Elevated Serum Bilirubin Concentrations Research Articles

Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases.

The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

Association between elevated serum bilirubin levels with preserved lung function under conditions of exposure to air pollution

BackgroundHigh serum bilirubin levels have been shown to be associated with an improved pulmonary function test results. Their potential ability to similarly benefit pulmonary function in an environment of polluted air has not been tested. We retrospectively analyzed data of 15,605 apparently healthy individuals in order to evaluate the effect of serum bilirubin levels on forced expiratory volume in 1 s (FEV1).MethodsIndividuals attended the Tel-Aviv Medical Center Inflammatory Survey for a routine annual health check between February, 2002 and June, 2009 and were divided into low, medium and high serum bilirubin levels. Their FEV1 results were compared under various levels of air pollution. Air pollution and weather data were obtained from air pollution monitoring stations of the Israeli Ministry of Environmental Protection.ResultsThe elevated serum bilirubin concentrations on FEV1 were evaluated under moderate and high pollution levels FEV1 and were significantly higher in participants with high blood bilirubin levels compared to medium or low levels (p < 0.001 and p = 0.018, respectively). Participants with high levels of bilirubin had preserved FEV1 under exposure to high and medium pollution levels of both Nitrogen Oxide (NOx) and Carbon Monoxide (CO) pollutants (p = 0.003 and p = 0.022, respectively). The multivariate regression analysis revealed that the influence of bilirubin under conditions of air pollution remained significant even after adjustment for FEV1 confounders, but the interaction was not significant.ConclusionsElevated serum bilirubin concentrations are associated with preserved lung function in healthy individuals in Israel exposed to high levels of air pollution.

Elite Athletes Have Mildly Elevated Serum Bilirubin Concentrations

Bilirubin is a potent endogenous antioxidant and immune system-modulating substance, which is implicated also in the cell signalization and in various metabolic pathways. Mild elevation of its systemic concentrations seems to provide substantial protection against numerous pathological conditions such as atherosclerotic and inflammatory diseases. Scarce reports in the literature suggest that serum bilirubin might have relevance also to the physical performance. PURPOSE: The aim of the current study was to assess serum bilirubin concentrations in the Czech elite athletes and to compare them with the Czech general population. METHODS: The study was performed in 145 consecutive healthy Czech elite athletes (M:F ratio=1.78) and in 2597 individuals (M:F ratio=0.91) of the Czech post-MONICA study randomly selected from the Czech general population. Serum bilirubin concentrations as well as prevalence of benign hyperbilirubinemia >17 umol/L (1 mg/dL, a phenotypic sign of Gilbert´s syndrome) were evaluated. RESULTS: The medians of serum bilirubin concentrations in the elite athletes were substantially higher compared to the general population (11.75 vs. 9.6 umol/L, p<0.001), and this substantial difference was observed in both men (13.02 vs. 11.3 umol/L, p=0.006) and women (10.29 vs. 8.3 umol/L, p<0.001). Compared to the general population, the prevalence of a phenotypic Gilbert´s syndrome (known also as benign hyperbilirubinemia) was significantly higher in both male (18.4% vs. 31.1%, p=0.004) and female athletes (7.4% vs. 17.3%, p<0.001). CONCLUSIONS: Elite athletes have significantly higher serum concentrations of bilirubin, the most potent endogenous antioxidant substance. Simultaneously, also the prevalence of Gilbert´s syndrome is higher in elite athletes, suggesting that the presence of Gilbert´s syndrome may predispose to better physical performance. This study was supported by grant No. SVV 260156/2019 provided by Charles University.

Bilirubin as a signaling molecule.

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the "classical" hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various "diseases of civilization." Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.

STEROIDAL SAPONIN TOXICITY IN EASTERN GREY KANGAROOS ( MACROPUS GIGANTEUS): A NOVEL CLINICOPATHOLOGIC PRESENTATION OF HEPATOGENOUS PHOTOSENSITIZATION.

We describe the clinicopathologic features of a mortality event characterized by blindness and dermatitis affecting eastern grey kangaroos ( Macropus giganteus), secondary to hepatogenous photosensitization. Affected animals exhibited photophobic behavior, blindness, ataxia, recumbency, lethargy, ear shaking, and behavior consistent with distress or depression. The photophobia manifested as abnormal shade-seeking during the day, including finding refuge under or in structures used frequently by people. Severely affected kangaroos were jaundiced and had markedly elevated serum bilirubin and gamma glutamyl-transpeptidase concentrations. Blindness in affected animals was attributed to moderate to severe corneal opacity due to corneal edema and inflammation. Skin lesions were typically subtle on gross examination even in cases which had severe necrotizing dermatitis histologically. Histologic lesions in the liver of affected animals included the presence of acicular clefts typical of steroidal saponins. The outbreak was associated with pasture dominated by the invasive grass, Panicum gilvum, which is a recognized source of saponin-induced photosensitization in livestock.

