Controlled Trial of Phetharbital,a Non-hypnotic Barbiturate,in Unconjugated Hyperbilirubinaemia

Eleven patients with mild unconjugated hyperbilirubinaemia (Gilbert''s syndrome) took part in a double-blind cross-over trial of phenobarbitone and phetharbital, a non-hypnotic barbiturate. Significant reductions in plasma bilirubin were observed with both drugs, but six patients complained of sleepiness on phenobarbitone, and phetharbital was preferred by most patients. Phetharbital was also effective in the rare severe unconjugated hyperbilirubinaemia of the Crigler-Najjar syndrome (Type 2). Symptoms attributed to Gilbert''s syndrome, including nausea and abdominal pain, were less consistently relieved.     

Effets de la novobiocine sur le fonctionnement du foie: I. Etude clinique

A case of novobiocin-induced jaundice is described in which the main feature was elevated unconjugated bilirubin in the serum. No evidence of hemolysis or hepato-cellular failure was demonstrated.The effect of novobiocin on serum bilirubin was studied by administering 2 g. of the drug daily in four divided oral doses for two days. An increase in serum unconjugated bilirubin was nearly always observed in the normal subjects and in patients with cirrhosis of the liver. This rise was particularly significant in three patients with hemolytic anemia and in two patients with Gilbert''s disease. After an oral dose of 500 mg. the BSP clearance was decreased after one hour and it was close to normal after three hours. Since hemolysis is not responsible for this elevation of serum unconjugated bilirubin, the novobiocin-induced hyperbilirubinemia appears to be due to a direct effect of the drug upon the liver.     

Sexual steroid levels and their clinical significance in the early neonatal age

Serum concentrations of progesterone (P) and estradiol (E2) in the umbilical cord blood were measured in healthy full term newborn infants and were related to the serum levels of indirect bilirubin at 72 hr postpartum in the same group of neonates. In those having higher concentration of bilirubin than 204 mumol/l at 72 hr after birth, cord P and E2 levels were significantly higher than in the rest of the group. Furthermore, strong correlation was found between serum levels of progesterone at 24 hr after birth and that of bilirubin at 72 hr postpartum in the same subjects. According to the authors' conclusion serum progesterone levels 24 hours after birth prognosticate the occurrence of neonatal hyperbilirubinaemia.     

Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing's syndrome.

Forty four subjects (23 obese controls, 11 patients with possible Cushing''s syndrome, and 10 patients with definite Cushing''s syndrome) underwent low dose (0 X 5 mg every six hours for two days) dexamethasone suppression tests during which serum cortisol concentration at 0800 and excretion of urinary free cortisol over 24 hours were measured. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in 31 subjects and remained above 250 nmol/1 (9 X 1 micrograms/100 ml) in the 13 others. Excretion of urinary free cortisol showed a similar response, falling to below 110 nmol (40 micrograms)/24 h in 31 and remaining above 180 nmol (65 micrograms)/24 h in the 13 others. There was complete concordance between the two variables in terms of the pattern of response. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in at least 97% (31 of a possible 32) of subjects without Cushing''s syndrome. On the other hand, a serum cortisol concentration of above 250 nmol/1 (9 X 1 micrograms/100 ml) after low dose dexamethasone gave a false positive diagnosis of Cushing''s syndrome in at most only one of 13 patients (7 X 7%). Measurement of serum cortisol concentration during the low dose dexamethasone test is simpler than, and as accurate and reliable as, measurements of urinary steroids.     

Studies of human liver bilirubin-glycosyl transferase. Bilirubin UDP-xylosyl and UDP-glucuronyl transferase activities in diseased human livers.

The activity of bilirubin UDP-xylosyl transferase as well as UDP-glucuronyl transferase in liver biopsy specimens of 3 control subjects, 42 cases with liver disease and 5 cases with Gilbert's syndrome was measured. Normal values of these enzyme levels were determined to be 142--302 U/kg protein for the former and 260--400 U/kg protein for the latter. Both enzyme levels in acute hepatitis in convalescence and chronic hepatitis were nearly in the normal range. In the cirrhotic liver they tended to a small decrease and patients with Gilbert's syndrome demonstrated significantly decreased enzyme levels. These enzyme levels were only correlated with serum unconjugated bilirubin concentration, but not with the other liver function tests. Finally, both enzyme activities were exactly correlated with each other.     

Fasting hyperbilirubinemia in normal squirrel monkeys.

