Elevated Alpha-Fetoprotein in Children and the Diagnosis of Tyrosinemia: The Contribution of Clinico-Biological Collaboration

Elevated Alpha-Fetoprotein in Children and the Diagnosis of Tyrosinemia: The Contribution of Clinico-Biological Collaboration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Elevated Alpha-Fetoprotein in Children and the Diagnosis of Tyrosinemia: The Contribution of Clinico-Biological Collaboration Asmaa MORJAN, Imane CHAHID, Mohamed OMARI, Nabiha KAMAL This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8184773/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Introduction: Type 1 hereditary tyrosinemia (HT1) is an autosomal recessive disorder that leads to toxic accumulation of tyrosine and its metabolites, causing hepatic stress that stimulates the production of alpha-fetoprotein (AFP). Objective: To assess the value of AFP as a biomarker for the diagnosis of tyrosinemia in children. Patients and Methods: This one-year prospective study was based on the review of medical records of patients hospitalized in the Metabolic Diseases Unit at the Abderrahim El Harouchi Mother-and-Child Hospital who presented with significantly elevated AFP levels. Results: A total of 21 cases with suspected HT1 were included. The most common reason for admission was jaundice (33.3%). In addition to laboratory testing, all children underwent abdominal ultrasound, which revealed five cases of biliary atresia. Serological assessment identified one case of viral hepatitis in an infant. One case each of cystic fibrosis and methylmalonic acidemia was diagnosed, and two patients were found to have ataxia-telangiectasia. The cause of hepatocellular failure remained unknown in five cases. HT1 was confirmed in seven patients. These children showed markedly elevated plasma tyrosine levels, supporting the clinical suspicion, and the diagnosis was confirmed by the detection of urinary succinylacetone. Conclusion: AFP remains a key biomarker in the diagnosis of HT1. Regular monitoring helps assess disease progression and evaluate treatment effectiveness. Alpha-fetoprotein Type 1 tyrosinemia Amino acid metabolism Serum tyrosine Fumarylacetoacetate hydrolase (FAH) Figures Figure 1 Figure 2 Figure 3 I. Introduction Alpha-fetoprotein (AFP) is a glycoprotein primarily produced by the fetal liver and yolk sac. After birth, AFP levels decline rapidly and typically reach normal values by approximately two months of age. Tyrosinemia is an autosomal recessive inherited disorder caused by enzymatic defects in the tyrosine degradation pathway, leading to the toxic accumulation of tyrosine and its metabolites. The most common forms include type I tyrosinemia, resulting from a deficiency in fumarylacetoacetate hydrolase, and type II tyrosinemia, caused by a deficiency in tyrosine aminotransferase. These metabolic defects can result in severe hepatic involvement, renal dysfunction, and neurological complications. In this context, AFP is widely used as a marker of liver dysfunction in children presenting with hepatic impairment, making it a valuable tool for the early detection of tyrosinemia. However, elevated AFP levels are not specific to tyrosinemia. Other conditions—such as viral hepatitis, liver malignancies, and various metabolic disorders—may also lead to increased AFP levels. Therefore, AFP must be interpreted within a broader clinical and biological context to ensure an accurate differential diagnosis. The objectives of this study were to highlight the value of AFP as a biomarker in the diagnosis of type I tyrosinemia in children, to outline the etiological evaluation performed in cases of elevated AFP, and to clarify the diagnostic and prognostic significance of AFP levels. II. Patients and Methods This retrospective study was conducted over a one-year period (June 2023 to July 2024). Data were extracted from the computerized database of the Biochemistry Laboratory at Ibn Rochd University Hospital in Casablanca (KALISIL), as well as from medical records. The study included patients hospitalized in the Metabolic Diseases Unit of the Abderrahim El Harouchi Mother-and-Child Hospital who presented with AFP levels significantly above age-specific reference ranges (Table 1). Eligible patients showed at least one of the following: Renal manifestations: renal tubular acidosis, vitamin D–resistant rickets, hypophosphatemia, or metabolic acidosis; Hepatic manifestations: vomiting, diarrhea, jaundice, abdominal distension, hepatomegaly and/or splenomegaly, or bleeding; Neurological manifestations: painful limb crises or irritability. Blood samples (5 mL collected in the morning after an overnight fast, using a dry tube) were sent to the Biochemistry Laboratory. After centrifugation, serum samples were either analyzed immediately or frozen when analysis was delayed. AFP measurement was performed using a microparticle chemiluminescent immunoassay (CMIA) for quantitative determination on the Abbott Alinity® analyzer. Table 1 : Age-specific AFP reference values Age Reference Range (ng/mL) Preterm infant 95,000 – 175,000 Newborn 13,000 – 83,000 2 weeks 500 – 66,000 2 weeks – 1 month 20 – 19,000 1 month 20 – 5,600 2 months 20 – 600 3 months 10 – 180 4 months 10 – 130 5 months 10 – 70 6 months 0 – 20 7 months 0 – 17 8 months 0 – 15 > 8 months < 10 To establish the diagnosis of HT1, plasma tyrosine levels were measured using high-performance liquid chromatography (HPLC). Reference range: 40–120 µmol/L. Urinary succinylacetone levels were assessed by gas chromatography (GC). The procedure required a minimum of 5 mL of overnight urine. Samples delivered to the laboratory within one hour were transported on ice; if transport exceeded one hour, samples were frozen prior to shipment. Reference range: 20–70 µmol/L. Ethics Approval and Consent to Participate This study is part of a larger research project on inflammatory proteins and chronic diseases conducted at CHU Ibn Rochd, Casablanca (Morocco). An ethics application for this overarching research project was submitted on 26 June 2023 (File number N27/23) to the Institutional Ethics Committee of CHU Ibn Rochd. The Ethics Committee granted approval on 25 December 2023 under reference number RSO/145. This approval covered the main project from which several sub-studies were developed, including the present work entitled “Elevated alpha-fetoprotein in children and diagnosis of tyrosinemia: contribution of clinico-biological collaboration.” The study used fully anonymized data extracted from the Kalisil hospital information system. In accordance with the ethics committee decision, the requirement for individual informed consent was waived due to the retrospective design and the absence of identifiable personal data. The study was conducted in accordance with the principles of the Declaration of Helsinki (2013 revision). III. Results Our study included 21 children with suspected Type 1 hereditary tyrosinemia (HT1), consisting of 14 boys and 7 girls (sex ratio = 2). Patient age ranged from 1 month to 9 years, with a median age of 2.5 years. Half of the children were born to consanguineous parents, and only one patient had a reported family history of a similar condition. The most frequent reason for hospitalization was jaundice (Table 2). AFP levels were elevated in