Consenso mexicano de tirosinemia tipo 1

INTRODUCTION: Tyrosinemia type 1 is a rare disease with autosomal recessive inheritance, featuring various clinical manifestations. These may encompass acute neonatal liver failure, neonatal cholestatic syndrome, chronic hepatitis, cirrhosis, hepatocellular carcinoma, and, alternatively, kidney disorders like renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, among other alterations. Diagnosis relies on detecting toxic metabolites in the blood and urine, ideally confirmed through molecular testing. METHOD: A consensus was reached with experts in the field of inborn errors of metabolism (EIM), including eight pediatric gastroenterologists, two EIM specialists, two geneticists, three pediatric nutritionists specialized in EIM, and a pediatric surgeon specializing in transplants. Six working groups were tasked with formulating statements and justifications, and 32 statements were anonymously voted on using the Likert scale and the Delphi method. The first virtual vote achieved an 80% consensus, with the remaining 20% determined in person. RESULTS: The statements were categorized into epidemiology, clinical presentation, diagnosis, nutritional and medical treatment, and genetic counseling. CONCLUSIONS: This consensus serves as a valuable tool for primary care physicians, pediatricians, and pediatric gastroenterologists, aiding in the prompt diagnosis and treatment of this disease. Its impact on the morbidity and mortality of patients with tyrosinemia type 1 is substantial.

INTRODUCCIÓN: La tirosinemia tipo 1 es una enfermedad rara, con herencia autosómica recesiva, con múltiples manifestaciones clínicas, que pueden comprender desde falla hepática aguda neonatal, síndrome colestásico neonatal, hepatitis crónica, cirrosis o hepatocarcinoma, hasta alteraciones renales como acidosis tubular renal, síndrome de Fanconi o raquitismo hipofosfatémico, entre otras. El diagnóstico se basa en la presencia de metabolitos tóxicos en la sangre y la orina, idealmente con la confirmación molecular de la enfermedad. MÉTODO: Se realizó un consenso con expertos en el área de los errores innatos del metabolismo (EIM): ocho gastroenterólogos pediatras, dos médicos especialistas en EIM, dos genetistas, tres nutriólogas pediatras especializadas en EIM y un cirujano pediatra especialista en trasplantes. Se formaron seis mesas de trabajo encargadas de desarrollar los enunciados con sus justificaciones y fueron votados anónimamente 32 enunciados en una escala Likert con un método Delphi. La primera votación fue virtual, obteniendo consenso del 80% de los enunciados, y la segunda fue presencial, obteniendo el 20% restante. RESULTADOS: Los enunciados fueron divididos en epidemiología, cuadro clínico, diagnóstico, tratamiento nutricional y médico, y consejo genético. CONCLUSIONES: Este consenso constituye una valiosa herramienta para los médicos de atención primaria, pediatras y gastroenterólogos pediátricos, ya que ayuda a diagnosticar y tratar rápidamente esta enfermedad. Su impacto en la morbilidad y mortalidad de los pacientes con tirosinemia tipo 1 es sustancial.

Mitochondrial depletion syndrome type 3: the Lebanese variant.

Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1 year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.

Mitochondrial hepatopathy: Respiratory chain disorders- 'breathing in and out of the liver'.

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.

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 Hereditary Fructose Intolerance: Diagnostic Misconceptions and the Role of Genomic Sequencing.

Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism due to deficiency of the enzyme aldolase B, preventing metabolism of fructose. Patients remain asymptomatic until exposed to fructose, sucrose, or sorbitol. HFI presenting as acute liver failure in the neonatal period is rare due to lack of exposure as breast milk and infant formulas are considered to be fructose free. Diagnosis can be delayed due to vague symptoms and lack of specific biomarkers. Recent advances in genetic testing have led to rapid diagnosis and favorable outcomes. We present the case of a formula-fed neonate who presented with acute liver failure where definitive diagnosis of HFI was made using expedited whole exome sequencing. Through this communication, we aim to bring attention to neonatal presentations of HFI from exposure to fructose in infant formulas and also highlight advances in rapid turnaround genomic testing in diagnosis.

Non-Immune Hydrops, Hypotonia, Encephalopathy, and Liver Failure with Novel Compound Heterozygous AHCY Mutations.

A late-preterm infant with a prenatal diagnosis of non-immune hydrops was born with hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days of life due to multisystem organ failure. Rapid whole exome sequencing revealed novel compound heterozygous mutations in the gene encoding S-adenosylhomocysteine hydrolase (AHCY); each novel variant was carried by an asymptomatic parent. Reports of neonates with other AHCY mutations describe a pathology of varying severity. AHCY mutations should be considered when seeking an etiology for neonates with the combination of non-immune hydrops, hypotonia, encephalopathy, and liver failure.

