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

OBJECTIVE: To 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 DESIGN: A single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 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. RESULTS: A total of 51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). Overall SNL rate was 43% (n = 22). Alpha fetoprotein levels were higher in SNL patients (P = .034) and differed more significantly by SNL status among nongestational alloimmune liver disease patients (n = 21, P = .001). An alpha fetoprotein < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in nongestational alloimmune liver disease patients with an area under the ROC curve of 0.81. A neonate-specific admission model (international normalized ratio and ammonia) and peak model (prothrombin time and ammonia) also predicted SNL with good accuracy (area under the ROC curve = 0.73 and 0.82, respectively). CONCLUSIONS: We 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.

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

OBJECTIVE: 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. STUDY DESIGN: Neonates with ALF (international normalized ratio ≥2 within 30 days of life) and deceased neonates without liver disease (<30 days 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. RESULTS: 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 ligand 14. CONCLUSIONS: 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.

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.

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.

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

BACKGROUND: Neonatal 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 εγδß-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation. CASE PRESENTATION: A 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδß-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. CONCLUSIONS: We reported that an infant with εγδß-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 Lupus presenting with neonatal hemochromatosis-like liver disease that responded to steroids: a case report.

BACKGROUND: Neonatal lupus erythematosus is a rare multisystem autoimmune disorder that predominantly involves the heart with congenital heart block but can involve other organs including the liver. The disease results from passage of maternal autoantibodies to the fetus and manifests in various forms depending on the organ involved. Neonatal lupus liver disease manifestations range from benign elevation in aminotransferases to fatal hepatic insufficiency with iron deposition that does not respond to therapy. Only a handful of cases have been reported to date. The antibodies implicated are Sjogren Syndrome types A and B antibodies. Other non-specific autoantibodies can be positive as well such as antinuclear antibodies. Smooth muscle antibodies are classically considered specific to autoimmune hepatitis, and while they have been described in other chronic liver diseases, they have not been described in neonatal lupus liver disease. Herein we report a rare case of neonatal cholestasis due to neonatal lupus liver disease that presented with a positive smooth muscle antibodies in addition to a biochemical picture of neonatal hemochromatosis, with a remarkably elevated ferritin, that responded well to steroid therapy. CASE PRESENTATION: An 8-day old full-term baby girl was referred to our center for evaluation of neonatal bradycardia and generalized jaundice that started in the first day of life. Prenatal history was significant for fetal bradycardia. Examination was unremarkable except for bradycardia and generalized jaundice. Laboratory findings included elevated alanine aminotransferase, aspartate aminotransferase, Alkaline Phosphatase, and total and direct bilirubin. Her ferritin was markedly elevated along with triglycerides. Sjogren syndrome antibodies were positive in addition to antinuclear and anti-smooth muscle antibodies. The diagnosis of cardiac neonatal lupus was given, and her liver disease was attributed to lupus despite the biochemical picture of neonatal hemochromatosis. She was started on oral prednisolone for which her liver function parameters showed a dramatic response and continued to be within the normal limits several weeks after discontinuation of steroids. CONCLUSION: Neonatal lupus liver disease is a rare cause of neonatal cholestasis that can rarely present with neonatal hemochromatosis picture which unlike other causes of neonatal hemochromatosis can be reversed with steroid therapy.

Magnetic resonance imaging of neonatal hemochromatosis.

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently resulting in fetal loss or neonatal death. It is thought that most cases of neonatal hemochromatosis are caused by gestational alloimmune liver disease (GALD), with neonatal hemochromatosis being a phenotype of GALD rather than a disease process. Extrahepatic siderosis in the pancreas, myocardium, thyroid and minor salivary gland is a characteristic feature of neonatal hemochromatosis. There is also sparing of the reticuloendothelial system with no iron deposition in the spleen. Hepatic and extrahepatic siderosis seen in neonatal hemochromatosis is from iron dysregulation secondary to liver damage rather than iron deposition causing the liver damage. The presence of extrahepatic siderosis in the pancreas and thyroid is diagnostic of neonatal hemochromatosis and can be detected noninvasively by multi-echo gradient recalled echo (GRE) T2*-weighted sequence of MRI within hours of birth. This helps to expedite the treatment in the form of intravenous immunoglobulin and exchange transfusion, which improves the survival in these babies. The finding of hepatic siderosis is nonspecific and does not help in the diagnosis of neonatal hemochromatosis because it is seen with other causes of advanced liver disease.

Sub-acute neonatal hemochromatosis in an infant with hypoplastic left heart syndrome on ventricular assist device awaiting transplantation.

Single-ventricle pediatric patients, amongst other children waiting for OHT, are a vulnerable population, especially if candidacy is established before any palliation. NH is a rare disease with poor prognosis in the post-natal period. We present a case of sub-acute NH diagnosed in an infant with HLHS who was listed for OHT while bridged with a pulsatile paracorporeal VAD, with an emphasis on the evolution of the condition throughout the patient's clinical course and the ultimate decision for compassionate deactivation of VAD.

Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation.