all patients, ranging from 224.8 ng/mL to 49,023 ng/mL. In addition to routine laboratory testing, all patients underwent abdominal ultrasonography, which identified 5 cases of biliary atresia. Serological evaluation revealed one case of viral hepatitis in an infant. One case of cystic fibrosis and one case of methylmalonic acidemia were diagnosed, while ataxia-telangiectasia was identified in two patients. In five children, the etiology of hepatocellular failure remained undetermined. HT1 was confirmed in 7 patients. These children showed markedly elevated plasma tyrosine levels supporting the suspected diagnosis, which was subsequently confirmed by the detection of urinary succinylacetone (Table 3). Consanguinity was present in 57% of confirmed cases. The age at diagnosis ranged from 2 months to 3 years, corresponding to a mean diagnostic delay of 18 months. Clinically, hepatic insufficiency and renal involvement were the predominant manifestations in children diagnosed with HT1 (Figure 1). From a biological standpoint, thrombocytopenia was observed in 3 patients (42.8%). Elevated aspartate aminotransferase (AST) levels were present in 4 patients (57%), while alanine aminotransferase (ALT) elevation was noted in only one patient (14.2%). Conjugated hyperbilirubinemia was detected in 2 patients (28.5%). Additionally, 4 patients (57%) presented with a prolonged prothrombin time. All patients received treatment with nitisinone along with a tyrosine- and phenylalanine-restricted diet. A favorable clinical evolution was observed in 4 patients (57%) (Figure 2). Table 2 : Clinical signs observed in the 21 patients Clinical Sign Frequency (%) Jaundice 33.3% Renal involvement 28.5% Hepatocellular insufficiency 28.5% Rickets 23.8% Table 3. Plasma Tyrosine Levels and Urinary Succinylacetone in the Seven Patients Diagnosed With Tyrosinemia Patient Sex Age Tyrosine Level (µmol/L) Urinary Succinylacetone (µmol/L) 1 F 7 years 484 200 2 M 6 months 660 280 3 M 4 years 740 748 4 M 6 years 447.7 85 5 F 5 years 463 200 6 F 4 years 760 450 7 F 7 years 510 240 IV. Discussion Type 1 tyrosinemia is caused by a deficiency in fumarylacetoacetate hydrolase. This enzymatic defect impairs the efficient conversion of tyrosine into non-toxic metabolites, leading to the accumulation of downstream toxic compounds, such as fumarylacetoacetate and maleylacetoacetate, which contributes to elevated AFP levels. The toxic accumulation has significant clinical consequences, resulting in hepatic failure with associated renal and neurological comorbidities (Figure 3). From a metabolic perspective, tyrosinemia is characterized by a cascade of biochemical events that disrupt tyrosine homeostasis. Tyrosine accumulates, causing oxidative stress in the liver and activating detoxification pathways. In response to this stress, the liver increases the synthesis of alpha-fetoprotein (AFP), a protein involved in tissue repair processes. AFP levels can thus serve as an indicator of the degree of hepatic stress and the extent of liver damage. Consequently, elevated AFP is commonly observed in patients with tyrosinemia, although it is not specific to this condition and may also be seen in other liver pathologies. Type 1 tyrosinemia (HT1) typically affects three organs—liver, kidney, and nervous system—which may co-occur in the same patient. In less common scenarios, the initial clinical presentation may be dominated by renal tubular dysfunction; however, liver involvement of varying severity is always present. The diagnosis in adults is exceptionally rare. Clinically, the presentation of tyrosinemia varies depending on age at onset and disease severity. Symptoms usually manifest before the age of 2 years. Infants with HT1 may present with prolonged jaundice, hepatomegaly, and signs of respiratory distress. If left undiagnosed or untreated, the condition can lead to severe complications, including acute liver failure, cirrhosis, and neurological impairment. The biological diagnosis of tyrosinemia relies on a systematic approach, starting with a non-specific metabolic workup to assess general metabolic status and detect potential anomalies. Initial routine tests, such as complete blood count, liver function tests, and urinary electrolytes, can guide further amino acid metabolic evaluation. Routine laboratory findings may include: Decreased prothrombin time (PT) and reduced coagulation factors (with factor V typically declining last), uncorrected by vitamin K administration, along with hypoalbuminemia due to hepatocellular insufficiency. Markedly elevated alkaline phosphatase (ALP) with relatively normal or slightly increased gamma-glutamyl transferase (GGT), and moderate transaminase elevation. Thrombocytopenia and anemia (related to δ-ALA inhibition of heme synthesis). Significant elevation of serum AFP. Signs of tubular dysfunction, including hypophosphatemia, phosphaturia, glycosuria, and proteinuria. Because AFP may also be elevated in other liver diseases, its interpretation must be contextual and combined with other clinical and biochemical data. The diagnosis is confirmed with specific investigations. Serum amino acid analysis typically shows markedly elevated tyrosine levels, often exceeding 500 µmol/L (normal range: 50–200 µmol/L). Urinary succinylacetone measurement is particularly significant, as it accumulates specifically in HT1 due to fumarylacetoacetate hydrolase (FAH) deficiency. Elevated urinary succinylacetone is a key diagnostic marker, confirming type 1 disease and assessing the severity of liver involvement. Additionally, evaluating FAH enzymatic activity in tissue or serum samples provides a fundamental diagnostic confirmation, with reduced activity confirming the presence of HT1. Molecular biology techniques, when combined with enzymatic assays, allow for a more precise diagnosis and help guide therapeutic decisions. The Central Role of AFP Serum AFP concentrations are naturally high at birth, particularly in preterm infants, where levels are inversely proportional to gestational age, and gradually decline to adult levels by around eight months of age. In the context of tyrosinemia, measuring AFP is particularly important because its elevation can serve as an early indicator of hepatic injury, aiding both diagnosis and patient monitoring. Several studies have demonstrated a correlation between AFP levels and the severity of tyrosinemia. Elevations often reflect the degree of hepatic involvement, making AFP a potentially useful biomarker for clinical follow-up, particularly in assessing the effectiveness of nitisinone therapy in inhibiting toxic metabolites. AFP also plays a key role in the differential diagnosis of pediatric liver diseases. Since other conditions—including viral hepatitis, hepatic tumors, and various metabolic disorders—can also cause elevated AFP, careful interpretation is essential to guide further targeted investigations. In some countries, systematic newborn screening programs include AFP measurement, which allows for early detection of metabolic abnormalities, including tyrosinemia, and enables timely intervention. Studies have shown that early detection through these programs can significantly improve clinical outcomes, reducing the risk of severe hepatic and neurological complications. It is