The plasma of Bolivian squirrel monkeys, unlike that of Brazilian squirrel monkeys, is markedly yellow due to unconjugated hyperbilirubinemia after an overnight fast. The fasting hyperbilirubinemia in Bolivian squirrel monkeys is likely due to two mechanisms. First, a twofold increase in the bilirubin turnover/production rate occurs during a 24-hour fast. A second mechanism is the decreased hepatic conjugation potential for bilirubin due to the presence of a higher bilirubin UDP-glucuronosyltransferase UDPGAKm and a lower Vm; this results in higher steady-state plasma and hepatic bilirubin levels during a fast when hepatic UDP-glucuronic acid levels are low. The Bolivian squirrel monkey provides an excellent animal model for human Gilbert's syndrome type I in which to study rate-limiting mechanisms in the movement of bilirubin from plasma to bile.     

Measurement of plasma unbound unconjugated bilirubin

A method is described for measuring the unconjugated fraction of the unbound bilirubin concentration in plasma by combining the peroxidase method for determining unbound bilirubin with a diazo method for measuring conjugated and unconjugated bilirubin. The accuracy of the unbound bilirubin determination is improved by decreasing sample dilution, eliminating interference by conjugated bilirubin, monitoring changes in bilirubin concentration using diazo derivatives, and correcting for rate-limiting dissociation of bilirubin from albumin. The unbound unconjugated bilirubin concentration by the combined method in plasma from 20 jaundiced newborns was significantly greater than and poorly correlated with the unbound bilirubin determined by the existing peroxidase method (r = 0.7), possibly due to differences in sample dilution between the methods. The unbound unconjugated bilirubin was an unpredictable fraction of the unbound bilirubin in plasma samples from patients with similar total bilirubin concentrations but varying levels of conjugated bilirubin. A bilirubin-binding competitor was readily detected at a sample dilution typically used for the combined test but not at the dilution used for the existing peroxidase method. The combined method is ideally suited to measuring unbound unconjugated bilirubin in jaundiced human newborns or animal models of kernicterus.     

DEVELOPMENTAL FEATURES OF CEREBELLAR HYPOPLASIA AND BRAIN BILIRUBIN LEVELS IN A MUTANT (GUNN) RAT WITH HEREDITARY HYPERBILIRUBINAEMIA 1

Abstract— The marked cerebellar hypoplasia found in the homozygous (jj) Gunn rat with hereditary unconjugated hyperbilirubinaemia may provide an explanation of bilirubin neurotoxicity in vivo. In the jj Gunn rat. Purkinje cells were nearly selectively affected in the cerebellar cortex, and the cerebellar weight showed no increase after 10 days of age. The development-dependency of the cerebellar lesion was supported by the observation that the cerebellar lobuli which developed earlier were less affected. Brain bilirubin in the developing jj Gunn rat was determined by a spectrophotometric method, and was found to be extremely low (1–3 μg). The level of brain bilirubin decreased after birth, and showed little correlation with the level of bilirubin free of albumin which correlated clearly with total serum bilirubin level even in the neonate. These findings suggest that there is an affinity of brain tissue for bilirubin associated with the blood-brain barrier to bilirubin. No significant difference was found between the levels of bilirubin in the cerebellum and those of other brain regions in jj Gunn rat. These results seem to imply that the development-dependency of cerebellar hypoplasia in the jj rat may be due to the characteristic nature of rat cerebellar development, i.e. the postnatal neurogenesis. and not to changes in brain bilirubin levels. In the jj Gunn rat. cerebellar cell proliferation appears to be in some way affected by bilirubin during cerebellar development.     

Chromium intake and urinary chromium excretion of trauma patients

Glucose metabolism is altered after trauma and those factors that affect glucose metabolism often affect chromium (Cr) metabolism and excretion. To ascertain whether urinary Cr excretion is affected by the elevated serum glucose and other factors associated with trauma, the serum glucose and urinary Cr and Creatinine (Cre) excretion of seven severely traumatized patients were determined. The Cr concentration of intravenous (IV) fluids administered was determined and approximate Cr intake calculated. For all patients, urinary Cr concentration was high in the initial sample collected within 24 h of admission (10.3 ± 2.5 ng/mL, mean ± SEM) and decreased significantly (P < 0.05) by 42 h (2.0 ±0.6 ng/mL). The mean urinary Cr concentration 42 h following admission was 10 times greater than the urinary Cr concentration of normal, healthy subjects (0.2 ± 0.02 ng/mL). There was no significant change in urinary Cre concentration within 42 h of admission, therefore the ratio of urinary Cr to Cre (ng Cr:mg Cre) also decreased. Serum glucose concentration was elevated at admission (170 ± 18 mg/dL, mean ± SD) and decreased to 145 ± 10 mg/dL by 48 h post-admission. The intravenous fluids, dextrose and NaCl, were the lowest in Cr of the samples tested, range 0.02 to 0.20 ng/mL; lactated Ringer’s solution, with or without dextrose, contained 10-20 times more Cr and plasma protein fraction contained approximately 32 ng/mL. The mean calculated Cr intake for the first 24 h postadmission was 37.1 µg/d, significantly greater (P < 0.01) than intake from 24 to 48 h (0.12 µg/d) and 48-72 h (1.63 µg/d). The IV intake of Cr varied for trauma patients depending on fluids required during treatment, but for all patients the relatively high IV Cr intake was rapidly excreted in the urine. These data demonstrate that urinary Cr concentration is elevated several-fold within 24 h of trauma and that Cr contents of intravenous fluids administered in the days immediately following injury vary dramatically. The effects of trauma alone on Cr excretion are difficult to assess because of the variable intake of Cr from IV fluids.     

