A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood

Medicina · 5 authors, 3 centres

AI SUMMARY

FIDELITY 100%

POPULATIONA 2-year-old girl with hereditary tyrosinemia type 1 presenting with acute liver failure

INTERVENTIONNitisinone (1 mg/kg/day) plus dietary restriction of tyrosine and phenylalanine

COMPARISONNo control group; comparison to historical cases and literature

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TL;DR

This paper presents the fourth case of hereditary tyrosinemia type 1 (HT1) diagnosed in Lithuania, manifesting as acute liver failure in a 2-year-old girl. Treatment with nitisinone led to rapid clinical improvement, normalizing liver function and reducing alpha-fetoprotein levels. The case highlights the critical need for universal newborn screening for tyrosinemia to enable early diagnosis and prevent severe complications.

Full summary

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**Background:** Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH), leading to accumulation of toxic metabolites (succinylacetone, fumarylacetoacetate) in liver and kidneys. It presents with progressive liver damage, renal tubular dysfunction, neurological crises, and high risk of hepatocellular carcinoma (HCC). Global prevalence is ~1 in 100,000–120,000 live births, but higher in Nordic countries (1 in 60,000–74,800) and Quebec (1 in 16,000). In Lithuania, universal newborn screening for tyrosinemia is not performed; only four cases have been diagnosed over two decades. Early diagnosis and treatment with nitisinone (NTBC) before age 1 month can prevent complications, but without screening, diagnosis often occurs after severe symptoms develop.

**Methods:** This is a case report of the fourth HT1 patient diagnosed in Lithuania, at the Children’s Diseases’ Clinic of LUHS Hospital Kaunas Clinics. The patient was a 2-year-old girl born prematurely at 34 weeks (birth weight 2600 g, Apgar 10–10) with unremarkable neonatal period. At 1.5 years, she developed frequent respiratory infections and was found to have mild normocytic normochromic anemia (Hb 98 g/L), neutropenia (0.7 × 10^9/L), and thrombocytopenia (117 × 10^9/L). Iron therapy for 5 months was ineffective. At age 2, she was referred for hepatomegaly (liver 3 cm below costal margin), splenomegaly, and acute liver failure: significantly reduced prothrombin complex activity, hyperammonemia, mild hypoalbuminemia, marked elevation of GGT and ALP. Kidney function was normal. Imaging (ultrasound and CT) showed enlarged liver (9.5–10 cm cranio-caudal) with irregular contour, heterogeneous parenchyma, and multiple hypodense lesions (largest 1.2–1.6 cm in left lobe). Liver biopsy revealed cirrhosis with steatosis, no neoplasia. Over one week, condition deteriorated with fever, lethargy, jaundice, ascites, and sepsis (S. aureus). HT1 was suspected due to markedly elevated alpha-fetoprotein (AFP: 47,863 kU/L). Blood amino acid analysis showed fourfold increased tyrosine (482.51 µmol/L, normal 22.43–125.11). Urine organic acids showed massively elevated succinylacetone (10,833.18 µmol/mmol creatinine, normal <2.67), 3-phenyllactic acid (91.60 µmol/mmol creatinine, normal <2.0), and P-hydroxyphenyllactic acid (481.29 µmol/mmol creatinine, normal <27.06). Molecular testing confirmed homozygous pathogenic variant c.1062+5G>A in FAH gene.

**Key Results:** Upon suspicion of HT1, nitisinone (1 mg/kg/day) was started. Clinical improvement was observed within 1 day: fever resolved, activity increased, ascites disappeared within 1.5 weeks, abdominal circumference reduced by ~6 cm. Laboratory tests showed rapid improvement: SPA increased from 14% to 66%, albumin from 26 to 40.1 g/L. AFP decreased from 47,863.6 kU/L before treatment to 100.2 kU/L after 9 months. Urine succinylacetone gradually decreased from 8.55 to 4.14 µmol/mmol creatinine. Blood tyrosine fluctuated between 400–520 µmol/L. After 1 month, GGT increased, so ursodeoxycholic acid was added, which reduced cholestasis. Liver size remained ~9.5 cm, spleen decreased to 9.0 × 2.5 cm. The patient continued nitisinone and a low-tyrosine/phenylalanine diet (protein 1–2 g/kg/day).

