Tyrosinemia Type 1 Presenting with Congestive Cardiac Failure

Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal.

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The outcome of seven patients with hereditary tyrosinemia type 1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0471 ◽

2016 ◽

Vol 29 (10) ◽

Cited By ~ 4

Author(s):

Songul Gokay ◽

Pembe Soylu Ustkoyuncu ◽

Fatih Kardas ◽

Mustafa Kendirci

Keyword(s):

Clinical Symptoms ◽

Age At Onset ◽

Nodule Formation ◽

First Year ◽

Tyrosine Metabolism ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia ◽

Biochemical Imaging

AbstractBackground:Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment.Methods:A retrospective study was carried out with seven HT1 patients.Results:The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up.Conclusions:This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

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An intrathoracic arteriovenous malformation discovered as an extremely uncommon reason of neonatal congestive cardiac failure

Cardiology in the Young ◽

10.1017/s1047951109991375 ◽

2009 ◽

Vol 19 (5) ◽

pp. 530-533 ◽

Cited By ~ 2

Author(s):

Sigrun R. Hofmann ◽

Matthias Weise ◽

Katharina I. Nitzsche

Keyword(s):

Arteriovenous Malformation ◽

Cardiac Failure ◽

Arteriovenous Malformations ◽

Neonatal Period ◽

High Flow ◽

Congestive Cardiac Failure ◽

Vein Of Galen ◽

Prenatal Detection ◽

First Case

AbstractCongenital arteriovenous malformations are rare causes of congestive cardiac failure in neonates. The most common sites are in the head and liver, but other sites include the thorax, the abdomen and the limbs. The onset of failure is usually not in the immediate neonatal period, but later on in life, albeit that lesions such as the arteriovenous malformation of the vein of Galen, and other arteriovenous malformations in different locations which produce high flow can present early. We describe here the first case, to the best of our knowledge, of prenatal detection of an intrathoracic arteriovenous malformation producing neonatal cardiac failure, which was successfully treated by surgery postnatally.

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