma had increased C6DC, C5, C12-OH acylcarnitine, alanine, and proline. Urine contained elevated organic acids (lactate/pyruvate, 2-ketoacids, 3-methylglutarate, 3-methylglutaconate), concerning acute mitochondrial respiratory chain dysfunction. Methods/Case Report: Case Study Results (if a Case Study enter NA) NA Conclusion Diagnosis of NH warrants exclusion of the most common etiology, GALD. Mitochondrial genetic mutations are the most difficult to diagnosis because of heterogeneity and typically undiagnosed maternal defects. This is the first report of NH with a homoplasmic maternal variant of uncertain significance. Neonatal lactic acidosis is the strongest clinical clue for mitochondrial dysfunction and should trigger phenotyping, maternal mitochondrial genetic variants (mtDNA, nuDNA), functional, biochemical, and genetic studies.

Fetal hemochromatosis: rare case of hepatic and extrahepatic siderosis involving thyroid on fetal MRI

BackgroundNeonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid.Case presentationWe present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero.ConclusionThis case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes.

Etiology, Characteristics, and Outcomes of Neonatal Liver Failure: Lessons Learned Over the Last 3 Decades

To evaluate trends in etiology and outcomes of neonatal liver failure (NLF) over 30years retrospectively at a single institution. Inclusion criteria for this retrospective cohort study were babies presenting at a chronological age of ≤28days between 1991 and 2020 with prothrombin time≥20seconds and biochemical liver injury. Demographics, etiology, laboratory investigations, need for extrahepatic organ support, acute kidney injury, and intervention with liver transplant (LT) were recorded. Survival outcomes were measured as discharge from the hospital alive with native liver or LT. The study period was stratified into 3 10-year blocks. Trends were analyzed for hospital admissions, etiology, and survival outcomes. One hundred twenty-six babies met the NLF criteria. Admissions to the hospital increased from 21 in 1991-2000 to 65 in 2011-2020. An increasing trend in infectious and metabolic causes, while a decreasing trend in indeterminate etiology, was noted. Survival with native liver improved from 23.8% in 1991-2000 to 55.4% in 2011-20 (P=.021), and mortality reduced from 52.4% to 35.4% during the same periods (P=.213). Twenty-three (18.2%) neonates received LT. Post-LT survival outcomes were 100% for gestational alloimmune liver disease, 66.6% in the indeterminate group, and 25% for herpes simplex virus. Specific etiologies (gestational alloimmune liver disease, OR=0.07 [0-0.77, P=.048]), presence of acute kidney injury (OR=6.22 [1.45, 29.38, P=.015]) and need for inotropes (OR=6.22 [1.45, 29.38, P=.028]) influenced mortality in multivariable logistic regression analysis. In the last 30years, advances in diagnosis, treatment, and increasing experience with LT have improved survival in NLF.

Drug-induced Liver Injury from Intravenous Immunoglobulin for Prevention of Recurrent Gestational Alloimmune Liver Disease: A Clinical Catch-22

Gestational alloimmune liver disease (GALD) is a rare autoimmune syndrome in which maternal antibodies lead to in utero fetal hepatocyte destruction, often presenting as neonatal liver failure and hemochromatosis. Antenatal intravenous immunoglobulin (IVIG) is generally accepted to be safe in pregnancy with demonstrable benefits for reducing GALD recurrence risk in subsequent pregnancies. Here we present a case of a 33-year-old woman with a prior neonatal demise due to GALD who received multiple prophylactic IVIG infusions in a subsequent twin pregnancy complicated by maternal jaundice and acute hepatitis. A liver biopsy demonstrated hepatocellular injury with bridging necrosis and cholestatic features consistent with drug-induced liver injury. This case demonstrates the importance of close clinical monitoring during IVIG therapy and the need for further research into alternative prophylaxis options for GALD. Key Points

Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China.

Neonatal acute liver failure (NALF), as a rare disease with high mortality, has limited relevant literature reports in China. We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group (P < 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48days; 26days for hypoxic/ischemic injury and 43days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients (P = 0.018). Conclusion: Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology. What is Known: • Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China. • Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations. • There are no reliable biochemical markers to predict the outcome of NALF. What is New: • In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF. • The overall prognosis of NALF is poor, and its etiology determines the short-term outcome.

Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

ObjectivesTo develop neonate-specific prediction models for survival with native liver (SNL) in neonatal acute liver failure (ALF) and to determine if these prediction models have superior accuracy to existing models for older children with ALF. Study designA single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (INR ≥ 2 or prothrombin time [PT] ≥ 20s and liver dysfunction). Statistical analysis included comparison of patients by outcome of SNL and generalized linear modeling to derive prediction models. The predictive accuracy of variables was evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis. Results51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (GALD) (16%). Overall SNL rate was 43% (n=22). AFP levels were higher in SNL patients (p=0.034) and differed more significantly by SNL status among non-GALD patients (n=21, p=0.001). An AFP < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in non-GALD patients with an area under the ROC curve (AUROC) of 0.81. A neonate-specific admission model (INR and ammonia) and peak model (PT and ammonia) also predicted SNL with good accuracy (AUROC = 0.73 and 0.82 respectively). ConclusionsWe identified neonate-specific prognostic variables for SNL in ALF. Findings from our study may help early risk stratification to guide medical decision-making and consideration for liver transplantation.

Congenital neonatal hemochromatosis with recurrent neonatal deaths - a diagnostic nightmare: A case report

Background: Neonatal hemochromatosis (NH) is a rare disorder and the most common cause of acuteliver failure in neonates. NH is characterized by severe hepatic injury and iron overload with highperinatal mortality and morbidity. There is a high risk of recurrence in subsequent pregnancies of womenwho have had a child with neonatal hemochromatosis.Case presentation: A 40-year-old para 13 with one living child and three previous cesarian scarspresented at ten weeks with a history of recurrent neonatal deaths. Her last infant death was at fourmonths after she delivered a baby via cesarian birth at 36 weeks. The infant developed severe jaundicewith reduced urine output. Laboratory investigations revealed deranged liver function tests with elevatedserum ferritin levels. The infant received repeated exchange transfusions, immunoglobulin, anddexoferamine. However, she succumbed at four months. Her management for the current pregnancyrequired close follow-up and she delivered at 37 weeks gestation to a live male infant who is faring well.Discussion: The cause of NH is not fully understood. Significant evidence indicates that most cases ofneonatal hemochromatosis result from fetal liver disease due to maternal-fetal alloimmunity, a conditiontermed gestational alloimmune liver disease (GALD). In GALD, these antibodies bind to fetal liverantigen and activate the terminal complement cascade, resulting in hepatocyte injury and death.Conclusion: NH is the most common cause of neonatal acute liver injury and should be considered in allcases of severe fetal liver injury as well as in cases of stillbirth, fetal demise, and early postnatal death.

Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD).

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.

Therapeutic plasma exchange for neonatal hepatic failure

We report a case of therapeutic plasma exchange in a neonate with fulminant liver failure. A six-day old, 2800-gram baby was referred to our medical center for evaluation and treatment of fulminant hepatic failure. The working diagnosis at admission was gestational alloimmune liver disease, and therapeutic plasma exchange was proposed. A double volume plasma exchange was successfully performed, using the Spectra Optia apheresis system, primed with packed red blood cells. Access was obtained via a radial artery catheter and a peripheral intravenous line. On hospital D-14 a diagnosis of E3 deficiency was confirmed, and disease-specific therapy was started. Automated TPE using peripheral arterial and venous catheters may be safely performed in neonates, and should be considered in the treatment of a variety of disorders including neonatal fulminant hepatic failure.

Neonatal Hemochromatosis: Systematic Review of Prenatal Ultrasound Findings-Is There a Place for MRI in the Diagnostic Process?

Neonatal hemochromatosis (NH) is an uncommon, severe disorder that results in fetal loss or neonatal death due to liver failure. NH is currently regarded as the phenotypic expression of gestational alloimmune liver disease (GALD). The diagnosis of NH-GALD is rarely prenatally established. In addition to providing a systematic review of the prenatal features that are identifiable using ultrasound (US) and MRI, we suggest a prenatal diagnosis algorithm for use in suspected NH during the first affected pregnancy. From a total of 586 database entries identified in PubMed, Google Scholar, and ResearchGate, we selected 18 studies published from 1993 to 2021 that reported maternal medical and obstetric history, prenatal ultrasound findings, and postpartum outcomes. We investigated the ultrasound and MRI features of these studies, along with the outcome due to this condition. A total of 74 cases were identified. The main reported prenatal US finding was fetal growth restriction (FGR) (33%), followed by oligohydramnios (13%) and hydrops fetalis (13%), with 13% cases described as uneventful. Other rare prenatal findings were fetal anemia, ascites, and abnormal fetal liver and spleen. Most pregnancies ended with fetal/perinatal death or therapeutic interruption of pregnancy. Favorable evolution with treatment (ensanguine transfusion and intravenous immunoglobulin (IVIG)) was reported for only 7% of fetuses. Using T2-weighted MRI, fetal extrahepatic siderosis confirmed prenatally in two cases and postnatally in 11 cases. IVIG treatment throughout subsequent pregnancies was found to significantly improve fetal prognosis. MRI should be indicated in selected cases of oligohydramnios, fetal hydrops, fetal hepatomegaly, ascites, or unexplained FGR or anemia after ruling out all other more frequently encountered conditions. MRI can be used to detect iron overload in the liver and extrahepatic siderosis.

