Non-invasive urinary metabolomic profiles discriminate biliary atresia from infantile hepatitis syndrome.

INTRODUCTION: Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring in the first 3 months of life. The most common causes of neonatal cholestasis are infantile hepatitis syndrome (IHS) and biliary atresia (BA). The clinical manifestations of the two diseases are too similar to distinguish them. However, early detection is very important in improving the clinical outcome of BA. Currently, a liver biopsy is the only proven and effective method used to differentially diagnose these two similar diseases in the clinic. However, this method is invasive. Therefore, sensitive and non-invasive biomarkers are needed to effectively differentiate between BA and IHS. We hypothesized that urinary metabolomics can produce unique metabolite profiles for BA and IHS. OBJECTIVES: The aim of this study was to characterize urinary metabolomic profiles in infants with BA and IHS, and to identify differences among infants with BA, IHS, and normal controls (NC). METHODS: Urine samples along with patient characteristics were obtained from 25 BA, 38 IHS, and 38 NC infants. A non-targeted gas chromatography-mass spectrometry (GC-MS) metabolomics method was used in conjunction with orthogonal partial least squares discriminant analysis (OPLS-DA) to explore the metabolomic profiles of BA, IHS, and NC infants. RESULTS: In total, 41 differentially expressed metabolites between BA vs. NC, IHS vs. NC, and BA vs. IHS were identified. N-acetyl-D-mannosamine and alpha-aminoadipic acid were found to be highly accurate at distinguishing between BA and IHS. CONCLUSIONS: BA and IHS infants have specific urinary metabolomic profiles. The results of our study underscore the clinical potential of metabolomic profiling to uncover metabolic changes that could be used to discriminate BA from IHS.

[The reassessment of the diagnostic value of 24-hour urinary copper excretion in children with Wilson's disease].

OBJECTIVE: To reassess the diagnostic value of 24 hour urinary copper excretion in children with Wilson disease (WD). METHODS: From July 2005 to June 2007, inpatients over three years old in a pediatric liver center were assigned into WD and non-WD group. RESULTS: 94 patients, including 26 cases in WD and 68 in non-WD group, were enrolled in this study. The median of 24 h urinary copper excretion was 98.5 microg in WD group and 25.8 microg in the non-WD group (Z = -6.111, P equal to 0.000). The area under receiver operator curve (ROC) was 0.909 (95% CI: 0.839-0.979, P equal to 0.000). The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 84.6%, 91.2%, 89.4%, 78.6% and 93.9% respectively using 52.0 ug as a cutoff value, and 50.0%, 97.1%, 84.0%, 86.7% and 83.5% using 100 microg as a cutoff value. The goodness of fitness of 52 microg criteria was significantly higher than 100 microg criteria (kappacoefficient 0.760, 0.541 respectively, P equal to 0.000). CONCLUSION: Comparing to 100, 52 microg of 24 h urinary copper excretion as a cutoff value significantly improves the sensitivity and accuracy for diagnosing WD in children.

Urinary excretion of methylarginine in human disease.

Methylated amino acids are excreted in urine upon degradation of some tissue proteins. The urinary excretion ratios of NG,N'G-dimethylarginine (syn-DMA) and NG,NG-dimethylarginine (unsym-DMA) were studied in healthy adults and in patients with various diseases. The normal ratio of sym- to unsym-DMA in urine was 0.98 and ranged from 0.71 to 1.33; ratios were not significantly different in multiple sclerosis, cerebrovascular accident, cancer, and systemic lupus erythematosus. However, patients with liver, disease, including chronic active hepatitis, were found on average to have a significantly altered ratio of 0.79, range 0.49-1.30, owing to an increase in the excretion of unsym-DMA. Hence measurements of the urinary excretion of dimethylarginine could become a useful aid in assessing recovery of liver cells in patients with chronic liver disease.

Guanidino compounds in serum and urine of cirrhotic patients.

To investigate the metabolic relationship between urea and guanidinosuccinic acid (GSA), we determined the levels of the guanidino compounds, including GSA, and urea in serum and urine of cirrhotic patients. Linear correlation studies between serum urea and GSA levels were performed. Good positive linear correlation coefficients were found in the Child-Turcotte C subgroup (r = .847, P < .001) and in the total subgroup including B and C patients (r = .848; P < .0001). Serum guanidinoacetic acid levels were significantly increased in the Child-Turcotte C subgroup (P < .0001 for men and P < .001 for women). In contrast, GSA levels were significantly (P < .0001) decreased in the three studied subgroups. Similar results were found for urinary GSA excretion levels. Within each subgroup, serum and urinary GSA levels were significantly lower in patients with alcohol-induced cirrhosis than in nonalcoholic cirrhotic patients. Similar results were obtained for urea. The findings in cirrhotic patients clearly demonstrate a metabolic relationship between urea and GSA. They also show that urea and GSA biosynthesis is significantly lower in cirrhotic patients with an alcoholic origin than in cirrhotic patients with a nonalcoholic origin.

