Early-Labeled Peak of Bile Pigment in Man

Robinson, Stephen H.; Lester, Roger; Crigler, John F.; Tsong, Maria

doi:10.1056/nejm196712212772501

Cited by 42 publications

(15 citation statements)

References 24 publications

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“…Since several investigators have indicated that the liver is the principle source of the labeled plasma bilirubin appearing under these conditions (43,44), our results indicate the existence of a pathway by which unconjugated bilirubin in the liver cell may reflux to plasma. A similar conclusion is suggested by the studies of Robinson, Owen, Flock, and Schmid (45), who found bilirubin-MH in plasma following ALA-2H administration to a child with Crigler-Najjar syndrome, in whom all plasma bilirubin is unconjugated. The presence of a bidirectional exchange of bilirubin between plasma and liver is also consistent with the general pattern of hepatic uptake of other organic anions such as BSP (46).…”

supporting

confidence: 80%

Studies of bilirubin kinetics in normal adults

Berk¹,

Howe²,

Bloomer³

et al. 1969

J. Clin. Invest.

225

132

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A B S T R A C T This report describes studies of bilirubin kinetics in 13 healthy young adults. The plasma content of unconjugated bilirubin-14C was determined at frequent intervals for 24-30 hr after the intravenous injection of a tracer dose of unconjugated isotopic bilirubin. Fecal and urinary radioactivity were measured for 7 days. During this time cumulative recovery averaged 96% of the injected dose. The plasma curves were processed by digital computer. For the 30 hr experimental period, a sum of three exponentials, with average half-times of 18, 81, and 578 min, was required to describe the data. Using the plasma curve integral method, the hepatic bilirubin clearance (47 +10 ml/min, mean +SD), the bilirubin production rate (3.8 ±0.6 mg/kg per day), and the mean red blood cell life span (101 ±13 days) were calculated directly from the parameters of this function. To gain further insight into the metabolism of unconjugated bilirubin, the data were also used to determine the parameters of a multicompartmental model. In the model proposed, plasma unconjugated bilirubin exchanges with two additional pools, one of which is thought to represent extrahepatic extravascular, and the other intrahepatic unconjugated bilirubin. Bilirubin is eliminated from the system via the proposed intrahepatic pool. From the data and the model, pool sizes and exchange rates between compartments were calculated, and the liver: plasma concentration gradient estimated. These studies provide a detailed analysis of the kinetics of unconjugated bilirubin in a healthy normal population and are intended to serve as a reference point for studies of abnormal states.

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supporting

confidence: 80%

Studies of bilirubin kinetics in normal adults

Berk¹,

Howe²,

Bloomer³

et al. 1969

J. Clin. Invest.

225

132

View full text Add to dashboard Cite

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“…5 Schmid and Hammaker (22), using bilirubin-'4C, have previously demonstrated a normal turnover of bilirubin in a 41 year old boy with congenital, nonhemolytic, hyperbilirubinemia. Since bilirubin turnover was essentially unaltered in our patient during phenobarbital treatment, it is assumed that any increase in bilirubin production from nonerythroid sources, claimed to occur in this patient during phenobarbital administration (44), was small in comparison to the total bilirubin turnover. This suggests that the same, slow, rate-limiting step may also be the dominant factor in controlling the rate of increase in serum bilirubin concentration upon withdrawal of phenobarbital.…”

Section: Methodsmentioning

confidence: 65%

Effect of sodium phenobarbital on bilirubin metabolism in an infant with congenital, nonhemolytic, unconjugated hyperbilirubinemia, and kernicterus

Crigler¹,

Gold²

1969

J. Clin. Invest.

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A B S T R A C T Sodium phenobarbital and various hormones, compounds capable of hepatic enzyme induction, were given to an infant boy with congenital, nonhemolytic, unconjugated, hyperbilirubinemia and severe kernicterus for prolonged periods between the ages of 2 and 25 months to determine their effect on serum bilirubin concentrations. Phenobarbital, 5 mg/day orally, on two occasions decreased serum bilirubin concentrations approximately threefold over a period of 30 days. Withdrawal of phenobarbital after the first study resulted in a gradual (30 days) return of serum bilirubin to pretreatment levels. The lower serum bilirubin concentrations observed when phenobarbital therapy was reinstituted were maintained for 61 days on 2.5 mg/kg per day of the drug. Orally administered L-triiodothyronine, 0.05-0.1 mg/day for 71 days, intramuscular human growth hormone, 1 mg/day for 21 days, and testosterone propionate, 0.1 mg/day for 9 days, did not decrease serum bilirubin levels below lowest control values of 18 mg/100 ml.Bilirubin-'H was administered twice before and once with bilirubin-"C during phenobarbital therapy to study the kinetics of bilirubin metabolism. Results of the first and second control studies and of the bilirubin-'H and bilirubin-"C phenobarbital studies, respectively, were as follows: tptal body bilirubin pools, 200, 184, 73, and 72 mg; half-lives, 111, 84, 37, and 39 hr; and turnover, 30, 37, 33, and 31 mg/day. The data show that the ap- tration and total body pool resulted from a comparable decrease in bilirubin half-life without a significant change in turnover.In vitro histological (electron microscopy) and enzymological studies of liver obtained by surgical biopsies before and during phenobaribtal administration showed that both the hepatocyte content of agranular endoplasmic reticulum (AER) and the ability of liver homogenate to conjugate p-nitrophenol were significantly increased during phenobarbital treatment.The observations suggest that phenobarbital affects bilirubin metabolism by the induction of an enzyme(s) with a slow rate(s) of degradation (or rapid rate of degradation with limited capacity).

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“…There are several intermediary metabolic steps in the biosynthesis of bilirubin from PBG. However, bilirubin becomes labeled rapidly after the administration of labeled 8ALA (4)(5)(6)(7)24) suggesting that the net effect of the existence of these intermediary steps in this context is merely to constitute a short delay in the synthesis of bilirubin from hepatic PBG. It seems likely, therefore, that the 14C specific activity of newly formed hepatic-synthesized bilirubin at a particular instant of time reflects that of hepatic PBG a short time earlier.…”

Section: Discussionmentioning

confidence: 99%

“…In this paper a new method is described for directly measuring the synthetic rate of bilirubin from hepatic hemes, which complements previous methods which have depended on administering a labeled precursor and then quantitating the "early labeled peak" in bile pigments in either blood or feces (1)(2)(3)(4)(5)(6)(7)(8). The method involves the biosynthetic labeling of porphobilinogen and bilirubin by means of an intravenous injection of 5-aminolevulinic acid-4-"C (ALA-4-"C).'…”

Section: Introductionmentioning

confidence: 99%