A262 NEONATAL ACUTE LIVER FAILURE DUE TO PRESUMED GESTATIONAL ALLOIMMUNE LIVER DISEASE - A CASE REPORT

Abstract Background Neonatal acute liver failure (NALF) is a rare disease that is distinct from acute liver failure seen in older children and adults. Gestational alloimmune liver disease (GALD) is the most frequent cause, is initiated in utero by sensitization of the maternal immune system to a fetal hepatocyte antigen and subsequent production of maternal immunoglobulin G antibodies that cross the placenta. Maternal IgG binds to a fetal hepatocyte antigen and initiates an innate immune response involving the terminal complement cascade and membrane attach complex. The understanding of the alloimmune origin has led to the use of intravenous immunoglobulin (IVIG) treatment and exchange transfusion, significantly increasing survival. However, approximately 25% of patients may not respond and require salvage liver transplantation. In spite of an increased rate of comorbidities, concern for technical difficulties and limited graft availability, young infants eligible for transplant have been shown to have similar overall patient and graft survival rates compared to older children with other indications for liver transplant. Purpose The primary aim of our study is to report a case of NALF with successful liver transplant. Method We present the case of a preterm girl with NALF due to GALD refractory to medical management, requiring liver transplantation. Result(s) This is a 35-week preterm girl, with scant pre-natal care, birth weight of 1.825 kg and Apgar 9/9. She is the seventh child of non-consanguineous parents, with healthy siblings. On day-of-life (DOL) 1 she presented with acute kidney injury, progressive worsening metabolic acidosis and hyperammonemia and was found to be profoundly coagulopathic (INR 6), with normal liver enzymes and liver failure was diagnosed. Initial investigation ruled out congenital infections, sepsis, neonatal hemophagocytic lymphohistiocytosis and metabolic diseases. Magnetic resonance imaging of the body demonstrated findings in keeping with iron deposition in the thyroid, liver and pancreas, suggestive of GALD. Completed double volume exchange transfusion and IVIG on DOL 9 and repeat IVIG on DOL 13 and 15, with partial improvement in INR. Due to persistent ascites, conjugated hyperbilirubinemia and hyperammonemia she was transferred for urgent liver transplant assessment. Persistent liver dysfunction in the form of hyperammonemia, hypoglycemia and progressive coagulopathy led to transplant listing on DOL 30. ABO incompatible deceased donor liver transplant was completed on DOL 62 (4.075 kg, estimated dry weight 3.5 kg). The procedure was uncomplicated, liver enzymes normalized, coagulopathy and hypoglycemia resolved. She was transferred to the ward on post-operative day (POD) 6. and weaned off sedatives and transitioned to oral feeds within 2 weeks of transplant, with complex abdominal wound closure on POD 29. Conclusion(s) Successful liver transplantation is possible in neonates with acute liver failure due to GALD refractory to medical management and weighing 4kg or less. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared MICROBIOME &amp; MICROBIAL THERAPY

RNA-Sequencing Analysis Identifies Etiology Specific Transcriptional Signatures in Neonatal Acute Liver Failure.

To assess hepatic transcriptional signatures in infants with gestational alloimmune liver disease (GALD) compared with other etiologies of neonatal acute liver failure (ALF) and older pediatric patients with ALF. Neonates with ALF (international normalized ratio ≥2 within 30days of life) and deceased neonates without liver disease (<30days of age) with available liver tissue between 2010 and 2021 were identified at Ann & Robert H. Lurie Children's Hospital of Chicago. Clinical information, liver histology, and data from RNA-sequencing analysis was compared between neonates with GALD, non-GALD etiologies of neonatal ALF, and nondiseased neonatal liver. Quantification of trichrome staining showed an increase in fibrosis in patients with GALD vs those with non-GALD neonatal ALF (P=.012); however, quantification of α-cytokeratin 19-positive ductules did not differ between groups (P=.244). Gene set enrichment analysis of RNA-sequencing data identified the pathways of complement activation, fibrosis, and organogenesis to be upregulated in patients with GALD with ALF. In contrast, patients with non-GALD causes of neonatal ALF had increased gene expression for interferon-driven immune pathways. Individual genes upregulated in GALD included matrix metallopeptidase 7, hepatocyte growth factor, and chemokine ligand14. We have identified distinct pathways that are significantly upregulated in patients with GALD and potential disease-specific diagnostic biomarkers. Future studies will aim to validate these findings and help identify GALD-specific diagnostic biomarkers to improve diagnostic accuracy and reduce GALD-associated patient mortality.