important to interpret AFP levels within the overall clinical context, taking into account age, nutritional status, and other comorbidities. While AFP is a valuable diagnostic tool, it should not be used in isolation; a multidisciplinary approach incorporating clinical, biochemical, and genetic data is required to establish an accurate diagnosis and treatment plan. In our series, HT1 was confirmed in 7 patients, excluded in 9, and unconfirmed in 5. The seven confirmed cases showed biological evidence of HT1: elevated AFP in association with hypertyrosinemia. Definitive diagnosis was achieved through measurement of urinary succinylacetone, which was pathological in all seven cases. Clinically, the predominant symptoms observed were jaundice and hepatocellular insufficiency. The severity and timing of symptoms allow for classification into three clinical forms: acute, subacute, and chronic. Acute form: The most severe, presenting within the first weeks of life, characterized by severe hepatocellular insufficiency, jaundice, edema, ascites, and coagulation disorders. Age at hospitalization typically ranges from 2 to 6 months. Subacute form: Develops between 6 and 24 months, presenting with features of tubulopathy and hepatopathy, potentially progressing to cirrhosis. Chronic form: Appears later and is characterized by the classical triad of hepatic cirrhosis, proximal tubulopathy, and hypophosphatemic rickets. Urinary succinylacetone was elevated in all seven confirmed patients, confirming the diagnosis of HT1. Diagnosis was initially suspected based on clinical features and supported by increased AFP and hypertyrosinemia. It is important to note that hypertyrosinemia is not specific to HT1; it can also be observed in transient tyrosinemia due to tyrosine oxidase deficiency, in type II tyrosinemia caused by tyrosine aminotransferase deficiency, and in any form of hepatocellular insufficiency regardless of cause. HT1 is primarily a biochemical diagnosis. Clinical signs alone are insufficient due to multiple differential diagnoses. Routine laboratory tests, amino acid chromatography in blood and urine, and δ-ALA measurement may guide the evaluation, but definitive diagnosis relies on urinary succinylacetone levels and/or FAH enzyme activity measurement. Hepatorenal involvement explains many laboratory abnormalities, including hypoglycemia, hypoproteinemia, hypoalbuminemia, and decreased coagulation factors, which reflect hepatocellular insufficiency. Hepatic cytolysis accounts for increased bilirubin and transaminase levels. AFP levels may be low or high: low levels are associated with mild cirrhosis, whereas high levels indicate advanced disease. Renally, hyperphosphatasemia may accompany rickets, and tubulopathy leads to urinary loss of glucose, phosphate, calcium, proteins, and amino acids. FAH enzyme assays are only available in specialized laboratories, highlighting the importance of succinylacetone measurement. Urinary succinylacetone is easy to measure, highly specific, sensitive, and reproducible, making it a reliable postnatal diagnostic marker for HT1. It can also be used prenatally via amniocentesis between the 15th and 16th weeks of gestation. Beyond diagnosis, succinylacetone monitoring evaluates the effectiveness of NTBC (nitisinone) therapy, which inhibits hydroxyphenylpyruvate dioxygenase, preventing the formation of toxic tyrosine metabolites. NTBC-induced hypertyrosinemia necessitates a diet restricted in tyrosine and phenylalanine. Conclusion In conclusion, alpha-fetoprotein (AFP) remains a valuable biomarker in the evaluation of children with suspected type 1 hereditary tyrosinemia (HT1). However, its elevation is not specific to HT1, and interpretation should always be combined with clinical findings, plasma tyrosine levels, and urinary succinylacetone measurement. While research on AFP in tyrosinemia continues to evolve, current evidence supports its role primarily as an adjunctive diagnostic and monitoring tool rather than a standalone marker. This study has several limitations, including a small sample size, single-center design, retrospective data collection, and the absence of molecular confirmation for all patients. AFP variability with age and comorbidities may also affect interpretation. Future multicenter and prospective studies are needed to better define the diagnostic and prognostic utility of AFP and to optimize patient management. Abbreviations AFP: Alpha-fetoprotein HT1: Type 1 hereditary tyrosinemia FAH: Fumarylacetoacetate hydrolase HPLC: High-performance liquid chromatography GC: Gas chromatography Declarations Ethics approval and consent to participate This study is part of a broader research project on inflammatory proteins and chronic diseases conducted at CHU Ibn Rochd, Casablanca (Morocco). An ethics application for the overall project was submitted on 26 June 2023 (File number N27/23) to the Institutional Ethics Committee of CHU Ibn Rochd. The Committee granted approval on 25 December 2023 under reference number RSO/145. The present study uses fully anonymized retrospective data extracted from the Kalisil hospital information system. In accordance with the committee’s decision, the requirement for individual informed consent was waived due to the retrospective design and absence of identifiable patient information. The study was conducted in accordance with the Declaration of Helsinki (2013 revision). Consent for publication Not applicable. No individual or identifiable patient data are included in this manuscript. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Due to institutional restrictions, raw data from the hospital information system cannot be publicly shared. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. The research was carried out using institutional laboratory and hospital resources. Authors’ contributions M. Morjan contributed to study design, data extraction, data analysis, manuscript drafting, scientific supervision, validation of analyses, and critical revision of the manuscript. M. Omari participated in study design, data extraction, data analysis, and manuscript drafting. I. Chahid provided scientific supervision, validated the analytical procedures, and critically revised the manuscript. N. Kamal supervised the overall project and contributed to methodological guidance. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank the medical and nursing staff of the Metabolic Diseases Unit at the Abderrahim El Harouchi Mother-and-Child Hospital, as well as the Biochemistry Laboratory team at CHU Ibn Rochd, for their collaboration and support throughout this work. References Škaričić A, Zekušić M, Fumić K, Rogić D, Uroić V, Petković Ramadža D, Žigman T, Barić I. Diagnosis and the importance of early treatment of tyrosinemia type 1: A case report. Clin Mass Spectrom. 2019 Feb 2;12:1-6. Sniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. In: Adam MP, Feldman J, Mirzaa GM, et al. editors. GeneReviews®. Seattle (WA): University of Washington . Angileri F, Bergeron A, Morrow G, Lettre F, Gray G, Hutchin T, Ball S, Tanguay RM. Distribution géographique et ethnique des mutations du gène de la fumarylacétoacétate hydrolase dans la tyrosinémie héréditaire de type 1. JIMD Rep. 2015;19:43–58. Sikonja J, Brecelj J, Zerjav Tansek M, Repic Lampret B, Drole Torkar A, Klemencic S, Lipovec N, Stefanova Kralj V, Bertok S, Kovac J, Faganel Kotnik B, Tesarova M, Remec ZI, Debeljak M, Battelino T, Groselj U. Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia - A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant. Mol Genet Metab Rep. 2021 Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017 Dec;19(12). Kawabata K, Kido J, Yoshida T, Matsumoto S, Nakamura K. A case report of two siblings with hypertyrosinemia type 1 presenting with hepatic disease with different onset time and severity. Mol Genet Metab Rep. 2022 Morrow G, Tanguay RM. Biochemical and Clinical Aspects of Hereditary Tyrosinemia Type 1. Adv Exp Med Biol. 2017;959:9-21. Jin SJ, Du CQ, Luo XP. [Update on pathogenesis, diagnosis and treatment of hereditary tyrosinemia type Ⅰ]. Zhonghua Er Ke Za Zhi. 2022 Jun 2. Biomnis 2012, Présis de biopathologie annalyses médicales spécialisés Toso C, Andres A, Kneteman N, Hernandez-Alejandro R, Majno P. Alpha-foetoprotein: further evidence to add a biological marker to refine Milan criteria. Liver Int. 2016 Tanguay RM, Angileri F, Vogel A. Molecular Pathogenesis of Liver Injury in Hereditary Tyrosinemia 1. Adv Exp Med Biol. 2017;959:49-64. Giguère Y, Berthier MT. Newborn Screening for Hereditary Tyrosinemia Type I in Québec: Update. Adv Exp Med Biol. 2017;959:139-146. Calvas, P. (1992). Place du dosage de l’alpha-fœto-protéine sérique maternelle dans le diagnostic prénatal des anomalies fœtales. Immuno-Analyse & Biologie Spécialisée, 7(3), 33–38. Halvorsen S, kvittingen EA, Flatmark A. Outcome of therapy of hereditary tyrosinemia - Acta. Pediatr. Scand, (1988); 30, p 425-428 Saudubray J M. Déficits héréditaires du catabolisme des acides aminés : aminoacidopathies et aciduries organiques- in P. Godeau, S. Herson et JC Piette, Traité de Médecine, Flammarion Médecine-science, troisième édition, (1996), p 1526-1528. Adnan M, Puranik S. Hypertyrosinemia. 2022 Nov 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Berger R, Smith GPA, Stoker SA De Vries and al. Deficiency of fumaryl-acetoacetase in a patient with hereditary tyrosinemia. Clin. Chim. Acta, (1981); 114, p 37-44. Nakamura K, Matsumoto S, Mitsubuchi H, Endo F. Diagnosis and treatment of hereditary tyrosinemia in Japan. Pediatr Int. 2015 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 14 Feb, 2026 Reviewers invited by journal 05 Feb, 2026 Editor invited by journal 26 Dec, 2025 Editor assigned by journal 03 Dec, 2025 Submission checks completed at journal 03 Dec, 2025 First submitted to journal 03 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8184773","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586480243,"identity":"f2f3de74-ffb3-42e8-a36f-52e201df716a","order_by":0,"name":"Asmaa MORJAN","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABHElEQVRIie3QsWqEMBjA8e8I5BYP14iH9wqRQBzqwyiFm+rQpbg1pWCXg1t9jAPBOSCcQ1O6WlycOnVwKi0ctOfZLkXrWmj+Uwj58SUB0On+dhKgpT4yu3UDQAHJaTJL4/XcEjATQUdwMD0HGaowqZwg5vY+bN8gd7yb4rlZJMhm5cZrgthngBfNECFVlFkbqNlS7j1qJZhxpVwRqDUHPKeDY6rFjhhQhylITtzEOOfVhSvCpPBhlQyK1eND9n44kfKVhAm5ztJvgvEgoTLK7X6K4kQqiijpCR8jbhXlZ0taMwLqyhJxgIjaX6bHtzA8QpzjxZ5e4tohpMztA/1A5t3trm1j392OkK/rdX8nf2z+BvpMMXlEp9Pp/mmf6gpi5tog2OoAAAAASUVORK5CYII=","orcid":"","institution":"Faculty of Medicine and Pharmacy","correspondingAuthor":true,"prefix":"","firstName":"Asmaa","middleName":"","lastName":"MORJAN","suffix":""},{"id":586480245,"identity":"fa11f1c3-f0c3-4046-998c-ca87a98981df","order_by":1,"name":"Imane CHAHID","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Imane","middleName":"","lastName":"CHAHID","suffix":""},{"id":586480246,"identity":"dd972d64-fb61-4a2a-8aa3-216e4d397dd4","order_by":2,"name":"Mohamed OMARI","email":"","orcid":"","institution":"Higher Institute of Nursing Professions and Health Techniques Professions (ISPITS) of Casablanca","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"OMARI","suffix":""},{"id":586480248,"identity":"349282aa-ab85-4150-a3e7-68ed73665af2","order_by":3,"name":"Nabiha KAMAL","email":"","orcid":"","institution":"Faculty of Medicine and Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Nabiha","middleName":"","lastName":"KAMAL","suffix":""}],"badges":[],"createdAt":"2025-11-23 10:23:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8184773/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8184773/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102438366,"identity":"1e8d4321-cb05-49a0-9586-3e5d856cb9ca","added_by":"auto","created_at":"2026-02-11 16:32:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31805,"visible":true,"origin":"","legend":"\u003cp\u003eMajor Clinical Signs Observed in Patients with Tyrosinemia\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8184773/v1/9403e9f3f728ffcfe0a4056c.jpg"},{"id":102746151,"identity":"64d3dbf9-1a5d-45da-ad06-bd4485f37e9a","added_by":"auto","created_at":"2026-02-16 08:55:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30524,"visible":true,"origin":"","legend":"\u003cp\u003eClinical Outcome of Patients Diagnosed With Tyrosinemia\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8184773/v1/468905f008104690bb47a88d.jpg"},{"id":102438364,"identity":"8b632d8f-87da-4c86-a099-71124b5331f3","added_by":"auto","created_at":"2026-02-11 16:32:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5713,"visible":true,"origin":"","legend":"\u003cp\u003eComplications of Tyrosinemia (Source: Author)\u003c/p\u003e","description":"","filename":"placeholderimage.png","url":"https://assets-eu.researchsquare.com/files/rs-8184773/v1/bf37cacdad1da65b06672871.png"},{"id":102750509,"identity":"80296604-2e81-4373-b391-9b5cfd39a432","added_by":"auto","created_at":"2026-02-16 09:20:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":699967,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8184773/v1/086da392-2702-44ab-98ec-2088af426693.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevated Alpha-Fetoprotein in Children and the Diagnosis of Tyrosinemia: The Contribution of Clinico-Biological Collaboration","fulltext":[{"header":"I. Introduction","content":"\u003cp\u003eAlpha-fetoprotein (AFP) is a glycoprotein primarily produced by the fetal liver and yolk sac. After birth, AFP levels decline rapidly and typically reach normal values by approximately two months of age. Tyrosinemia is an autosomal recessive inherited disorder caused by enzymatic defects in the tyrosine degradation pathway, leading to the toxic accumulation of tyrosine and its metabolites. The most common forms include type I tyrosinemia, resulting from a deficiency in fumarylacetoacetate hydrolase, and type II tyrosinemia, caused by a deficiency in tyrosine aminotransferase. These metabolic defects can result in severe hepatic involvement, renal dysfunction, and neurological complications.\u003c/p\u003e \u003cp\u003eIn this context, AFP is widely used as a marker of liver dysfunction in children presenting with hepatic impairment, making it a valuable tool for the early detection of tyrosinemia.\u003c/p\u003e \u003cp\u003eHowever, elevated AFP levels are not specific to tyrosinemia. Other conditions\u0026mdash;such as viral hepatitis, liver malignancies, and various metabolic disorders\u0026mdash;may also lead to increased AFP levels. Therefore, AFP must be interpreted within a broader clinical and biological context to ensure an accurate differential diagnosis.