Specificity of elevated cerebrospinal fluid bilirubin in the investigation of subarachnoid haemorrhage.

The spectrophotometric examination of cerebrospinal fluid for bilirubin is an established investigation in patients with suspected subarachnoid haemorrhage. This study assesses the diagnostic specificity of an elevated cerebrospinal fluid bilirubin and how this may be influenced by the presence of oxyhaemoglobin and the concentration of cerebrospinal fluid total protein. One thousand cerebrospinal fluid spectroscopy reports were reviewed. Electronic patient records were examined to determine the clinical outcome in patients with an elevated cerebrospinal fluid bilirubin. Forty-four out of 1000 cerebrospinal fluid scans showed an increase in cerebrospinal fluid bilirubin unrelated to elevated serum bilirubin concentrations. This was associated with subarachnoid haemorrhage in 16 (36%) cases. Subarachnoid haemorrhage was confirmed in 5/17 (29%) patients positive for cerebrospinal fluid bilirubin alone and in 11/27 (41%) patients positive for both cerebrospinal fluid bilirubin and oxyhaemoglobin. At cerebrospinal fluid total protein concentrations <1 g/L, the specificity for subarachnoid haemorrhage improved: 4/9 (44%) vs. 1/8 (13%) with an increase in cerebrospinal fluid bilirubin alone; 6/10 (60%) vs. 5/17 (29%) in patients with increases in both bilirubin and oxyhaemoglobin. While an increase in cerebrospinal fluid bilirubin may be considered consistent with subarachnoid haemorrhage, the likelihood that a subarachnoid haemorrhage has occurred is influenced by the presence of oxyhaemoglobin and the concentration of total protein in the cerebrospinal fluid.

Risk Factors for Liver Injury with an Elevated Serum Bilirubin Concentration Caused by Antituberculous Drugs

No studies have so far sufficiently investigated the risk factors for drug-induced liver injury (DILI) with an elevated serum bilirubin concentration. We conducted a historical cohort study observing inpatients admitted to two hospitals in Japan. A decreased level of activities of daily living (ADL) was defined as a Barthel Index score of <80. The patients were treated with standard regimens under a directly observed treatment short-course strategy. The cohort of 356 patients comprised 244 men (68.5%) and 112 women (31.5%), with a mean age of 63.8±20.2 years. Compared with the patients who did not experience DILI with a bilirubin level of ≥2.0 mg/dL, the patients who experienced DILI with a bilirubin level of ≥2.0 mg/dL more often had a decreased level of ADLs, were more likely to suffer from chronic cardiac disease, had lower serum albumin levels and were less often treated with four-drug regimens involving pyrazinamide (PZA). In a logistic regression analysis in which these five factors acted as independent variables, a decreased level of ADLs was the strongest predictor for DILI with a bilirubin level of ≥2.0 mg/dL, with an odds ratio of 16.5 (95%CI: 1.7-159; p=0.015), followed by chronic cardiac disease, with an odds ratio of 4.0 (95%CI: 1.2-12.6; p=0.020). A decreased level of ADLs and chronic cardiac disease are strong risk factors for DILI with a bilirubin level of ≥2.0 mg/dL resulting from the use of antituberculous drugs. Physicians should pay close attention to the possibility of DILI with a bilirubin level of ≥2.0 mg/dL when treating tuberculosis patients with a decreased level of ADLs and/or chronic heart disease.

Increased Serum Bilirubin Level is Related to Good Collateral Development in Patients with Chronic Total Coronary Occlusion

