NTBC Treatment Monitoring in Chilean Patients with Tyrosinemia Type 1 and Its Association with Biochemical Parameters and Liver Biomarkers (original) (raw)
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Experience of a Single Center in NTBC Use in Management of Hereditary Tyrosinemia Type I in Libya
Iranian Journal of Pediatrics, 2015
Background: Hereditary Tyrosinemia type I (HTI) is a metabolic disease caused by deficiency of fumarylacetoacetate hydrolase enzyme. Objectives: This study reports beside its clinical and biochemical presentation, the outcome of NTBC [2-(2-nitro-4-trifloro-methylbenzoyl)-1, 3-cyclohexanedion] treatment of the disease and evaluates its biochemical markers in 16 pediatric Libyan patients. Patients and Methods: The diagnosis was based on presence of high tyrosine levels in blood and succinylacetone in urine. Results: The consanguinity rate was 81.2%, the median age at onset, at diagnosis and at starting treatment were 4.5, 8, and 9.5 months respectively. At presentation hepatomegaly, jaundice, rickets and high gamma glutamyl transferase (GGT) were observed in 87.5% of patients. All patients had extremely high alpha fetoprotein (AFP) and high alkaline phosphatase (ALP) levels. Fifteen patients were treated with NTBC, normalization of PT (Prothrombine time) was achieved in average in 14 days. The other biochemical parameters of liver function (transaminases, GGT, ALP, bilirubin and albumin) took longer to improve and several months to be normalized. Survival rate with NTBC was 86.6%. Patients who started treatment in a median of 3 months post onset observed a fast drop of AFP in 90.6% of patients (P = 0.003). Abnormal liver function and rickets were the common presentations, GGT was an early cholestatic sensitive test. ALP was constantly high even in asymptomatic patients. Conclusions: In HT1 a faster dropping of AFP is a marker of good prognosis.
Journal of inherited metabolic disease, 2018
In 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. All 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. NTBC concentrations varied significantly during the day especially if NTBC was ta...
Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain
Medicine
Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution. We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome. The average follow-up period was 6.1 ± 4.9 and 10.6 ± 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma. Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ± 4.43 vs 24.30 ± 6.10; P = .08) and those with good pharmacological adherence (21.19 ± 4.68 vs 28.58 ± 213.79). intellectual quotient was ≥85 in all NBS-and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure. Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T. After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018). This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.
Molecular Genetics and Metabolism, 2002
In human patients with hereditary tyrosinemia type I (HT1) a combination therapy of 2-(2-nitro-4trifluoromethylbenzoyl)-1,3 cyclohexane dione (NTBC) and dietary restriction of phenylalanine and tyrosine is currently widely used. We previously reported that the use of NTBC in a murine model of HT1 abolished acute liver failure but did not prevent the development of hepatocellular carcinoma (HCC) in the setting of nonrestricted protein intake. Here we present the results obtained with higher doses of NTBC plus dietary tyrosine restriction on long-term follow up (>2 years). Liver function tests and succinylacetone levels were completely corrected with this regimen and cancer-free survival was improved when compared to historical controls. However, while no HT1 animals had HCC at age 13 months, the incidence was 2/16 (13%) at age 18 months and 1/6 (17%) after 24 months. Thus, even the most stringent therapy could not prevent the emergence of HCC in the mouse model of HT1, even when initiated prenatally.
Phenotype, genotype, and outcome of 25 Palestinian patients with hereditary tyrosinemia type 1
Metabolism Open
Background: Tyrosinemia type 1 (hepatorenal tyrosinemia, HT1) is a rare autosomal recessive inborn error of tyrosine metabolism caused by deficiency of the last enzyme in the tyrosine catabolic pathway, fumarylacetoacetate hydrolase (FAH) leading to severe hepatic, renal and peripheral nerve damage if left untreated. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. Material and methods: A retrospective single center study was carried out based on the clinical and biochemical presentation, therapy and outcome of 25 Palestinian patients with HT1 diagnosed during the last 25 years. Results: HT1 is not included in newborn screening program in Palestine. The mean age at diagnosis was 8 months and the main clinical manifestations were coagulopathy, hepatomegaly, splenomegaly and renal tubular dysfunction. The main biochemical abnormalities were elevated plasma tyrosine, serum transaminases and prothrombin time, and low serum phosphorous with elevated alkaline phosphatase compatible with hypophosphatemic rickets secondary to renal tubular dysfunction. All patients were treated with nitisinone. The mean duration of nitisinone treatment was 74 months and the mean dosage was 0.89 mg/kg/day. None developed HCC or neurological crisis. Conclusions: Most patients present with liver failure and renal tubular dysfunction. Nitisinone treatment was effective therapy in all patients and improved both short-and long-term prognosis of HT1. Renal tubular dysfunction improved in all patients within the first week of starting nitisinone. Early diagnosis is necessary because delay in the treatment increases the risk of progressive liver failure HCC, progressive renal disease and neuropathy.