\u003c/p\u003e \u003cp\u003eThe objectives of this study were to highlight the value of AFP as a biomarker in the diagnosis of type I tyrosinemia in children, to outline the etiological evaluation performed in cases of elevated AFP, and to clarify the diagnostic and prognostic significance of AFP levels.\u003c/p\u003e"},{"header":"II. Patients and Methods","content":"\u003cp\u003eThis retrospective study was conducted over a one-year period (June 2023 to July 2024). Data were extracted from the computerized database of the Biochemistry Laboratory at Ibn Rochd University Hospital in Casablanca (KALISIL), as well as from medical records. The study included patients hospitalized in the Metabolic Diseases Unit of the Abderrahim El Harouchi Mother-and-Child Hospital who presented with AFP levels significantly above age-specific reference ranges (Table 1).\u003c/p\u003e\n\u003cp\u003eEligible patients showed at least one of the following:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRenal manifestations: renal tubular acidosis, vitamin D\u0026ndash;resistant rickets, hypophosphatemia, or metabolic acidosis;\u003c/li\u003e\n \u003cli\u003eHepatic manifestations: vomiting, diarrhea, jaundice, abdominal distension, hepatomegaly and/or splenomegaly, or bleeding;\u003c/li\u003e\n \u003cli\u003eNeurological manifestations: painful limb crises or irritability.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eBlood samples (5 mL collected in the morning after an overnight fast, using a dry tube) were sent to the Biochemistry Laboratory. After centrifugation, serum samples were either analyzed immediately or frozen when analysis was delayed.\u003c/p\u003e\n\u003cp\u003eAFP measurement was performed using a microparticle chemiluminescent immunoassay (CMIA) for quantitative determination on the Abbott Alinity\u0026reg; analyzer.\u003c/p\u003e\n\u003cp\u003eTable 1\u003cstrong\u003e:\u003c/strong\u003e Age-specific AFP reference values\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference Range (ng/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreterm infant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e95,000 \u0026ndash; 175,000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNewborn\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e13,000 \u0026ndash; 83,000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 weeks\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e500 \u0026ndash; 66,000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 weeks \u0026ndash; 1 month\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e20 \u0026ndash; 19,000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 month\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e20 \u0026ndash; 5,600\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e20 \u0026ndash; 600\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e10 \u0026ndash; 180\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e10 \u0026ndash; 130\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e10 \u0026ndash; 70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e0 \u0026ndash; 20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e0 \u0026ndash; 17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e0 \u0026ndash; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.115%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026gt; 8 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.885%;\"\u003e\n \u003cp\u003e\u0026lt; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTo establish the diagnosis of HT1, plasma tyrosine levels were measured using high-performance liquid chromatography (HPLC).\u003cbr\u003e\u0026nbsp;Reference range: 40\u0026ndash;120 \u0026micro;mol/L.\u003c/p\u003e\n\u003cp\u003eUrinary succinylacetone levels were assessed by gas chromatography (GC). The procedure required a minimum of 5 mL of overnight urine. Samples delivered to the laboratory within one hour were transported on ice; if transport exceeded one hour, samples were frozen prior to shipment.\u003cbr\u003e\u0026nbsp;Reference range: 20\u0026ndash;70 \u0026micro;mol/L.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is part of a larger research project on inflammatory proteins and chronic diseases conducted at CHU Ibn Rochd, Casablanca (Morocco). An ethics application for this overarching research project was submitted on 26 June 2023 (File number N27/23) to the Institutional Ethics Committee of CHU Ibn Rochd.\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee granted approval on 25 December 2023 under reference number RSO/145. This approval covered the main project from which several sub-studies were developed, including the present work entitled \u0026ldquo;Elevated alpha-fetoprotein in children and diagnosis of tyrosinemia: contribution of clinico-biological collaboration.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eThe study used fully anonymized data extracted from the Kalisil hospital information system. In accordance with the ethics committee decision, the requirement for individual informed consent was waived due to the retrospective design and the absence of identifiable personal data.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki (2013 revision).\u003c/p\u003e"},{"header":"III. Results","content":"\u003cp\u003eOur study included 21 children with suspected Type 1 hereditary tyrosinemia (HT1), consisting of 14 boys and 7 girls (sex ratio = 2). Patient age ranged from 1 month to 9 years, with a median age of 2.5 years. Half of the children were born to consanguineous parents, and only one patient had a reported family history of a similar condition.\u003c/p\u003e\n\u003cp\u003eThe most frequent reason for hospitalization was jaundice (Table 2). AFP levels were elevated in all patients, ranging from 224.8 ng/mL to 49,023 ng/mL.\u003c/p\u003e\n\u003cp\u003eIn addition to routine laboratory testing, all patients underwent abdominal ultrasonography, which identified 5 cases of biliary atresia. Serological evaluation revealed one case of viral hepatitis in an infant. One case of cystic fibrosis and one case of methylmalonic acidemia were diagnosed, while ataxia-telangiectasia was identified in two patients.\u003cbr\u003e\u0026nbsp;In five children, the etiology of hepatocellular failure remained undetermined.\u003c/p\u003e\n\u003cp\u003eHT1 was confirmed in 7 patients. These children showed markedly elevated plasma tyrosine levels supporting the suspected diagnosis, which was subsequently confirmed by the detection of urinary succinylacetone (Table 3).\u003cbr\u003e\u0026nbsp;Consanguinity was present in 57% of confirmed cases. The age at diagnosis ranged from 2 months to 3 years, corresponding to a mean diagnostic delay of 18 months.\u003c/p\u003e\n\u003cp\u003eClinically, hepatic insufficiency and renal involvement were the predominant manifestations in children diagnosed with HT1 (Figure 1).\u003c/p\u003e\n\u003cp\u003eFrom a biological standpoint, thrombocytopenia was observed in 3 patients (42.8%). Elevated aspartate aminotransferase (AST) levels were present in 4 patients (57%), while alanine aminotransferase (ALT) elevation was noted in only one patient (14.2%). Conjugated hyperbilirubinemia was detected in 2 patients (28.5%). Additionally, 4 patients (57%) presented with a prolonged prothrombin time.