Oxidative Stress in Patients with Hepatitis, Cirrhosis, and Hepatoma Evaluated by Plasma Antioxidants

(First of Two Parts) IN recent years, there has been a substantial increase in the application of mathematical modeling and dynamic systems analysis to quantitative studies of metabolic pathways. Such technics, when applied by those who fully appreciate their merits and limitations, are important investigative tools. To obtain the optimal amount of useful information, there is a need for close collaboration between workers in the different disciplines involved. Adoption of inappropriate models or mathematical technics can lead to results that, at best, fail to make full use of the available data but more often are physiologically implausible. This review outlines . . .

Use of kinetic analysis and mathematical modeling in the study of metabolic pathways in vivo. Applications to hepatic organic anion metabolism. (First of two parts).

Most previous compartmental models describing bilirubin transport and metabolism in the liver have been validated solely by analysis of the plasma disappearance of radiolabeled bilirubin in human subjects. We now have determined the transport kinetics of a bilirubin tracer pulse by analysis of plasma, liver, and bile radioactivity data from 30 intact rats. Plasma [3H]bilirubin disappearance was best described by the sum of three exponentials, and a six-compartment model, derived by simulation analysis, was necessary and adequate to describe all experimental data. Examination of the injected radiolabeled bilirubin by extraction with hexadecyltrimethylammonium bromide and thin-layer chromatography revealed that 6.6% (mean) of the original pigment had been degraded to labeled nonbilirubin derivatives during preparation of the tracer dose. This material exhibited a significantly longer half-life (mean 50.6 min) of the plasma terminal exponential than that of authentic radiobilirubin (20.6 min). In isolated perfused rat liver, the kinetics of [3H]bilirubin in perfusate and bile readily fitted the proposed model. Compatibility of the model with the data obtained, both in the isolated liver and in vivo, required that a fraction of bilirubin conjugated in the liver be deconjugated and returned to the plasma. Deconjugation of bilirubin glucuronides was evaluated directly by infusion of bilirubin monoglucuronides, containing 14C in the glucuronosyl group, into rats with an external bile fistula. Since metabolic degradation of hydrolyzed 14C-labeled glucuronic acid yields 14CO2, this was measured in expired air. Whereas 86% of the administered labeled pigment was recovered in bile, 7% of the label appeared in 14CO2. These findings directly validate a portion of the proposed kinetic model and suggest that hepatic deconjugation of a small fraction of bilirubin glucuronides is a physiological event. Deconjugation may also account, at least in part, for the presence of increased concentrations of unconjugated bilirubin in the plasma of patients with cholestasis.

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Bilirubin kinetics in intact rats and isolated perfused liver. Evidence for hepatic deconjugation of bilirubin glucuronides.

Background: Diabetes is often not diagnosed until complications appear, and one-third of those with diabetes may be undiagnosed. Prediabetes and diabetes are conditions in which early detection would be appropriate, because the duration of hyperglycemia is a predictor of adverse outcomes, and there are effective interventions to prevent disease progression and to reduce complications. Objectives: The objectives were to determine the prevalence of diabetes mellitus and prediabetes in emergency department (ED) patients with an elevated random glucose or risk factors for diabetes but without previously diagnosed diabetes and to identify which at-risk ED patients should be considered for referral for confirmatory diagnostic testing. Methods: This two-part study was composed of a prospective 2-year cohort study, and a 1-week crosssectional survey substudy, set in an urban ED in Los Angeles County, California. A convenience sample was enrolled of 528 ED patients without previously diagnosed diabetes with either 1) a random serum glucose ‡ 140 mg ⁄dL regardless of the time of last food intake or a random serum glucose ‡ 126 mg ⁄dL if more than 2 hours since last food intake or 2) at least two predefined diabetes risk factors. Measurements included presence of diabetes risk factors, ED glucose, cortisol, insulin and glycosylated hemoglobin (HbA1c), and 2-hour oral glucose tolerance test results, administered at 6-week follow-up. Results: Glycemic status was confirmed at follow-up in 256 (48%) of the 528 patients. Twenty-seven (11%) were found to have diabetes, 141 (55%) had prediabetes, and 88 (34%) had normal results. Age, ED glucose, HbA1c, cortisol, and random serum glucose ‡ 140 mg ⁄dL were associated with both diabetes and prediabetes on univariate analysis. A random serum glucose ‡ 126 mg ⁄dL after 2 hours of fasting was associated with diabetes but not prediabetes; ED cortisol, insulin, age ‡ 45 years, race, and calculated body mass index (BMI) were associated with prediabetes but not diabetes. In multivariable models, among factors measurable in the ED, the only independent predictor of diabetes was ED glucose, while ED glucose, age ‡ 45 years, and symptoms of polyuria and polydipsia were independent predictors of prediabetes. All at-risk subjects with a random ED blood glucose > 155 mg ⁄dL had either prediabetes or diabetes on follow-up testing. Conclusions: A substantial fraction of this urban ED study population was at risk for undiagnosed diabetes and prediabetes, and among the at-risk patients referred for follow-up, the majority demonstrated diabetes or prediabetes. Notably, all patients with two risk factors and a random serum glucose > 155 mg ⁄dL were later diagnosed with prediabetes or diabetes. Consideration should be given to referring ED patients with risk factors and a random glucose > 155 mg ⁄dL for follow-up testing. ACADEMIC EMERGENCY MEDICINE 2009; 16:394‐402 a 2009 by the Society for Academic Emergency Medicine

