Modification Patterns of Urinary Albumin Correlates With Serum Albumin and Outcome in Severe Alcoholic Hepatitis.

BACKGROUND AND AIMS: Albumin modifications and deranged functions are well documented in serum of severe alcoholic hepatitis (SAH). We investigated whether urinary albumin (u-Alb) can serve as surrogate marker of circulatory albumin phenotype, functionality, and could predict outcome in SAH patients. PATIENTS AND METHODS: Baseline serum and urine samples from 100 SAH, 20 alcoholic cirrhosis, and 20 healthy controls were subjected to u-Alb, ischemia modified albumin (IMA), IMA to albumin ratio (IMAr), advanced oxidation protein products, advanced glycation end-products, albumin-binding capacity determination. In addition, SAH urinary samples were also analyzed at day 4 and day 7 to predict nonresponse to corticosteroid therapy. RESULTS: Urine and serum levels of IMA, advanced oxidation protein products and advanced glycation end-products were higher (P<0.05) in SAH versus alcoholic cirrhosis and healthy controls. IMAr was low in urine but high in serum of SAH (P<0.05). Albumin-binding capacity was lower (P<0.05) in both urinary and serum albumin of SAH. Urinary and serum albumin parameters showed direct correlation, whereas IMAr showed inverse correlation (cc>0.2, P<0.05). Baseline u-Alb level was significantly higher in SAH, and was correlated directly with corticosteroid treatment outcome and 12-month mortality in SAH. Baseline u-Alb showed an area under the receivers operating curve analysis of 0.7 and a hazard ratio of 1.23 for prediction of 12-month mortality in SAH. Baseline u-Alb level >9.0 mg/dL was associated with reduced 12-month survival in SAH (log rank <0.01). CONCLUSIONS: u-Alb modifications are reflective of serum albumin modifications. Further baseline u-Alb levels could be exploited to predict steroid response and mortality in SAH patients.

All That Glitters Yellow Is Not Gold: Presentation and Pathophysiology of Bile Cast Nephropathy.

BACKGROUND: Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice. It is characterized by the presence of bile casts in renal tubules, which can possibly cause tubular injury through obstructive and direct toxic effects. Thus, AKI in patients with liver disease may have a structural component in addition to a functional one. METHODS: In this study, we describe 2 patients with severe hyperbilirubinemia who developed AKI and underwent a kidney biopsy that revealed bile casts in tubular lumens, consistent with bile cast nephropathy. RESULTS: One patient was treated aggressively for alcoholic hepatitis and required hemodialysis for AKI. The second patient was treated conservatively for drug-induced liver injury and did not require dialysis. Both patients saw a reduction in their bilirubin and creatinine toward baseline. CONCLUSION: Bile cast nephropathy is an important pathological entity that may account for the renal dysfunction in some patients with liver disease. It requires kidney biopsy for diagnosis and may often be overlooked given the scarcity of kidney biopsy in this particular clinical setting. The etiology is multifactorial, and it is often difficult to predict without the aid of a renal biopsy.

UPLC/Q-TOFMS-Based Metabolomics Studies on the Protective Effect of Panax notoginseng Saponins on Alcoholic Liver Injury.

Consistent, excessive alcohol consumption leads to liver injury. The aim of the present study is to evaluate the possible efficacy of Panax notoginseng saponins (PNS) against chronic alcohol-induced liver injury using LC-MS-based urinary metabolomics. Mice were fed a Lieber-DeCarli liquid diet containing alcohol or isocaloric maltose dextrin as a control diet with or without PNS (200 mg/kg/BW) for 4 weeks. Treatment with PNS significantly reduced the increases in plasma ALT and AST levels, hepatic levels of reactive oxygen species (ROS) and malondialdehyde (MDA), which induced by chronic alcohol exposure. Conversely, PNS was also found to restore the glutathione (GSH) depletion and increase the superoxide dismutase (SOD) activities. The end-point urine sample of each mouse was collected overnight (24 h) in metabolic cages and their metabolic profiling changes were analyzed using UPLC/Q-TOFMS followed by multivariate statistical analysis. After 4 week of Lieber-DeCarli alcohol diet feeding, the metabolic profile experienced great perturbation in PCA score plot, and the treatment of PNS could assist to regulate the disturbed metabolic profile induced by alcohol exposure. Additionally, sixteen potential biomarkers responsible for derivations of the metabolic profile induced by alcohol exposure were identified, and the alcohol-induced changes in these biomarkers, except hexanoylglycine, could be partially or nearly reversed by PNS treatment. Taken together, PNS protects against chronic alcohol-induced liver injury. Our findings demonstrated that the LC-MS-based metabolomics approach is a useful tool to investigate the efficacy of Chinese medicines.

Hepatotoxicity is not increased in alcoholics with positive urinary cocaine metabolites.