\u003c/p\u003e\n\u003cp\u003eAll patients received treatment with nitisinone along with a tyrosine- and phenylalanine-restricted diet. A favorable clinical evolution was observed in 4 patients (57%) (Figure 2).\u003c/p\u003e\n\u003cp\u003eTable 2\u003cstrong\u003e:\u003c/strong\u003e Clinical signs observed in the 21 patients\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Sign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrequency (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJaundice\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRenal involvement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatocellular insufficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRickets\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3. Plasma\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eTyrosine Levels and Urinary Succinylacetone in the Seven Patients Diagnosed With Tyrosinemia\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTyrosine Level (\u0026micro;mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary Succinylacetone (\u0026micro;mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e484\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e447.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e463\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e760\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e510\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"IV. Discussion","content":"\u003cp\u003eType 1 tyrosinemia is caused by a deficiency in fumarylacetoacetate hydrolase. This enzymatic defect impairs the efficient conversion of tyrosine into non-toxic metabolites, leading to the accumulation of downstream toxic compounds, such as fumarylacetoacetate and maleylacetoacetate, which contributes to elevated AFP levels. The toxic accumulation has significant clinical consequences, resulting in hepatic failure with associated renal and neurological comorbidities (Figure 3).\u003c/p\u003e\n\u003cp\u003eFrom a metabolic perspective, tyrosinemia is characterized by a cascade of biochemical events that disrupt tyrosine homeostasis. Tyrosine accumulates, causing oxidative stress in the liver and activating detoxification pathways. In response to this stress, the liver increases the synthesis of alpha-fetoprotein (AFP), a protein involved in tissue repair processes. AFP levels can thus serve as an indicator of the degree of hepatic stress and the extent of liver damage. Consequently, elevated AFP is commonly observed in patients with tyrosinemia, although it is not specific to this condition and may also be seen in other liver pathologies.\u003c/p\u003e\n\u003cp\u003eType 1 tyrosinemia (HT1) typically affects three organs\u0026mdash;liver, kidney, and nervous system\u0026mdash;which may co-occur in the same patient. In less common scenarios, the initial clinical presentation may be dominated by renal tubular dysfunction; however, liver involvement of varying severity is always present. The diagnosis in adults is exceptionally rare.\u003c/p\u003e\n\u003cp\u003eClinically, the presentation of tyrosinemia varies depending on age at onset and disease severity. Symptoms usually manifest before the age of 2 years. Infants with HT1 may present with prolonged jaundice, hepatomegaly, and signs of respiratory distress. If left undiagnosed or untreated, the condition can lead to severe complications, including acute liver failure, cirrhosis, and neurological impairment.\u003c/p\u003e\n\u003cp\u003eThe biological diagnosis of tyrosinemia relies on a systematic approach, starting with a non-specific metabolic workup to assess general metabolic status and detect potential anomalies. Initial routine tests, such as complete blood count, liver function tests, and urinary electrolytes, can guide further amino acid metabolic evaluation.\u003c/p\u003e\n\u003cp\u003eRoutine laboratory findings may include:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDecreased prothrombin time (PT) and reduced coagulation factors (with factor V typically declining last), uncorrected by vitamin K administration, along with hypoalbuminemia due to hepatocellular insufficiency.\u003c/li\u003e\n \u003cli\u003eMarkedly elevated alkaline phosphatase (ALP) with relatively normal or slightly increased gamma-glutamyl transferase (GGT), and moderate transaminase elevation.\u003c/li\u003e\n \u003cli\u003eThrombocytopenia and anemia (related to \u0026delta;-ALA inhibition of heme synthesis).\u003c/li\u003e\n \u003cli\u003eSignificant elevation of serum AFP.\u003c/li\u003e\n \u003cli\u003eSigns of tubular dysfunction, including hypophosphatemia, phosphaturia, glycosuria, and proteinuria.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eBecause AFP may also be elevated in other liver diseases, its interpretation must be contextual and combined with other clinical and biochemical data.\u003c/p\u003e\n\u003cp\u003eThe diagnosis is confirmed with specific investigations. Serum amino acid analysis typically shows markedly elevated tyrosine levels, often exceeding 500 \u0026micro;mol/L (normal range: 50\u0026ndash;200 \u0026micro;mol/L). Urinary succinylacetone measurement is particularly significant, as it accumulates specifically in HT1 due to fumarylacetoacetate hydrolase (FAH) deficiency. Elevated urinary succinylacetone is a key diagnostic marker, confirming type 1 disease and assessing the severity of liver involvement. Additionally, evaluating FAH enzymatic activity in tissue or serum samples provides a fundamental diagnostic confirmation, with reduced activity confirming the presence of HT1.\u003c/p\u003e\n\u003cp\u003eMolecular biology techniques, when combined with enzymatic assays, allow for a more precise diagnosis and help guide therapeutic decisions.\u003c/p\u003e\n\u003ch3\u003eThe Central Role of AFP\u003c/h3\u003e\n\u003cp\u003eSerum AFP concentrations are naturally high at birth, particularly in preterm infants, where levels are inversely proportional to gestational age, and gradually decline to adult levels by around eight months of age. In the context of tyrosinemia, measuring AFP is particularly important because its elevation can serve as an early indicator of hepatic injury, aiding both diagnosis and patient monitoring.\u003c/p\u003e\n\u003cp\u003eSeveral studies have demonstrated a correlation between AFP levels and the severity of tyrosinemia. Elevations often reflect the degree of hepatic involvement, making AFP a potentially useful biomarker for clinical follow-up, particularly in assessing the effectiveness of nitisinone therapy in inhibiting toxic metabolites. AFP also plays a key role in the differential diagnosis of pediatric liver diseases. Since other conditions\u0026mdash;including viral hepatitis, hepatic tumors, and various metabolic disorders\u0026mdash;can also cause elevated AFP, careful interpretation is essential to guide further targeted investigations.