Bilirubin is a bile pigment with potent anti-oxidant properties; in previous studies it has been reported to be negatively associated with coronary artery disease (CAD). Although elevated serum bilirubin concentrations may protect against endothelial dysfunction, it is not clear whether higher serum bilirubin levels (SBLs) in physiological ranges may work in favor of good collateral development in patients with chronic total coronary occlusion (CTO). The study population consisted of patients who underwent coronary angiography with a suspicion of CAD. Patients who had CTO in at least one major coronary artery were included. Coronary angiograms of 179 eligible patients from our database were reanalyzed and 110 of them had good collateral development and 69 had poor collateral development according to the Cohen-Rentrop method. Patients with good collateral development had a lower fasting plasma glucose level (FPG) (p=0.024) and higher SBLs in comparison to patients with poor collateral development (p<0.001). The number of CTO vessels (p=0.013) and left ventricular ejection fraction (EF%) were higher in good collateral group than poor collateral group (p=0.017). In multivariate analysis, FPG negatively (odds ratio [OR]: 0.981, p=0.003) and SBL (OR for per 0.1-mg/dL increase: 1.832, p<0.001) and the number of CTO vessels (OR: 5.642, p=0.007) were positively related to coronary collateral development. This study suggests that higher bilirubin levels within relatively normal ranges were related with favorable coronary collateral growth in patients with CTO. SBL may be responsible for the difference in coronary collateral vessel development among different patients with coronary artery disease. The anti-inflammatory and anti-oxidant properties of bilirubin may mediate this effect.

Association of Arterial Stiffness with Serum Bilirubin Levels in Established Coronary Artery Disease

Elevated serum bilirubin concentrations protect from atherosclerotic diseases, however it is not clear whether or not higher serum bilirubin concentrations have the same effect in coronary artery disease (CAD). The brachial-ankle pulse wave velocity (baPWV) is a reproducible method to assess arterial stiffness. This study was aimed to investigate the relationship between serum total bilirubin (TB) and baPWV in patients with established CAD. We enrolled 638 patients (390 men, 248 women) with established CAD. TB was divided into tertiles. Simple and multiple linear regression analyses were used to assess the correlation between baPWV and TB. The mean baPWV tended to decrease in men according to TB tertiles: Tertile 1=2,126.0, Tertile 2=1,832.5, and Tertile 3=1,692.5 cm/s. Likewise, the mean baPWV tended to decrease in women according to TB tertiles: Tertile 1=1,920.8, Tertile 2=1,829.0, and Tertile 3=1,701.3 cm/s. Univariate analysis showed that age, BMI, TB, ALT, GGT, Cho, SBP, DBP, UA, and TC were significantly associated with baPWV in men. In women, age, BMI, current smoker, Cho, SBP, DBP, UA, TC, TG, HDL-C, and LDL-C were significantly associated with baPWV. BMI, LnSBP, UA, TB, LnCho, and LnTC were correlated with baPWV in men in the multivariate model. However, only LnSBP, UA, and LnHDL-C were correlated with baPWV in women. TB was found to be a significant determinant for decreased baPWV only in men (β=-0.136; p<0.001). Our findings show that the level of total serum bilirubin is negatively correlated with arterial stiffness in men with established CAD.

Legal Briefs

A 2,222-g 34-weeks' gestation male twin was delivered in the winter to a mother whose pregnancy was unremarkable except for diamniotic, dichorionic twins. This twin was delivered via normal spontaneous vaginal delivery. Apgar scores were 8 at 1 and 5 minutes. Both twins were admitted to the newborn intensive care unit because of their gestational age. The male twin exhibited tachypnea at birth and received a 7-day course of antibiotics. Findings on chest radiography were consistent with transient tachypnea, and a blood culture was negative after 1 week. Other than mild apnea of prematurity and a slightly elevated serum bilirubin concentration, his course was unremarkable. The mother missed several days of visitation near the time of discharge because she had an upper respiratory tract infection. The infant was discharged 16 days after birth at 36–1/7 weeks' gestation. He had three siblings at home: his twin sister, who was discharged close to the time he went home; a 3-year-old brother who had an upper respiratory tract infection; and a 7-year-old healthy sister. After being home for 6 days, when he was 22 days old (37 weeks' gestation), his mother called the pediatrician because the infant had developed nasal congestion, refused to nurse, and seemed excessively sleepy. The pediatrician reassured the mother over the telephone. A few hours later, she brought the infant to the hospital because he had vomited three times and she had ongoing concerns about his poor feeding and excessive sleepiness. On physical examination, the infant's respiratory rate was 40 breaths/min, temperature was 37.4°C, heart rate was 140 beats/min, and oxygen saturation was 97% in room air. The emergency department (ED) physician noted clear breath sounds, unlabored breathing, and moist mucous membranes. The ED nurse noted and documented a congested cough for the infant, and the heart rate was …

Autoimmune hemolytic anemia associated with a formulation of traditional Chinese medicines