Current management options for tyrosinemia
Orphan Drugs: Research and Reviews, 2013
Hypertyrosinemia is observed in three inherited disorders of tyrosine metabolism. Hereditary Tyrosinemia Type I (HTT-I), or hepatorenal tyrosinemia, is an autosomal recessive disorder caused by mutation in the fumarylacetoacetate hydrolase (FAH) gene. HTT-I is associated with severe involvement of the liver, kidneys, and central nervous system, and is due to toxic accumulation of metabolites of tyrosine, such as succinylacetone. HTT-I is the inborn error with the highest incidence of progression to hepatocellular carcinoma. Elevated succinylacetone, in dried filter paper blood samples, or in plasma or urine, is pathognomonic and diagnostic for HTT-I and is the most reliable neonatal screening method. Liver transplantation is the definitive management, but the need for this is markedly decreased by the combined dietary and drug management. A diet low in tyrosine and phenylalanine, plus nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione) (NCTB) are considered the gold standard management options. Carnitine and 1,25-OH-vitamin D are adjuvant therapy. Strict follow up with succinylacetone level for monitoring of treatment should be done. Abdominal ultrasonography and abdominal computerized tomography scan or magnetic resonance imaging should also be done for surveillance of the possible development of hepatocellular carcinoma.
Pediatric and Developmental Pathology, 2001
Hypertyrosinemia encompasses several entities, of which tyrosinemia type I (or hepatorenal tyrosinemia, HT1) results in the most extensive clinical and pathological manifestations involving mainly the liver, kidney, and peripheral nerves. The clinical findings range from a severe hepatopathy of early infancy to chronic liver disease and rickets in the older child; gradual refinements in the diagnosis and medical management of this disorder have greatly altered its natural course, mirroring recent advances in the field of metabolic diseases in the past quarter century. Hepatorenal tyrosinemia is the inborn error with the highest incidence of progression to hepatocellular carcinoma, likely due to profound mutagenic effects and influences on the cell cycle by accumulated metabolites. The appropriate follow-up of patients with cirrhosis, the proper timing of liver transplantation in the prevention of carcinoma, and the long-term evolution of chronic renal disease remain important unresolved issues. The introduction of a new pharmacologic agent, NTBC, holds the hope of significantly alleviating some of the burdens of this disease. Mouse models of this disease have permitted the exploration of newer treatment modalities, such as gene therapy by viral vectors, including ex vivo and in utero methods. Finally, recent observations on spontaneous genetic reversion of the mutation in HT1 livers challenge conventional concepts in human genetics.
Hepatology, 1994
Hereditary tyrosinemia type 1 (McKusick 27670) is a heterogeneous disease with poor prognosis, yet there are few reports of the long-term prognosis. It is therefore difficult to decide on the treatment for individual patients. We have conducted an international survey of patients with tyrosinemia type I and examined the probability of survival on dietary treatment and the causes of death in 108 patients with tyrosinemia type I. The survival after the onset of symptoms varied with the age at onset; the earlier the symptoms developed the poorer the outlook. Liver failure and recurrent bleeding (67%), hepatocellular carcinoma (17%) and the porphyria-like syndrome with respiratory failure (10%) were the most common causes of death. The 1and 2-yr survival probability after the onset of symptoms in patients in whom symptoms developed before 2 mo, between 2 and 6 mo and after 6 mo were 38%/29%, 74%/74% and 96%/96%, respectively. On the basis of these survival rates, a new classificationwhich is important with respect to choices in treatmentis proposed: very early (onset of symptoms < 2 mo), early (2 to 6 mo) andlate presentingform ( > 6 mo).
A Review of Metabolic Disorder of Amino Acid Tyrosinemia type I: When to Suspect and how to Diagnose
Background: Hereditary Tyrosinemia I (HT1) is an inborn error of tyrosine catabolism; an autosomal recessive disorder caused by defective activity of fumarylacetoacetate hydrolase (FAH) enzyme, is characterized by progressive liver disease, renal tubular dysfunction, and porphyria-like crises. Succinylacetone (SA); a compound derived from the tyrosine catabolic intermediate fumarylacetoacetate has been demonstrated to be a mitochondrial toxin. Symptoms may start during the first few months (acute type); in second half of the first year (subacute type) or in the following years up to adulthood (chronic type). All patients stand a high risk of developing hepatocellular carcinoma (HCC) secondary to cirrhosis. Diagnostic methods: Elevated levels of SA, α fetoprotein and plasma levels of tyrosine, phenylalanine and methionine, Newborn screening and prenatal diagnosis are available in many countries. Management and treatment: A dramatic improvement in prognosis following treatment with Nitisinone, along with protein-restricted diet and option of liver transplantation in acutely ill infants fails to respond to Nitisinone, or diagnosed HCC. Conclusion: HTI is a treatable disease, it has heterogeneous hepatorenal manifestations. Elevated levels of SA in plasma or urine are diagnostic. An early diagnosis and treatment with Nitisinone is critical to normal development and survival. Individuals should follow a lifelong low-tyrosine and phenylalanine diet.