Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

Background Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations

Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients&rsquo; lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography&ndash;mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 &micro;M, p &lt; 0.0001), ADMA (0.62 vs. 0.57 &micro;M, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 &micro;M, p = 0.03) and nitrate (43.3 vs. 33.1 &micro;M, p &lt; 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 &micro;M/mM creatinine, p &lt; 0.001) and nitrate (159 vs. 115 &micro;M/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation

Local and Systemic Alterations of the L-Arginine/Nitric Oxide Pathway in Sputum, Blood, and Urine of Pediatric Cystic Fibrosis Patients and Effects of Antibiotic Treatment

Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 &plusmn; 19.1% (mean &plusmn; SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additionally, the Arg/NO pathway in sputum samples of five CF patients was analyzed before and after routine antibiotic therapy. CF patients with low fractionally exhaled NO (FENO) showed lower plasma Arg and nitrate concentrations. During acute exacerbation, sputum Arg and hArg levels were high and dropped after antibiotic treatment: Arg: pre-antibiotics: 4.14 nmol/25 mg sputum vs. post-antibiotics: 2.33 nmol/25 mg sputum, p = 0.008; hArg: pre-antibiotics: 0.042 nmol/25 mg sputum vs. post-antibiotics: 0.029 nmol/25 mg sputum, p = 0.035. The activated Arg/NO metabolism in stable CF patients may be a result of chronic inflammation. PSA infection did not play a major role regarding these differences. Exacerbation increased and antibiotic therapy decreased sputum Arg concentrations