The fish odour syndrome: biochemical,familial, and clinical aspects.

OBJECTIVES--To study the biochemical, familial, and clinical features of the fish odour syndrome among subjects with suspected body malodour. DESIGN--Subjects who responded to a newspaper article were screened for the fish odour syndrome by interview and biochemical tests. Families of subjects with the syndrome were tested if possible. SETTING--St Mary''s Hospital, London, and some interviews at subjects'' homes. SUBJECTS--187 subjects (28 males) with suspected body malodour, of whom 156 (19 males) underwent biochemical tests. Five families of six of the subjects with the fish odour syndrome agreed to further tests. MAIN OUTCOME MEASURES--Amounts of trimethylamine and trimethylamine N-oxide in urine collected over 24 hours under normal dietary conditions and for eight hours after oral challenge with 600 mg trimethylamine. RESULTS--The fish odour syndrome was diagnosed in 11 subjects: the percentage of total trimethylamine excreted in their urine samples that was oxidised to trimethylamine N-oxide was < 55% under normal dietary conditions and < 25% after oral challenge with trimethylamine (in normal subjects > 80% of trimethylamine was N-oxidised). Parents of six of the subjects with the syndrome were tested: all showed impaired N-oxidation of excreted trimethylamine (< 80%) after oral challenge, indicating that they were heterozygous carriers of the allele for the syndrome. The syndrome was associated with various psychosocial reactions including clinical depression. CONCLUSIONS--The fish odour syndrome can be inherited in an autosomal recessive fashion. It should be considered as a possible causative factor in patients complaining of body malodour.     

Early predictive value of cord blood bilirubin and dynamic monitoring of transcutaneous bilirubin for hyperbilirubinemia of newborns

ObjectiveTo study the early predictive value of cord blood bilirubin and dynamic monitoring of transcutaneous bilirubin for hyperbilirubinemia of newborns.Methods389 newborns delivered from June 2014 to December 2015 were enrolled as the research subjects; detailed records were made about the general data of newborns and mothers, and after cord blood bilirubin being graded, the incidence of hyperbilirubinemia was counted, and the prediction efficiency of cord blood bilirubin was analyzed by receiver operator characteristic (ROC) curve. At the same time, the transcutaneous bilirubin was detected continuously when the neonate was born and 24 h, 48 h and 72 h after birth, and the relativity between transcutaneous bilirubin at 72 h and serum bilirubin was analyzed.ResultsNo significant difference was found in the hyperbilirubinemia group and the non-hyperbilirubinemia group concerning general data of the newborns and their mothers. With the concentration of cord blood bilirubin increased, the incidence of hyperbilirubinemia also increased; separate prediction of hyperbilirubinemia by cord blood bilirubin showed a sensitivity and specificity of 71.4% and 65.6% respectively, and they need further dynamic monitoring. The daily mean of transcutaneous bilirubin in hyperbilirubinemia group was significantly higher than that in non-hyperbilirubinemia group at 24 h, 48 h and 72 h, and the measurement value of transcutaneous bilirubin at 72 h had a high correlation with serum bilirubin. When transcutaneous bilirubin value is higher than 18, the incidence of hyperbilirubinemia should be considered.ConclusionsThe increase of cord blood bilirubin effectively predict the occurrence of neonatal hyperbilirubinemia. There is a good correlation between levels of transcutaneous bilirubin and serum bilirubin. Moreover, combined detection of transcutaneous bilirubin and cord blood bilirubin can significantly improve the prediction accuracy of hyperbilirubinemia.     

Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study.