BACKGROUND: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). OBJECTIVE: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. METHODS: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks. RESULTS: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded. CONCLUSION: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.

Neonatal liver failure owing to gestational alloimmune liver disease without iron overload.

Although neonatal hemochromatosis (NH) is a well-known cause of liver failure during the neonatal period and iron deposition in extrahepatic tissues is considered essential in the diagnosis of NH, there is no consensus regarding the pathology or diagnostic criteria of NH. Recent studies of immunohistochemical assays have shown that the C5b-9 complex (the terminal membrane attack complement complex) is strongly expressed in the liver of NH cases, suggesting that a gestational alloimmune mechanism is the cause of liver injury. The patient was a low birthweight primiparous male born at 37 weeks of gestation by vaginal delivery. Blood tests 3 h after birth showed signs of liver failure, including high transferrin saturation, resembling the clinical characteristics of NH. However, magnetic resonance imaging and a lip biopsy showed no obvious iron deposition outside the liver. The patient was refractory to exchange transfusion and immunoglobulin therapy but was successfully treated by liver transplantation. Histologically, the explanted liver showed established cirrhosis, with large amounts of human C5b-9 in the residual hepatocytes, suggesting the alloimmune mechanism of liver injury was the cause of his liver failure. Liver failure caused by a gestational alloimmune mechanism should be considered in patients with antenatal liver failure, even without obvious extrahepatic siderosis.

Case report of fetal liver cirrhosis due to gestational alloimmune liver disease in a primigravida female, in the northeast region of India.

Introduction: Fetal liver failure is a major cause of neonatal morbidity and mortality, presenting as acute liver failure and/or congenital cirrhosis. Gestational alloimmune liver disease associated with neonatal haemochromatosis is a rare cause of fetal liver failure. Case report: 24-year-old primigravida on Level II ultrasound scan showed intrauterine live fetus, with the fetal liver showing nodular architecture and coarse echotexture. Moderate fetal ascites were present. Scalp oedema was present with minimal bilateral pleural effusion. Suspicious fetal liver cirrhosis was raised, and the patient was counseled for a poor prognosis of pregnancy. Surgical termination of pregnancy was performed at 19 weeks through Cesarean section, and postmortem histopathological examination revealed haemochromatosis, hence gestational alloimmune liver disease was confirmed. Discussion: The presence of a nodular echotexture of the liver, with ascites, pleural effusion, and scalp oedema suggested chronic liver injury. Gestational alloimmune liver disease-neonatal haemochromatosis is often diagnosed late and patients are therefore referred late to specialized centers, delaying treatment. Conclusion: This case highlights the consequences of late diagnosis and treatment of gestational alloimmune liver disease-neonatal haemochromatosis and emphasizes the importance of a high grade of suspicion of this disease. Level II ultrasound scan should include scanning of the liver, as a part of the protocol. A high grade of suspicion is key for the diagnosis of gestational alloimmune liver disease-neonatal haemochromatosis, and early use of intravenous immunoglobulin should not be postponed to allow longer survival of the native liver.

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.

Premature birth associated with a favorable course in gestational alloimmune liver disease (GALD): A case report.

Gestational alloimmune liver disease (GALD) is a rare neonatal disorder with high mortality and morbidity. The patients come to caregivers' attention aged a few hours or days. The disease manifests as acute liver failure with or without siderosis. The differential diagnosis of neonatal acute liver failure (NALF) is broad, including mainly immunologic, infectious, metabolic and toxic disorders. The most common cause, however, is GALD followed by herpes simplex virus (HSV) infection. The best suited pathophysiological paradigm of GALD is that of a maternofetal alloimmune disorder. State of the art treatment combines intravenously administered immunoglobulin (IVIG) with exchange transfusion (ET). We report an infant born at 35 + 2 weeks' gestation in whom GALD had a favorable course, of interest because premature birth in our patient may have exerted protective aspects and lessened morbidity in that intrauterine exposure to maternal complement-fixing antibodies was shortened. The diagnosis of GALD was challenging and difficult. We suggest a modified diagnostic algorithm combining clinical findings with histopathologic findings in liver and lip mucosa and, if available, on abdominal magnetic resonance imaging-study focusing on the liver, spleen, and pancreas. This diagnostic workup must be followed by ET and subsequent administration of IVIG without delay.

Successful pregnancy outcomes following intravenous immunoglobulin treatment in a woman with a previous fetal death in utero due to gestational alloimmune liver disease: A case report.

Gestational alloimmune liver disease resulting in neonatal haemochromatosis is a rare but often lethal neonatal and fetal condition and is the leading cause of fetal and neonatal liver injury. Chelation-antioxidant treatment, intravenous immunoglobulin therapy and exchange transfusions, as well as liver transplantation have been used as treatments for the affected newborn at birth. In the reported case, a woman with previous neonatal death at 34 weeks of gestation due to gestational alloimmune liver disease commenced weekly doses of intravenous immunoglobulin (1 mg/kg) from 15 weeks in a subsequent pregnancy. A healthy baby boy was delivered following induction of labour at 36 weeks and 5 days of gestation. Following the same protocol, another healthy baby boy was delivered at 37 weeks of gestation. This case report emphasises the clinical utility of antenatal prophylaxis with intravenous immunoglobulin in women at high risk of recurrent gestational alloimmune liver disease.