\u003c/p\u003e\n\u003cp\u003eIn some countries, systematic newborn screening programs include AFP measurement, which allows for early detection of metabolic abnormalities, including tyrosinemia, and enables timely intervention. Studies have shown that early detection through these programs can significantly improve clinical outcomes, reducing the risk of severe hepatic and neurological complications. It is important to interpret AFP levels within the overall clinical context, taking into account age, nutritional status, and other comorbidities. While AFP is a valuable diagnostic tool, it should not be used in isolation; a multidisciplinary approach incorporating clinical, biochemical, and genetic data is required to establish an accurate diagnosis and treatment plan.\u003c/p\u003e\n\u003cp\u003eIn our series, HT1 was confirmed in 7 patients, excluded in 9, and unconfirmed in 5. The seven confirmed cases showed biological evidence of HT1: elevated AFP in association with hypertyrosinemia. Definitive diagnosis was achieved through measurement of urinary succinylacetone, which was pathological in all seven cases.\u003c/p\u003e\n\u003cp\u003eClinically, the predominant symptoms observed were jaundice and hepatocellular insufficiency. The severity and timing of symptoms allow for classification into three clinical forms: acute, subacute, and chronic.\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eAcute form:\u003c/strong\u003e The most severe, presenting within the first weeks of life, characterized by severe hepatocellular insufficiency, jaundice, edema, ascites, and coagulation disorders. Age at hospitalization typically ranges from 2 to 6 months.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSubacute form:\u003c/strong\u003e Develops between 6 and 24 months, presenting with features of tubulopathy and hepatopathy, potentially progressing to cirrhosis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eChronic form:\u003c/strong\u003e Appears later and is characterized by the classical triad of hepatic cirrhosis, proximal tubulopathy, and hypophosphatemic rickets.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eUrinary succinylacetone was elevated in all seven confirmed patients, confirming the diagnosis of HT1. Diagnosis was initially suspected based on clinical features and supported by increased AFP and hypertyrosinemia. It is important to note that hypertyrosinemia is not specific to HT1; it can also be observed in transient tyrosinemia due to tyrosine oxidase deficiency, in type II tyrosinemia caused by tyrosine aminotransferase deficiency, and in any form of hepatocellular insufficiency regardless of cause.\u003c/p\u003e\n\u003cp\u003eHT1 is primarily a biochemical diagnosis. Clinical signs alone are insufficient due to multiple differential diagnoses. Routine laboratory tests, amino acid chromatography in blood and urine, and \u0026delta;-ALA measurement may guide the evaluation, but definitive diagnosis relies on urinary succinylacetone levels and/or FAH enzyme activity measurement.\u003c/p\u003e\n\u003cp\u003eHepatorenal involvement explains many laboratory abnormalities, including hypoglycemia, hypoproteinemia, hypoalbuminemia, and decreased coagulation factors, which reflect hepatocellular insufficiency. Hepatic cytolysis accounts for increased bilirubin and transaminase levels. AFP levels may be low or high: low levels are associated with mild cirrhosis, whereas high levels indicate advanced disease. Renally, hyperphosphatasemia may accompany rickets, and tubulopathy leads to urinary loss of glucose, phosphate, calcium, proteins, and amino acids.\u003c/p\u003e\n\u003cp\u003eFAH enzyme assays are only available in specialized laboratories, highlighting the importance of succinylacetone measurement. Urinary succinylacetone is easy to measure, highly specific, sensitive, and reproducible, making it a reliable postnatal diagnostic marker for HT1. It can also be used prenatally via amniocentesis between the 15th and 16th weeks of gestation. Beyond diagnosis, succinylacetone monitoring evaluates the effectiveness of NTBC (nitisinone) therapy, which inhibits hydroxyphenylpyruvate dioxygenase, preventing the formation of toxic tyrosine metabolites. NTBC-induced hypertyrosinemia necessitates a diet restricted in tyrosine and phenylalanine.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, alpha-fetoprotein (AFP) remains a valuable biomarker in the evaluation of children with suspected type 1 hereditary tyrosinemia (HT1). However, its elevation is not specific to HT1, and interpretation should always be combined with clinical findings, plasma tyrosine levels, and urinary succinylacetone measurement. While research on AFP in tyrosinemia continues to evolve, current evidence supports its role primarily as an adjunctive diagnostic and monitoring tool rather than a standalone marker.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations, including a small sample size, single-center design, retrospective data collection, and the absence of molecular confirmation for all patients. AFP variability with age and comorbidities may also affect interpretation.\u003c/p\u003e\n\u003cp\u003eFuture multicenter and prospective studies are needed to better define the diagnostic and prognostic utility of AFP and to optimize patient management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFP: Alpha-fetoprotein\u003cbr\u003e\u0026nbsp;HT1: Type 1 hereditary tyrosinemia\u003cbr\u003e\u0026nbsp;FAH: Fumarylacetoacetate hydrolase\u003cbr\u003e\u0026nbsp;HPLC: High-performance liquid chromatography\u003cbr\u003e\u0026nbsp;GC: Gas chromatography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is part of a broader research project on inflammatory proteins and chronic diseases conducted at CHU Ibn Rochd, Casablanca (Morocco).\u003c/p\u003e\n\u003cp\u003eAn ethics application for the overall project was submitted on 26 June 2023 (File number N27/23) to the Institutional Ethics Committee of CHU Ibn Rochd.\u003c/p\u003e\n\u003cp\u003eThe Committee granted approval on 25 December 2023 under reference number RSO/145.\u003c/p\u003e\n\u003cp\u003eThe present study uses fully anonymized retrospective data extracted from the Kalisil hospital information system.\u003c/p\u003e\n\u003cp\u003eIn accordance with the committee\u0026rsquo;s decision, the requirement for individual informed consent was waived due to the retrospective design and absence of identifiable patient information.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki (2013 revision).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No individual or identifiable patient data are included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Due to institutional restrictions, raw data from the hospital information system cannot be publicly shared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study. The research was carried out using institutional laboratory and hospital resources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM. Morjan contributed to study design, data extraction, data analysis, manuscript drafting, scientific supervision, validation of analyses, and critical revision of the manuscript.\u003cbr\u003e\u0026nbsp;M. Omari participated in study design, data extraction, data analysis, and manuscript drafting.\u003cbr\u003e\u0026nbsp;I. Chahid provided scientific supervision, validated the analytical procedures, and critically revised the manuscript.\u003cbr\u003e\u0026nbsp;N. Kamal supervised the overall project and contributed to methodological guidance.