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1553-2712.2009.00374.x

Detection of Undiagnosed Diabetes and Prediabetic States in High‐risk Emergency Department Patients

BACKGROUND AND PURPOSE Bilirubin and biliverdin possess antioxidant and anti-inflammatory properties and their exogenous administration protects against the effects of inflammation and trauma in experimental models. Despite the therapeutic potential of bile pigments, little is known about their in vivo parenteral or enteral absorption after exogenous administration. This study investigated the absorption and pharmacokinetics of bile pigments after i.v., i.p. and intraduodenal (i.d.) administration in addition to their metabolism and routes of excretion.



EXPERIMENTAL APPROACH Anaesthetized Wistar rats had their bile duct, jugular and portal veins cannulated. Bile pigments were infused and their circulating concentrations/biliary excretion were measured over 180 min.



KEY RESULTS After i.v. administration of unconjugated bilirubin, biliverdin and bilirubin ditaurate, their plasma concentrations decreased exponentially over time. Subsequently, native and metabolized compounds appeared in the bile. When administered i.p., their absolute bioavailabilities equalled 14.0, 16.1 and 33.1%, respectively, and correspondingly 38, 28 and 34% of the same bile pigment doses were excreted in the bile. Administration of unconjugated bilirubin and bilirubin ditaurate i.d. increased their portal and systemic concentrations and their systemic bioavailability equalled 1.0 and 2.0%, respectively. Correspondingly, 2.7 and 4.6%, of the doses were excreted in the bile. Biliverdin was rapidly metabolized and these products were absorbed and excreted via the urine and bile.



CONCLUSIONS AND IMPLICATIONS Bile pigment absorption from the peritoneal and duodenal cavities demonstrate new routes of administration for the treatment of inflammatory and traumatic pathology. Oral biliverdin administration may lead to the production of active metabolite that protect from inflammation/complement activation.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2011.01413.x

Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration

1. The kinetics of unconjugated [ 14 C]-bilirubin metabolism have been investigated and analysed in terms of a three-pool model in a group of seven normal subjects and in a group of eight cirrhotic patients who had appreciable impairment of liver cell function. 2. In the patients with cirrhosis, the plasma unconjugated bilirubin was either normal or only slightly increased but the metabolism of unconjugated bilirubin was deranged. 3. The mean volume of distribution, the mean 4 h retention, and the mean mass of the rapidly mixing pool were all significantly greater than in the normal subjects. In contrast, mean fractional clearance rate and mean estimated erythrocyte life-span were significantly less than in the normal subjects. 4. The mean fractional transfer rates and fluxes from pool 1 (rapidly mixing pool—‘plasma’) to pool 3 (‘extravascular’) and vice versa were significantly greater than the corresponding values in the normal subjects. 5. The results indicate that, in patients with compensated cirrhosis, the efficiency of the liver in extracting unconjugated bilirubin from plasma against a concentration gradient is impaired, even though the liver9s capacity to conjugate bilirubin may be normal. As a consequence of the increased volume of distribution, the absolute hepatic clearance of unconjugated bilirubin is relatively well maintained.

D. Owens

Papers

Studies on the Kinetics of Unconjugated [14C]Bilirubin Metabolism in Normal Subjects and Patients with Compensated Cirrhosis