Urinary hydroxyproline and hydroxylysine excretions in relation to hepatic hydroxyproline content in chronic liver disease.

In patients with or without various chronic liver diseases, the total urinary excretion of hydroxyproline and hydroxylysine and the hepatic content of hydroxyproline were examined. In 7 patients without liver disease, the urinary excretion of hydroxyproline and hydroxylysine were 10.3 +/- 1.5 and 1.31 +/- 0.21 mmol/mol creatinine, respectively, and the hepatic content of hydroxyproline was 4.9 +/- 0.6 mumol/g of wet liver. In 33 patients with liver disease, the urinary excretion of hydroxyproline and hydroxylysine and the hepatic content of hydroxyproline were increased in proportion to the severity of liver disease. The hepatic content of hydroxyproline showed a significant correlation with the urinary excretion of hydroxyproline and hydroxylysine (r = +0.406 and r = +0.531, respectively). These results suggest that the study of urinary hydroxyproline and hydroxylysine excretion may yield useful information on the metabolism of hepatic collagen in chronic liver disease. Moreover, urinary hydroxylysine excretion seemed to be a better index of hepatic collagen metabolism than urinary hydroxyproline excretion; perhaps urinary hydroxylysine excretion is not much affected by dietary collagen intake.

Increased urinary excretion of L-xylulose in patients with liver cirrhosis.

The urinary excretions of L-xylulose, xylitol and D-glucarate after the oral administration of glucuronolactone (5 g) were measured in normal healthy persons, patients with diabetes mellitus, acute hepatitis in recovery stage, chronic hepatitis and liver cirrhosis. In normal subjects, the mean value of L-xylulose excretion was 14.6 +/- 1.4 mumol/2 h with a range from 6.5 to 21.8. Marked increase of L-xylulose excretion was observed in cirrhotic patients, the mean value was 97.1 +/- 19.8 with a range from 22.0 to 236.6. Though some cases of acute and chronic hepatitis showed higher values than the normal range, no case exceeded 50 mumol/2 h. The urinary excretion of xylitol in cirrhotic patients was also higher than normal no increase was observed in D-glucarate excretion. The values of L-xylulose excretion in cirrhosis were correlated with the values of serum total bilirubin, albumin, albumin/globulin ratio, lactate dehydrogenase and prothrombin time. These findings indicate that the measurement of L-xylulose in urine after the oral glucuronolactone loading provides a useful tool for evaluation of the severity of liver cirrhosis.

Large amounts of 1 beta-hydroxylated bile acids in urine during taurine therapy.

The management of infants with cholestasis remains a difficult challenge. On the hypothesis that taurine is effective in treating neonatal cholestasis, taurine (1 g/day, per os) was administered to 2 patients with neonatal hepatitis and the bile acids were analyzed using gas chromatography-mass spectrometry (GC-MS). The serum levels of bilirubin and bile acids were significantly decreased by taurine. Before the treatment, cholic acid (CA) and chenodeoxycholic acid (CDCA) were predominant (79.2% in both patients) in the urine. There was a significant elevation of 1 beta-hydroxylated bile acids (1 beta BA), especially 1 beta, 3 alpha, 7 alpha, 12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid (CA-1 beta-ol), in urine collected during the taurine therapy, and 1 beta BA became predominant (57.7-78.3%). Therefore, increased amounts of urine 1 beta BA were excreted during taurine administration. Taurine therapy is recommended, because it might be effective for treating neonatal cholestasis.

Latent distal renal tubular acidosis (dRTA) in primary biliary cirrhosis (PBC) and chronic autoimmune hepatitis (CAH).

In an attempt to evaluate the latent distal renal tubular acidosis (dRTA7) in patients with primary biliary cirrhosis (PBC), and chronic autoimmune hepatitis (CAH), and differences between them in relation to the sodium urinary excretion ([Na]u), thirty four patients divided in two groups were studied. Group A: 17 patients who fulfilled criteria for PBC diagnosis (clinical and humoral evidence antimitochondrial antibody titles of 1/80 or above by indirect immunofluorescence technique, and liver biopsy). Group B: 17 patients who fulfilled criteria for CAH diagnosis (clinical and humoral evidence, antinuclear and smooth muscle antibody titles of 1/80 or above and liver biopsy). Patients with ascitis and/or edema were excluded from the study. Ability to acidify urine was evaluated by gradient between pC02 in urine and blood (U-BpC02) after alkali infusion. Five patients in Group A (29.4%7) and six in Group B(35.2%) had dRTA, (p = 0.49). When analyzing patients with dRTA in both groups, the mean [Na]u in Group A was 152.2 +/- 33.8, versus 50.8 +/- 8.1 mEq/l, in Group B. (p = 0.00016). We concluded that the prevalence of dRTA was similar in patients with PBC and CAH but the urinary acidifications impairment of the former did not correlate with [Na]u, as it did with the latter.