\u003cbr\u003e\u0026nbsp;All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the medical and nursing staff of the Metabolic Diseases Unit at the Abderrahim El Harouchi Mother-and-Child Hospital, as well as the Biochemistry Laboratory team at CHU Ibn Rochd, for their collaboration and support throughout this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u0026Scaron;karičić A, Zeku\u0026scaron;ić M, Fumić K, Rogić D, Uroić V, Petković Ramadža D, Žigman T, Barić I. Diagnosis and the importance of early treatment of tyrosinemia type 1: A case report. Clin Mass Spectrom. 2019 Feb 2;12:1-6.\u003c/li\u003e\n\u003cli\u003eSniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. In: Adam MP, Feldman J, Mirzaa GM, et al. editors. GeneReviews\u0026reg;. Seattle (WA): University of Washington . \u003c/li\u003e\n\u003cli\u003eAngileri F, Bergeron A, Morrow G, Lettre F, Gray G, Hutchin T, Ball S, Tanguay RM. Distribution g\u0026eacute;ographique et ethnique des mutations du g\u0026egrave;ne de la fumarylac\u0026eacute;toac\u0026eacute;tate hydrolase dans la tyrosin\u0026eacute;mie h\u0026eacute;r\u0026eacute;ditaire de type 1. JIMD Rep. 2015;19:43\u0026ndash;58.\u003c/li\u003e\n\u003cli\u003eSikonja J, Brecelj J, Zerjav Tansek M, Repic Lampret B, Drole Torkar A, Klemencic S, Lipovec N, Stefanova Kralj V, Bertok S, Kovac J, Faganel Kotnik B, Tesarova M, Remec ZI, Debeljak M, Battelino T, Groselj U. Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia - A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant. Mol Genet Metab Rep. 2021\u003c/li\u003e\n\u003cli\u003eChinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017 Dec;19(12). \u003c/li\u003e\n\u003cli\u003eKawabata K, Kido J, Yoshida T, Matsumoto S, Nakamura K. A case report of two siblings with hypertyrosinemia type 1 presenting with hepatic disease with different onset time and severity. Mol Genet Metab Rep. 2022\u003c/li\u003e\n\u003cli\u003eMorrow G, Tanguay RM. Biochemical and Clinical Aspects of Hereditary Tyrosinemia Type 1. Adv Exp Med Biol. 2017;959:9-21. \u003c/li\u003e\n\u003cli\u003eJin SJ, Du CQ, Luo XP. [Update on pathogenesis, diagnosis and treatment of hereditary tyrosinemia type Ⅰ]. Zhonghua Er Ke Za Zhi. 2022 Jun 2.\u003c/li\u003e\n\u003cli\u003eBiomnis 2012, Pr\u0026eacute;sis de biopathologie annalyses m\u0026eacute;dicales sp\u0026eacute;cialis\u0026eacute;s\u003c/li\u003e\n\u003cli\u003eToso C, Andres A, Kneteman N, Hernandez-Alejandro R, Majno P. Alpha-foetoprotein: further evidence to add a biological marker to refine Milan criteria. Liver Int. 2016\u003c/li\u003e\n\u003cli\u003eTanguay RM, Angileri F, Vogel A. Molecular Pathogenesis of Liver Injury in Hereditary Tyrosinemia 1. Adv Exp Med Biol. 2017;959:49-64.\u003c/li\u003e\n\u003cli\u003eGigu\u0026egrave;re Y, Berthier MT. Newborn Screening for Hereditary Tyrosinemia Type I in Qu\u0026eacute;bec: Update. Adv Exp Med Biol. 2017;959:139-146.\u003c/li\u003e\n\u003cli\u003eCalvas, P. (1992). Place du dosage de l\u0026rsquo;alpha-f\u0026oelig;to-prot\u0026eacute;ine s\u0026eacute;rique maternelle dans le diagnostic pr\u0026eacute;natal des anomalies f\u0026oelig;tales. Immuno-Analyse \u0026amp; Biologie Sp\u0026eacute;cialis\u0026eacute;e, 7(3), 33\u0026ndash;38.\u003c/li\u003e\n\u003cli\u003eHalvorsen S, kvittingen EA, Flatmark A. Outcome of therapy of hereditary tyrosinemia - Acta. Pediatr. Scand, (1988); 30, p 425-428\u003c/li\u003e\n\u003cli\u003eSaudubray J M. D\u0026eacute;ficits h\u0026eacute;r\u0026eacute;ditaires du catabolisme des acides amin\u0026eacute;s : aminoacidopathies et aciduries organiques- in P. Godeau, S. Herson et JC Piette, Trait\u0026eacute; de M\u0026eacute;decine, Flammarion M\u0026eacute;decine-science, troisi\u0026egrave;me \u0026eacute;dition, (1996), p 1526-1528.\u003c/li\u003e\n\u003cli\u003eAdnan M, Puranik S. Hypertyrosinemia. 2022 Nov 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 \u003c/li\u003e\n\u003cli\u003eBerger R, Smith GPA, Stoker SA De Vries and al. Deficiency of fumaryl-acetoacetase in a patient with hereditary tyrosinemia. Clin. Chim. Acta, (1981); 114, p 37-44.\u003c/li\u003e\n\u003cli\u003eNakamura K, Matsumoto S, Mitsubuchi H, Endo F. Diagnosis and treatment of hereditary tyrosinemia in Japan. Pediatr Int. 2015\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alpha-fetoprotein, Type 1 tyrosinemia, Amino acid metabolism, Serum tyrosine, Fumarylacetoacetate hydrolase (FAH)","lastPublishedDoi":"10.21203/rs.3.rs-8184773/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8184773/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Type 1 hereditary tyrosinemia (HT1) is an autosomal recessive disorder that leads to toxic accumulation of tyrosine and its metabolites, causing hepatic stress that stimulates the production of alpha-fetoprotein (AFP).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To assess the value of AFP as a biomarker for the diagnosis of tyrosinemia in children.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods:\u003c/strong\u003e This one-year prospective study was based on the review of medical records of patients hospitalized in the Metabolic Diseases Unit at the Abderrahim El Harouchi Mother-and-Child Hospital who presented with significantly elevated AFP levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 21 cases with suspected HT1 were included. The most common reason for admission was jaundice (33.3%). In addition to laboratory testing, all children underwent abdominal ultrasound, which revealed five cases of biliary atresia. Serological assessment identified one case of viral hepatitis in an infant. One case each of cystic fibrosis and methylmalonic acidemia was diagnosed, and two patients were found to have ataxia-telangiectasia. The cause of hepatocellular failure remained unknown in five cases. HT1 was confirmed in seven patients. These children showed markedly elevated plasma tyrosine levels, supporting the clinical suspicion, and the diagnosis was confirmed by the detection of urinary succinylacetone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e AFP remains a key biomarker in the diagnosis of HT1. Regular monitoring helps assess disease progression and evaluate treatment effectiveness.\u003c/p\u003e","manuscriptTitle":"Elevated Alpha-Fetoprotein in Children and the Diagnosis of Tyrosinemia: The Contribution of Clinico-Biological Collaboration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 16:32:28","doi":"10.21203/rs.3.rs-8184773/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"258063921763370245780217108374390156230","date":"2026-02-14T20:32:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-05T07:40:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-26T15:14:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-04T02:39:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-03T14:19:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-12-03T14:13:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e9a145e-ec73-4255-a49c-ad4b45e127eb","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-11T16:32:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 16:32:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8184773","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8184773","identity":"rs-8184773","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}