The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality.

OBJECTIVES: To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort. STUDY DESIGN: We prospectively collected data from women with a prior offspring with proven neonatal hemochromatosis between 1997 and 2015 and analyzed pregnancy outcomes. RESULTS: The pedigrees from 150 women included 350 gestations with outcomes potentially related to GALD. There were 105 live-born infants without liver disease, 157 live-born infants with liver failure, and 88 fetal losses. Fetal loss occurred in 25% of total gestations. Ninety-seven pedigrees contained a single affected offspring, whereas 53 contained multiple affected offspring. Analysis of these 53 pedigrees yielded a per-pregnancy repeat occurrence rate of 95%. Notably, the first poor outcome occurred in the first pregnancy in 60% of pedigrees. Outcomes of the 157 live-born infants with liver failure were poor: 18% survived, 82% died. Of the 134 live-born infants with treatment data, 20 received intravenous immunoglobulin with or without double-volume exchange transfusion of which 9 (45%) survived; 14 infants (10%) received a liver transplant of which 6 (43%) survived. CONCLUSIONS: GALD is a significant cause of both fetal loss and neonatal mortality with a high rate of disease recurrence in untreated pregnancies at risk. Poor outcomes related to GALD commonly occur in the first gestation, necessitating a high index of suspicion to diagnose this disorder at first presentation.

Insuficiencia hepática aguda neonatal: un desafío diagnóstico / Neonatal acute liver failure: a diagnosis challenge

La insuficiencia hepática aguda durante el período neonatal es una enfermedad rara, muy grave, con elevada mortalidad. Se diferencia clínica y etiológicamente de la insuficiencia hepática aguda del niño mayor y del adulto. La coagulopatía, con un Rango Internacional Normatizado > 3, es el parámetro fundamental para definirla. Las causas más frecuentes son la hepatitis fetal aloinmune, previamente denominada hemocromatosis neonatal, las infecciones virales, las enfermedades metabólicas y la linfohistiocitosis hemofagocítica. Existe un grupo de enfermedades tratables que es necesario diagnosticar con mucha rapidez para brindarles el tratamiento correspondiente. El paciente debe ser derivado precozmente a un centro especializado con disponibilidad de trasplante hepático pediátrico para poder darle esta alternativa terapéutica cuando esté indicada.

Neonatal acute liver failure is a rare, very severe disease with a high rate of mortality. It is clinically and etiologically different from acute liver failure seen in older children and adults. Coagulopathy with an international normalized ratio > 3 is the critical parameter that defines it. The most common causes are fetal alloimmune hepatitis, previously called neonatal hemochromatosis, viral infections, metabolic disorders, and hemophagocytic lymphohistiocytosis. There is a group of treatable diseases that require a very early diagnosis for the prescription of an adequate treatment. Patients should be immediately referred to a specialized facility where pediatric liver transplantation is available to implement such therapeutic alternative, if indicated.

Neonatal acute liver failure: a diagnosis challenge. / Insuficiencia hepática aguda neonatal: un desafío diagnóstico.

Neonatal acute liver failure is a rare, very severe disease with a high rate of mortality. It is clinically and etiologically different from acute liver failure seen in older children and adults. Coagulopathy with an international normalized ratio ≥ 3 is the critical parameter that defines it. The most common causes are fetal alloimmune hepatitis, previously called neonatal hemochromatosis, viral infections, metabolic disorders, and hemophagocytic lymphohistiocytosis. There is a group of treatable diseases that require a very early diagnosis for the prescription of an adequate treatment. Patients should be immediately referred to a specialized facility where pediatric liver transplantation is available to implement such therapeutic alternative, if indicated.

La insuficiencia hepática aguda durante el período neonatal es una enfermedad rara, muy grave, con elevada mortalidad. Se diferencia clínica y etiológicamente de la insuficiencia hepática aguda del niño mayor y del adulto. La coagulopatía, con un Rango Internacional normatizado ≥ 3, es el parámetro fundamental para definirla. Las causas más frecuentes son la hepatitis fetal aloinmune, previamente denominada hemocromatosis neonatal, las infecciones virales, las enfermedades metabólicas y la linfohistiocitosis hemofagocítica. Existe un grupo de enfermedades tratables que es necesario diagnosticar con mucha rapidez para brindarles el tratamiento correspondiente. El paciente debe ser derivado precozmente a un centro especializado con disponibilidad de trasplante hepático pediátrico para poder darle esta alternativa terapéutica cuando esté indicada.

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.