Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of AFP

Ginkel, Willem G. van; Gouw, Annette; Jagt, Eric J. van der; Jong, Koert P. de; Verkade, Henkjan J.; Spronsen, Francjan J. van

doi:10.1542/peds.2014-1913

Cited by 26 publications

(26 citation statements)

References 18 publications

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“…However, elevated AFP levels are not diagnostic for HT-1. 71 In contrast, elevated blood or urine SA levels are diagnostic for HT-1. SA should return to undetectable (or normal per reference laboratory) levels with NTBC therapy and throughout life as evidence of compliance with drug therapy.…”

Section: Clinical Findings In Ht-1mentioning

confidence: 99%

“…Cases of hepatocellular carcinoma have been reported several years after the initiation of NTBC, even after dramatic declines in the initial elevated AFP levels. 71 , 72 It is of note that neither ultrasound, nor computed tomography, nor magnetic resonance imaging can discriminate between all benign and malignant hepatic nodules that appear in up to 75% of non-NTBC-treated patients. 9 , 32 , 73 , 74 , 75 Prior to the NTBC therapy era, the presence of HCC was an indication for hepatic transplantation in HT-1 patients.…”

Section: Clinical Findings In Ht-1mentioning

confidence: 99%

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Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Chinsky

Singh

Fıçıcıoğlu

et al. 2017

Genetics in Medicine

177

222

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Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.

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Section: Clinical Findings In Ht-1mentioning

confidence: 99%

Section: Clinical Findings In Ht-1mentioning

confidence: 99%

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Chinsky

Singh

Fıçıcıoğlu

et al. 2017

Genetics in Medicine

177

222

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“…Despite improved treatment with NTBC, previous reports indicate that HT1 patients are still at risk for developing hepatocellular carcinoma (van Spronsen et al 2005, Koelink et al 2006, van Ginkel et al 2015. This may be related to suboptimal treatment with NTBC.…”

Section: Introductionmentioning

confidence: 99%

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day

Kienstra

Reemst

Ginkel

et al. 2017

J of Inher Metab Disea

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IntroductionIn hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens.MethodsAll patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively.ResultsNTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 μmol/l.DiscussionNTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.Electronic supplementary materialThe online version of this article (10.1007/s10545-017-0112-9) contains supplementary material, which is available to authorized users.

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“…56,[63][64][65] These patients usually have a slow decrease in α-fetoprotein (AFP) levels without reaching normal levels despite treatment or persistent high levels of AFP. 66 Despite these findings, nitisinone decreases the risk of HCC compared to those before nitisinone treatment, as HCC incidence was reported to be 18%-37% among children who have survived past their second birthday. 35,67 Early treatment has been shown to decrease the risk of HCC.…”

mentioning

confidence: 99%

Nitisinone: a review

Aktuglu-Zeybek¹,

Zübarioğlu²

2017

ODRR

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Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]cyclohexane-1,3-dione), an effective triketone herbicide, is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the tyrosine catabolic pathway. Since 1992, the drug has become an effective pharmacological treatment for hereditary tyrosinemia type 1 (HT1). Nitisinone can prevent the development of liver disease, reverse and prevent the renal tubular dysfunction, severe neurological crisis and cardiomyopathy and significantly reduce the risk of developing hepatocellular carcinoma in HT1 patients. Its mode of action, with few side effects reported, make the drug a potential candidate for the treatment of other disorders of tyrosine metabolism, including alkaptonuria, with successful reduction in homogentisic acid production to prevent long-term complications. Nitisinone could also be a promising agent in the treatment of tumors with active tyrosine metabolic pathways. In this review, we discuss the effects of nitisinone for various tyrosine pathway disorders.

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Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of AFP

Cited by 26 publications

References 18 publications

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day

Nitisinone: a review

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