Intravenous immunoglobulin induced pancytopenia while preventing development of gestational alloimmune liver disease: A case report.

Gestational alloimmune liver disease is a rare complication associated with reactive maternal immunoglobulins resulting in neonatal liver pathology. The mainstay treatment for prevention in future pregnancies is intravenous immunoglobulins. Although relatively well tolerated, adverse reactions may occur. In this report, we highlight a case of intravenous immunoglobulin induced pancytopenia diagnosed by exclusion after thorough work-up. The patient was counseled on options and an informed decision was made to proceed with re-trial of intravenous immunoglobulin without systemic prednisone. This resulted in the delivery of a healthy neonate. We propose that future adverse reactions to intravenous immunoglobulin in pregnancy may warrant the trial of a new medication lot and use of systemic steroids only if subsequently indicated.

Efficacy of Intravenous Immunoglobulin/Exchange Transfusion Therapy on Gestational Alloimmune Liver Disease.

Background: Gestational alloimmune liver disease (GALD) is a rare but critical cause of neonatal liver failure. After discovering the maternal-fetal alloimmune mechanism, intravenous immunoglobulin (IVIG) with or without exchange transfusion (ET) has gradually replaced antioxidant cocktails as the first-line therapy. Whether such therapy changes the outcome of neonates with GALD is yet to be defined. Method: We reported a pair of twins with discordant presentations, mild and self-limited in the older, whereas liver failure in the younger, who was successfully rescued by ET and IVIG. To investigate the outcome after therapeutic alteration, 39 cases between 2005 and 2020 from literature research were collected. Results: Half of the collected cases (47.1%) were preterm. Common presentations were ascites, jaundice, respiratory distress, hepatomegaly, and edema. Leading laboratory abnormalities were coagulopathy, hypoalbuminemia, and elevated serum ferritin. Salivary gland biopsy and magnetic resonance imaging detected extrahepatic siderosis in 70% (14/20) and 56% (14/25), respectively. IVIG, ET, and liver transplantation were performed in 19 (48.7%), 15 (38.5%), and 8 (20.5%) patients, respectively. The overall survival (OS) rate and native liver survival (NLS) rate were 64.1% (25/39) and 43.6% (17/39), respectively. Although the compiled results did not support a significant benefit, the OS and NLS were higher in the IVIG with/without ET group compared with those treated with conventional therapy [OS (70 vs. 57.9%) and NLS (55 vs. 31.6%), respectively]. Conclusion: A high index of suspicion for GALD is crucial when facing a neonate with liver failure. Despite no significant influence on the outcome over conventional therapy in such a rare and detrimental disease, IVIG with or without ET can be worth trying before resorting to liver transplantation, which is resource-demanding and technique-challenging in small infants.

Neonatal Acute Liver Failure.

Neonatal acute liver failure (NALF) is a rare disease with a few known primary causes: gestational alloimmune liver disease (GALD), viral infections, metabolic diseases, and ischemic injury. Many cases still do not have a known cause. Laboratory evaluation may suggest a diagnosis. Most of the known causes have disease-specific treatments that improve outcomes. Survival is improving with better knowledge about and treatment options for GALD; however, overall mortality for NALF is still 24%. Liver transplant remains an important option for neonates with an indeterminate cause of NALF and those who do not respond to established treatments.

Heterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins.

Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies.

Gestational autoimmune disease in newborns with an indeterminate cause of death following a complete autopsy.

Gestational alloimmune liver disease (GALD) is the result of neonatal complement-mediated severe liver injury mediated by maternal alloantibodies, which is detected by immunohistochemistry staining for the complement C5b-9 complex. GALD leads to the neonatal hemochromatosis (NH) phenotype, which also shows extrahepatic siderosis, and can result in neonatal death. At autopsy, the histologic damage of the liver in GALD may be subtle and misinterpreted as non-specific post-mortem changes, resulting in the cause of death classified as indeterminate. We reviewed the pathologic diagnoses from autopsy material from 1996 to 2011 of infants 0-90 days of age from our institution. Liver samples were stained with H&E, trichrome and for C5b-9. 13 cases originally diagnosed as indeterminate cause of death were identified and divided in 3 groups: (1) No clinical or autopsy-derived diagnoses (n = 7), (2) Defined clinical diagnoses but no cause of death determined at autopsy (n = 2), and (3) Liver disease, but no clinical or autopsy diagnoses to establish the cause of the liver injury (n = 4). On reexamination, all group 1 and 3 cases were reclassified as GALD, based on a positive C5b-9 stain. Group 2 cases were not GALD, retaining the original, clinically-based cause of death. We conclude that, in cases of indeterminate cause of neonatal death, very careful examination for hepatocyte injury/necrosis, extrahepatic siderosis, liver fibrosis and/or C5b-9 stain should be considered.