**Clinical Implications:** This case demonstrates that HT1 can present with subacute symptoms (anemia, neutropenia, thrombocytopenia) before progressing to acute liver failure. In countries without universal newborn screening, physicians must consider HT1 in children with unexplained cytopenias, elevated liver enzymes (especially GGT, ALP), and markedly elevated AFP. Succinylacetone in urine is pathognomonic. Nitisinone treatment should be started immediately upon suspicion; response is typically rapid (within 1 week) and can prevent liver transplantation. Lifelong monitoring of AFP, liver function, and imaging is essential due to high HCC risk. The paper emphasizes that universal newborn screening for tyrosinemia is the only way to achieve early diagnosis and optimal outcomes, as treatment before age 1 month reduces HCC risk to <1% and improves survival (>90% with combination therapy).

PICO

PPOPULATION

A 2-year-old girl with hereditary tyrosinemia type 1 presenting with acute liver failure

IINTERVENTION

Nitisinone (1 mg/kg/day) plus dietary restriction of tyrosine and phenylalanine

OOUTCOME

Clinical improvement within 1 day; liver function normalized (SPA increased from 14% to 66%, albumin from 26 to 40.1 g/L); AFP decreased from 47,863.6 to 100.2 kU/L over 9 months; ascites resolved; no liver transplantation needed

STUDY TYPE

case_report

SPECIALTY

pediatric ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10820469

A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood

Medicina

READ THE FULL PAPER

ABSTRACT

Hereditary type 1 tyrosinemia (HT1) is a rare inherited autosomal recessive disorder of tyrosine metabolism, characterized by progressive liver damage, dysfunction of kidney tubules, and neurological crises. In the course of this disease, due to the deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), toxic intermediate metabolites of tyrosine breakdown, such as fumarylacetoacetate (FAA), succinylacetoacetate (SAA), and succinylacetone (SA), accumulate in liver and kidney cells, causing cellular damage. Because of this, an increased SA concentration in the blood or urine is pathognomonic of HT1. In the year 2000, HT1 was diagnosed in Lithuania for the first time, and this was the first time when a specific treatment for HT1 was administered in the country. Over two decades, four cases of this disease have been diagnosed in Lithuania. In the first of these patients, the disease was diagnosed in infancy, manifesting as liver damage with liver failure. Treatment with nitisinone was initiated, which continues to be administered, maintaining normal liver function. Liver transplantation was performed on two subsequent patients due to complications of HT1. It is crucial to diagnose HT1 as early as possible in order to reduce or completely eliminate complications related to the disease, including progressive liver failure and kidney dysfunction, among others. This can only be achieved by conducting a universal newborn screening for tyrosinemia and by starting treatment with nitisinone (NTBC) before the age of 1 month in all cases of HT1. However, in those countries where this screening is not being carried out, physicians must be aware of and consider this highly rare disorder. They should be vigilant, paying attention to even minimal changes in a few specific laboratory test results—such as unexplained anemia alongside neutropenia and thrombocytopenia—and should conduct more detailed examinations to determine the causes of these changes. In this article, we present the latest clinical case of HT1 in Lithuania, diagnosed at the Children’s Diseases’ Clinic of the Lithuanian University of Health Sciences (LUHS) Hospital Kaunas Clinics. The case manifested as life-threatening acute liver failure in early childhood. This article explores and discusses the peculiarities of diagnosing this condition in the absence of universal newborn screening for tyrosinemia in the country, as well as the course, treatment, and ongoing monitoring of patients with this disorder.

CITATION EXPORT

Rūta Rokaitė, Agnė Čibirkaitė, Vykinta Zeleckytė et al.. A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood. Medicina. (2024). https://doi.org/10.3390/medicina60010135

AUTHORS

5 · 3 CENTRES

Rūta Rokaitė, Agnė Čibirkaitė, Vykinta Zeleckytė, Gabija Lazdinytė, Mindaugas Dženkaitis

1Department of Pediatrics, Medical Academy, Lithuanian University of Health Sciences, LT 44307 Kaunas, Lithuania
2Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, LT 44307 Kaunas, Lithuania
3School of Medicine, College of Health and Agricultural Sciences, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland

EDITOR / REVIEWER

Felix Bende, Alina Popescu, Matteo Rosselli