Urinary and serum oxysterols in children: developmental pattern and potential biomarker for pediatric liver disease.

Few reports describe oxysterols in healthy children or in children with liver disease. We aimed to determine whether developmental changes in urinary and serum oxysterols occur during childhood, and to assess whether oxysterols might be biomarkers for pediatric liver disease. Healthy children enrolled as subjects (36 and 35 for urine and serum analysis, respectively) included neonates, infants, preschoolers, and school-age children, studied along with 14 healthy adults and 8 children with liver disease. We quantitated 7 oxysterols including 4ß-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol using liquid chromatography/electrospray ionization-tandem mass spectrometry. Urinary total oxysterols were significantly greater in neonates than in infants (P < 0.05), preschoolers (P < 0.001), school-age children (P < 0.001), or adults (P < 0.001), declining with age. Serum total oxysterols in neonates were significantly lower than in infants (P < 0.05), preschoolers (P < 0.001), school-age children (P < 0.05), or adults (P < 0.01). Compared with healthy children, total oxysterols and 24(S)-hydroxycholesterol in liver disease were significantly increased in both urine (P < 0.001 and P < 0.001, respectively) and serum (P < 0.001 and P < 0.05, respectively). Oxysterols in liver disease, particularly 24(S)-hydroxycholesterol, were greater in urine than serum. Oxysterols change developmentally and might serve as a biomarker for pediatric liver disease. To our knowledge, this is the first such report.

Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

Acute kidney injury following acute liver failure: potential role of systemic cadmium mobilization?

OBJECTIVE: A significant fraction of patients with acute liver failure (ALF) suffer from a concomitant acute kidney injury (AKI), the mechanism of which is probably multifactorial. Cadmium (Cd) is a widespread environmental pollutant and a tubulotoxic metal that accumulates in the liver. We tested the hypothesis that a release of Cd during ALF may cause a redistribution of Cd from the liver to the kidneys and play a role in the occurrence of ALF-associated AKI. METHODS: Twenty patients with ALF (ALF-patients), 20 patients from the ICU with no liver damage at admission (ICU-controls) and 20 healthy controls were recruited to compare the 24-h urinary excretion rate of Cd with that of lead (Pb), a nephrotoxic metal that does not accumulate in the liver, and zinc (Zn), a non-nephrotoxic element found in high amounts in the liver. The excretion rates of the low-molecular-weight proteins (LMWPs) were monitored. RESULTS: ALF-patients excreted markedly more Cd than the healthy controls and ICU-controls. In ALF-patients, the four urinary LMWPs (RBP, ß2-MG, CC16 and α1-MG) increased as a function of Cd excretion, with high correlation coefficients. The prevalence of patients excreting a high amount of LMWPs also increased with increasing Cd excretion. No relationship was found between the other elements investigated and the LMWPs, with the exception of copper, which shares close toxicokinetic similarities with Cd. CONCLUSIONS: This study shows a strong association between urinary Cd levels and the excretion rates of LMWPs in patients with ALF. A causal relationship is possible but could not be fully demonstrated in this study.

The enterohepatic circulation of amanitin: kinetics and therapeutical implications.

BACKGROUND: Amatoxin poisoning induces a delayed onset of acute liver failure which might be explained by the prolonged persistence of the toxin in the enterohepatic circulation. Aim of the study was to demonstrate amanitin kinetics in the enterohepatic circulation. METHODS: Four pigs underwent α-amanitin intoxication receiving 0.35 mg/kg (n=2) or 0.15 mg/kg (n=2) intraportally. All pigs remained under general anesthesia throughout the observation period of 72 h. Laboratory values and amanitin concentration in systemic and portal plasma, bile and urine samples were measured. RESULTS: Amanitin concentrations measured 5h after intoxication of 219±5ng/mL (0.35 mg/kg) and 64±3 (0.15 mg/kg) in systemic plasma and 201±8ng/mL, 80±13ng/mL in portal plasma declined to baseline levels within 24h. Bile concentrations simultaneously recorded showed 153±28ng/mL and 99±58ng/mL and decreased slightly delayed to baseline within 32 h. No difference between portal and systemic amanitin concentration was detected after 24h. CONCLUSIONS: Amanitin disappeared almost completely from systemic and enterohepatic circulation within 24 h. Systemic detoxification and/or interrupting the enterohepatic circulation at a later date might be poorly effective.

1H NMR spectroscopy for the prediction of therapeutic outcome in patients with fulminant hepatic failure.

A high-resolution (1)H NMR study of serum and urine of fulminant hepatic failure patients (n = 22) [surviving (n = 12) and non-surviving (n = 10)] is reported. Glutamine in serum and urine glutamine:creatinine ratio were higher in non-surviving patients compared with surviving patients [serum glutamine, 3.08 (1.68-7.11) vs 0.56 (0.34-0.99) mM, median and range; p = 0.0001 and urine glutamine:creatinine ratio, 1.72 (0.24-7.76) vs 0.39 (0.1-0.84), p = 0.1], and urine urea:creatinine ratio was higher in surviving patients compared with non-surviving patients [10.83 (0.2-22.6) vs 2.09 (0.96-4.0), p = 0.002]. On the other hand, no significant differences were found in the conventionally employed clinical parameters such as serum alanylaminotransferase, aspartylaminotransferase and bilirubin except prothrombin time (p = 0.02). The difference in serum glutamine and urine urea was significant in the two categories of patients and distinctly different values of serum glutamine for both the categories of patients correctly predicted the outcome. These results promise immense potential for NMR spectroscopy in rapidly deciding on the need for advanced therapeutic intervention such as artificial liver support or emergency liver transplantation in FHF.

Causal relationship between a case of severe hepatic dysfunction and low exposure concentrations of N,N-dimethylformamide in the synthetics industry.

A 19-year-old man suffered hepatic dysfunction after 5 months of exposure to N,N-dimethylformamide (DMF) at his job in the synthetic resins industry. Laboratory data revealed elevated levels of AST (578 IU/l), ALT (1193 IU/l), and gamma-GTP (107 IU/l), no viral infection with HAV, HBV, or HCV, and no history or evidence of hepatic injury, although he did have a slight abdominal abnormality and swelling which was detected by palpation. His urinary N-methylformamide level, as a biological exposure index of DMF, was 42.8 mg/l, indicating 10-30 ppm of DMF exposure. After 2 months he was reinstated in two workplaces, the former where he worked in the morning and the other in the afternoon where environmental DMF concentrations were less than those in the former workplace. On the 18th day after his reinstatement, his liver function became exasperated again. After the second period of medication and one month of rest from work, he had fully recovered and was reinstated, but to a workshop without DMF exposure.