Prevention of Gestational Alloimmune Liver Disease by Intravenous Immunoglobulin Administration in the Second Trimester: A Presentation of Two Cases

Prevention of Gestational Alloimmune Liver Disease by Intravenous Immunoglobulin Administration in the Second Trimester: A Presentation of Two Cases

Neonatal hemochromatosis with εγδβ-thalassemia: a case report and analysis of serum iron regulators

BackgroundNeonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation.Case presentationA 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation.ConclusionsWe reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia.

Neonatal Distant Transport for Liver Transplantation

A 36 weeks old baby boy was transferred interstate to the national paediatric liver transplant unit at the Children's Hospital, Westmead in Sydney for liver transplantation on Day 32 of life. Patient received liver transplantation at 41 weeks corrected age, which was three days after arrival to the transplant unit. This transfer involved road and aircraft ambulance utilization. We report this transport process in the setting of severe neonatal liver failure, complicated by persistent, uncorrectable coagulopathy, thrombocytopenia, ascites, hyperammonia and portal hypertension with particular reference to pre-transport preparations and the treatments undertaken during the difficult transport which spanned over eight hours. Keywords: Neonatal; Transport; Liver; Transplantation Abbreviations: FFP: fresh frozen plasma, PRBC: packed red blood cells, NICU: Neonatal Intensive Care Unit, PCH: Perth Children’s Hospital, NETS WA: Newborn Emergency Transfer Service of Western Australia, IVIG: intravenous immunoglobulin, GALD: gestational alloimmune liver disease, IgG: immunoglobulin G

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

Could distal variants in ALG13 lead to atypical clinical presentation?

Congenital disorders of glycosylation (CDG) represent a wide range of some 150 inherited metabolic diseases, continually expanding in terms of newly identified genes and the heterogeneity of clinical and molecular presentations within each subtype. Heterozygous pathogenic variants in ALG13 are associated with early-onset epileptic encephalopathy, typically in females. The majority of subjects described so far harbour one of the two recurrent pathogenic variants, namely p.(Asn107Ser) and p.(Ala81Thr) in the C-terminal glycosyltransferase domain. We report a novel ALG13 variant (c.1709G > A, p.(Gly570Glu)) in an adult female with unremarkable past developmental and medical history, except for mild kinetic tremor. Our proband presented with acute onset of neurological and psychiatric features, along with liver dysfunction, during pregnancy, all of which gradually resolved after delivery. The proband's newborn baby died at 22 days of life from neonatal liver disease, due to gestational alloimmune liver disease (GALD). Functional assessment on fibroblasts derived from our case showed alterations in 2 of 3 cellular glycosylation markers (LAMP2, Factor IX), suggesting a functional effect of this novel ALG13 variant on glycosylation. This paper raises the possibility that variants outside the glycosyltransferase domain may have a hypomorphic effect leading to atypical clinical manifestations.

A Male Infant with Cholestatic Jaundice, Hemolytic Anemia, and Thrombocytopenia.

A Male Infant with Cholestatic Jaundice, Hemolytic Anemia, and Thrombocytopenia.

Hepatosplenomegaly and Periventricular Cyst in a Neonate with Direct Hyperbilirubinemia

Hepatosplenomegaly and Periventricular Cyst in a Neonate with Direct Hyperbilirubinemia

Gestational alloimmune liver disease treated with exchange transfusion and intravenous immunoglobulin: A case study

Gestational alloimmune liver disease (GALD) is a materno-fetal alloimmune disorder that targets the fetal liver and often causes neonatal liver failure. GALD most commonly presents as neonatal hemochromatosis (NH), which is a severe neonatal liver injury confirmed by extra-hepatic iron accumulation at various sites. With the discovery of the alloimmune mechanism of GALD, exchange transfusion and intravenous immunoglobulin (IVIG) administration are being used as novel treatments. Here, we present a rare case of an 11-day-old female infant who presented with marked hyperbilirubinemia. Laboratory findings showed significantly elevated direct and indirect bilirubin, high ferritin and alpha fetoprotein levels, high transferrin saturation, and severe coagulopathy. Abdominal magnetic resonance imaging revealed markedly reduced T2 signal intensity in the liver and pancreas compared to the spleen, suggesting iron deposition. The infant was diagnosed with NH and successfully treated with exchange transfusion and four doses of IVIG.