OBJECTIVE--To estimate the prevalence of dementia and its subtypes in the general population and examine the relation of the disease to education. DESIGN--Population based cross sectional study. SETTING--Ommoord, a suburb of Rotterdam. SUBJECTS--7528 participants of the Rotterdam study aged 55-106 years. RESULTS--474 cases of dementia were detected, giving an overall prevalence of 6.3%. Prevalence ranged from 0.4% (5/1181 subjects) at age 55-59 years to 43.2% (19/44) at 95 years and over. Alzheimer''s disease was the main subdiagnosis (339 cases; 72%); it was also the main cause of the pronounced increase in dementia with age. The relative proportion of vascular dementia (76 cases; 16%), Parkinson''s disease dementia (30; 6%), and other dementias (24; 5%) decreased with age. A substantially higher prevalence of dementia was found in subjects with a low level of education. The association with education was not due to confounding by cardiovascular disease. CONCLUSIONS--The prevalence of dementia increases exponentially with age. About one third of the population aged 85 and over has dementia. Three quarters of all dementia is due to Alzheimer''s disease. In this study an inverse dose-response relation was found between education and dementia--in particular, Alzheimer''s disease.     

The Effect of Mannan Oligosaccharide Supplementation on Body Weight Gain and Fat Accrual in C57Bl/6J Mice

The prevalence of obesity in industrialized societies has become markedly elevated. In contrast, model organism research shows that reducing caloric intake below ad libitum levels provides many health and longevity benefits. Despite these benefits, few people are willing and able to reduce caloric intake over prolonged periods. Prior research suggests that mannooligosaccharide (MOS or mannan) supplementation can increase lifespan of some livestock and in rodents can reduce visceral fat without reducing caloric intake. Hence, we tested the effect of MOS supplementation as a possible calorie restriction (CR) mimetic (CRM) in mice. C57Bl/6J male mice were fed a high‐fat “western” type diet with or without 1% MOS (by weight) supplementation (n = 24/group) from 8 to 20 weeks of age. Animals were housed individually and provided 95% of ad libitum food intake throughout the study. Body weight was measured weekly and body composition (lean and fat mass) measured noninvasively every 3 weeks. Individual fat depot weights were acquired by dissection at study completion. Supplementation of a high‐fat diet with 1% MOS tended to reduce total food intake (mean ± s.d.; control (CON): 293.69 ± 10.53 g, MOS: 288.10 ± 11.82 g; P = 0.09) during the study. Moreover, MOS supplementation had no significant effect on final body weight (CON: 25.21 ± 2.31 g, MOS: 25.28 ± 1.49 g; P = 0.91), total fat (CON: 4.72 ± 0.90 g, MOS: 4.82 ± 0.83 g; P = 0.69), or visceral fat (CON: 1.048 ± 0.276 g, MOS: 1.004 ± 0.247 g; P = 0.57). Contrary to previous research, MOS supplementation had no discernable effect on body weight gain or composition during this 12‐week study, challenging the potential use of MOS as a CRM or body composition enhancer.     

Triamcinolone activation of renal ammonia production.

The effects of scillaren and dinitrophenol on bilirubin excretion by the perfused rat liver were studied. Both compounds inhibited bile flow, scillaren by 20 to 40%, and dinitrophenol by 60 to 80%. Bilirubin excretion was also impaired. However, the effect of scillaren on bilirubin excretion was less than that on bile flow, as indicated by an increase in the bile bilirubin concentration, whereas dinitrophenol had a greater effect on bilirubin excretion than on bile flow. Dinitrophenol also inhibited the hepatic removal of unconjugated bilirubin from the perfusate, probably because it impaired the initial uptake and/or storage of unconjugated bilirubin by the perfused liver.     

Role of apolipoprotein D in the transport of bilirubin in plasma

Apolipoprotein D (apo D) is a 30-kDa glycoprotein of unknown function that is associated with high-density lipoproteins (HDL). Because unconjugated bilirubin has been shown to bind apo D with a 0. 8:1 stoichiometry, we examined the contribution of this protein to transport of bilirubin in human plasma. Density gradient centrifugation analysis using physiological concentrations of [(14)C]bilirubin reveals that 9% of unconjugated bilirubin is associated with HDL, with the remaining pigment bound primarily to serum proteins (i.e., albumin). The percentage of total plasma bilirubin bound to HDL was found to increase proportionally with bilirubin concentration. Affinity of human apo D for bilirubin was determined by steady-state fluorescence quenching, with Scatchard analysis demonstrating a single binding site for unconjugated bilirubin with an affinity constant (K(a)) of approximately 3 x 10(7) M(-1). Incorporation of apo D into phosphatidylcholine vesicles had no effect on K(a), suggesting that a lipid environment does not alter the affinity of the protein for bilirubin. Using stopped-flow techniques, the first-order rate constant for bilirubin dissociation from apo D was measured at 5.4 s(-1) (half-time = 129 ms). Our findings indicate that HDL is the principal nonalbumin carrier of bilirubin in human plasma and further support the proposition that the affinity of HDL for bilirubin is primarily the result of binding to apo D.     