Cocaine hepatotoxicity in mice has been reported by numerous investigators. Such hepatotoxicity in other animal models has been more difficult to produce. We prospectively assessed 1212 alcoholics admitted for detoxification for historical, clinical and laboratory evidence of concomitant cocaine/crack use and evidence of liver disease. The 470 cocaine positive subjects had both longer durations and higher average daily costs of cocaine/crack use than the 742 cocaine negative subjects, but had a shorter duration of alcohol use. Serum transaminases were higher in the cocaine negative group. There were no clinically severe cases of liver disease or rhabdomyolysis in either group. Serum hepatitis B surface antibody and hepatitis A antibody were more frequent in the cocaine positive subjects. In conclusion, in this large sample of alcoholics abusing cocaine, severe hepatotoxicity was not at all evident. The previous reports of hepatotoxicity may represent co-morbidity. Some possibilities include infection with a hepatitis or other virus, the presence of an adulterant, an idiosyncratic reaction or an enzymatic abnormality.

Urinary neopterin levels in acute viral hepatitis.

Elevated neopterin levels in blood or urine have been shown to be a marker for the activation of cell-mediated immunity in vitro and in vivo. To evaluate whether neopterin levels are elevated in patients with acute viral hepatitis, we measured urinary levels in 13 patients with hepatitis A, 26 with hepatitis B, 12 with non-A, non-B hepatitis, 8 with jaundice and/or cholestasis due to biliary and pancreatic disorders and 3 with alcoholic hepatitis and in 62 apparently healthy HBsAg carriers. Neopterin levels in patients with virus-induced hepatitis were significantly higher than those in patients with other diagnoses. Urinary neopterin levels were above normal in 49 of 51 patients with viral hepatitis and elevations during the course of hepatitis showed a pattern similar to that of the usual liver biochemical tests, suggesting that neopterin levels were related to the clinical activity of the viral disease. In patients with nonviral biliary and hepatic disorders, neopterin levels were usually normal and did not correlate with other liver biochemical tests. These findings suggest that cell-mediated immune mechanisms are activated during viral hepatitis and that neopterin measurement may be of value as an additional surrogate marker for non-A, non-B hepatitis.

Hepatorenal syndrome without avid sodium retention.

A urinary sodium concentration [U(Na)] of less than 10 mmoles per liter is considered important in differentiating hepatorenal syndrome from other causes of progressive renal impairment in patients with liver disease. However, occasionally, patients with hepatorenal syndrome have been recognized in whom the U(Na) is consistently greater than 10 mmoles per liter. Eight such patients, in all of whom there was no clinical or laboratory evidence to implicate other causes of progressive renal impairment, were identified. The clinical features, hepatic and renal status and hospital course were compared with eight other patients who had hepatorenal syndrome and a U(Na) consistently less than 10 mmoles per liter. The mean U(Na) was 24 +/- 4 mmoles per liter in the high U(Na) group and 3.7 +/- 1.8 mmoles per liter in the low U(Na) group. All patients in both groups had acutely decompensated alcoholic hepatitis of similar severity and activity. The high U(Na) group had significantly less clinical ascites and peripheral edema and higher serum levels of sodium and chloride both at the onset of the hepatorenal syndrome and throughout the clinical course. Significant differences in the serum potassium and blood urea nitrogen levels became apparent between the two groups of patients as renal failure progressed, and the mean average blood urea nitrogen to serum creatinine ratio was significantly higher (p less than 0.025) in the low U(Na) group (13.8 +/- 0.9 vs. 10.1 +/- 1.1). Mean urinary potassium concentration was significantly higher in the high U(Na) patients but urinary creatinine concentrations, specific gravity and sediment were similar in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic trial of thromboxane synthesis inhibition in the hepatorenal syndrome.

Urinary excretion of the vasoconstrictor metabolite thromboxane B2 is increased in some patients with the hepatorenal syndrome. To define the role of thromboxanes in this syndrome and to evaluate a potential treatment for the renal impairment, we administered the thromboxane synthetase inhibitor dazoxiben to 5 patients with alcoholic hepatitis and rapidly progressive renal failure. Dazoxiben 200 mg/day followed by 400 mg/day reduced urinary thromboxane B2 by approximately 50% without altering prostaglandin E2 or 6-keto prostaglandin F1 alpha and without improving creatinine clearance (6 +/- 2 to 6 +/- 3 ml/min). In 3 additional patients, a higher dose of dazoxiben of 600 mg/day reduced thromboxane B2 by approximately 75% without consistent improvement in renal function. Thus, as judged by selective thromboxane inhibition with dazoxiben, thromboxanes are unlikely to be the key renal vasoconstrictor factor in the hepatorenal syndrome.

Estimation of urinary nitrogen losses from urea excretion in patients with intestinal diseases requiring parenteral nutrition, and in those with hepatic decompensation.

A comparison of daily urinary nitrogen excretion measured directly, with values derived from urea excretion, was carried out on 110 occasions in patients with either gastrointestinal disease requiring total parenteral nutrition or with alcoholic liver disease. The values were found to correlate well in both patient groups (r = 0.88 and 0.9 respectively). Values of urinary nitrogen loss calculated from urea excretion may safely be used when performing nitrogen balance studies in such cases.

Ratio of urinary 6beta-hydroxycortisol to 17-hydroxycorticosteroids in patients with liver disease.

The ratio of 6beta-hydroxycortisol to 17-hydroxycorticosteroids in the urine of 73 patients with liver disease, and 53 controls has been measured. The mean ratio was significantly greater in the liver disease group (p less than 0.001), this elevation being most marked among patients with liver metastases and patients with acute hepatitis. We feel that the use of the ratio as a test of early liver cell dysfunction requires further evaluation, in particular in the early recognition of metastatic liver disease.