Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires lifelong dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life. Key Points Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been found to be generally safe and has clearly improved treatment and outcomes for patients with tyrosinemia type 1.
Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long‐term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single‐center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website http://www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at http://www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in‐hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium‐chain Acyl CoA dehydrogenase deficiency. The website http://www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.
Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal–Wallis, Fisher’s exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.
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