Optimization of mass transfer for toxin removal and immunoprotection of hepatocytes in a bioartificial liver

This study was designed to determine optimal operating conditions of a bioartificial liver (BAL) based on mass transfer of representative hepatotoxins and mediators of immune damage. A microprocessor‐controlled BAL was used to study mass transfer between patient and cell compartments separated by a hollow fiber membrane. Membrane permeability (70, 150, or 400 kDa molecular weight cut‐off—MWCO), membrane convection (high: 50 mL/min; medium: 25 mL/min; low: 10 mL/min; diffusion: 0 mL/min), and albumin concentration in the cell compartment (0.5 or 5 g%) were considered for a total of 24 test conditions. Initially, the patient compartment contained pig plasma supplemented with ammonia (0.017 kDa), unconjugated bilirubin (0.585 kDa), conjugated bilirubin (0.760 kDa), TNF‐α (17 kDa), pig albumin (67 kDa), pig IgG (147 kDa), and pig IgM (900 kDa). Mass transfer of each substance was determined by its rate of appearance in the cell compartment. Membrane fouling was assessed by dextran polymer technique. Of the three tested variables (membrane pore size, convection, and albumin concentration), membrane permeability had the greatest impact on mass transfer (P < 0.001). Mass transfer of all toxins was greatest under high convection with a 400 kDa membrane. Transfer of IgG and IgM was insignificant under all conditions. Bilirubin transfer was increased under high albumin conditions (P = 0.055). Fouling of membranes ranged from 7% (400 kDa), 24% (150 kDa) to 62% (70 kDa) during a 2‐h test interval. In conclusion, optimal toxin removal was achieved under high convection with a 400‐kDa membrane, a condition which should provide adequate immunoprotection of hepatocytes in the BAL. Biotechnol. Bioeng. 2009; 104: 995–1003. © 2009 Wiley Periodicals, Inc.     

Bilirubin excretion into bile after partial hepatectomy in rats

Biliary excretion of bilirubin was studied in Wistar rats at different intervals following two-thirds hepatectomy. Endogenous bilirubin excretion was not significantly modified during liver regeneration. The maximal biliary excretion rate (Tm) of bilirubin, expressed per 100 g of body weight, significantly decreased immediately after hepatectomy with a recovery to presurgery values by 16 days. Values expressed per g of liver were significantly lowered only by 12- and 24h posthepatectomy. In these early periods there was a significant increase in the liver concentration of unconjugated bilirubin and a decrease in bile flow following bile pigment infusion. Maximal excretion of bilirubin in the rat seems to change parallel to the regeneration of liver mass except during the first 24h in which the inhibitory effects exerted by the high load of exogenous bilirubin would cause a decline in its own biliary output with an added cholestatic effect.     

Further Study into Obstructive Jaundice and Ischaemic Renal Damage

Renal ischaemia for one hour in two groups of Gunn rats, one with and the other without bile-duct ligation, produced comparable reversible renal tubular lesions in both groups. Since Gunn rats have an unconjugated hyperbilirubinaemia, which is unaffected by bile-duct ligation, it seems likely that the high levels of bilirubin glucuronide are responsible for sensitizing the renal tubules to ischaemia, possibly by depressing cell respiration.     

Maternal serum screening for Down's syndrome in early pregnancy.

The possibility of improving the effectiveness of antenatal screening for Down''s syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Down''s syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Down''s syndrome in the United Kingdom from about 900 a year to about 350 a year.     

Fatal self-poisoning with lithium carbonate.

In a fatal case of self-poisoning with lithium carbonate there was a progressive increase in serum lithium concentration for 48 hours after ingestion of the overdose. It is suggested that the continuous increase in serum lithium concentration reflects prolonged absorption of lithium from relatively insoluble aggregates of lithium carbonate in the gastrointestinal tract. In this case there was an interval of 45 hours between ingestion of the overdose and the onset of central nervous system depression. Simultaneous peritoneal dialysis and hemodialysis were effective in rapidly reducing the serum lithium concentration but there was little concomitant change in the patient''s level of consciousness. The terminal event was a respiratory complication of the comatose state.