A case of autoimmune hemolytic anemia (AIHA) after treatment with a Chinese herbal preparation is reported. A 29-year-old woman was admitted to the hospital with the primary complaints of jaundice, tea-colored urine, and fatigue lasting 10 days. Thirteen days prior, she went to a local private clinic seeking treatment for mild stomach pain and general malaise and was given weidean tablets. She took four tablets of weidean, a Chinese herbal preparation, orally three times daily for 2 days. After 2 days, she experienced fatigue, dizziness, and chest distress and subsequently discontinued treatment. Upon examination, she exhibited mild scleral and mucosal icterus. Her conjunctivas were pale, and her skin was slightly jaundiced. Preliminary laboratory tests found a low hemoglobin level and an elevated reticulocyte count. Biochemical tests showed an elevated total serum bilirubin concentration with indirect hyperbilirubinemia. Coombs' test results were positive for immunoglobulin G but negative for C3. All other test results were normal. The patient was diagnosed with AIHA secondary to weidean use, and she was treated promptly with oral prednisone, i.v. cimetidine, and oral sodium bicarbonate tablets. Seven days later, she showed clinical improvement. Her hemoglobin level rapidly increased to above 100 g/L, with a corresponding decrease in her reticulocyte count and serum bilirubin value over the next 8 days. She was discharged 15 days after admission and was asymptomatic at a three-week follow-up visit. Weidean, a formulation of Chinese medicinal herbs and other constituents, was associated with AIHA in a woman taking the remedy for gastritis.

Conjugated Hyperbilirubinemia: Screening and Treatment in Older Infants and Children

1. Rula Harb, MD* 2. Daniel W. Thomas, MD† 1. *Children’s Hospital of Los Angeles, Los Angeles, Calif 2. †Editorial Board After completing this article, readers should be able to: 1. Describe the metabolism of bilirubin. 2. Evaluate a child of any age who has conjugated hyperbilirubinemia. 3. Recognize the signs and symptoms of Wilson disease. Jaundice refers to yellow discoloration of the skin, sclera, mucous membranes, and body fluids. It is a common problem that can be the presenting sign for many disorders. The challenge for the physician is to identify patients who need additional evaluation. The differential diagnosis for jaundice is age-specific; this review addresses the causative conditions in infants beyond the newborn period, older children, and adolescents. Jaundice is caused by elevated serum bilirubin concentrations. It is apparent in infants when the serum bilirubin value is greater than 4 to 5 mg/dL (68.4 to 85.5 mcmol/L) and in older children at values greater than 2 to 3 mg/dL (34.2 to 51.3 mmol/L). Serum total bilirubin is measured in the laboratory as the sum of two components: unconjugated (“indirect”) and conjugated (“direct”) fractions. The terms “direct” and conjugated hyperbilirubinemia often are used interchangeably. However, this usage is not always accurate because direct bilirubin may include both the conjugated fraction and bilirubin bound to albumin (delta bilirubin). Delta bilirubin is formed by covalent bonding between conjugated bilirubin in the serum and albumin; it is metabolized with albumin and has a similar half-life of 21 days. The presence of delta bilirubin often prolongs direct hyperbilirubinemia while results of the other liver tests are normalizing. Many hospitals continue to measure direct bilirubin by a method that includes both direct and delta bilirubin. Clinicians should consider asking for a breakdown of the direct bilirubin fraction if the jaundice is prolonged or presenting atypically. Conjugated hyperbilirubinemia is defined as a conjugated bilirubin concentration greater than 2 mg/dL (34.2 mmol/L) or more than 20% of total bilirubin. It …

Low serum bilirubin concentrations are associated with impaired aortic elastic properties, but not impaired left ventricular diastolic function

Elevated serum bilirubin concentrations protect from atherosclerotic diseases; however,it is not clear whether higher serum bilirubin concentrations in physiological ranges do the same. To investigate the association of high and low serum bilirubin concentrations with left ventricular diastolic function and aortic elastic properties.We evaluated left ventricular diastolic function and aortic elastic properties of 42 healthy subjects with hypobilirubinemia (total bilirubin 0.40 ± 0.08 mg ⁄ dl; mean age 37.0 ± 3.9) and 40 healthy subjects with hyperbilirubinemia (total bilirubin 1.56 ± 0.49 mg ⁄ dl; mean age 36.2 ± 6.0) using transthoracic second harmonic Doppler echocardiography. Age, gender, body mass index and coronary risk factors were similar between the groups, except high-sensitivity C-reactive protein (hsCRP).Left ventricular diastolic parameters were similar between the two groups. Aortic distensibility (AoD) was found to be significantly lower (11.1 ± 3.9 vs. 13.2 ± 4.9,p = 0.03) and aortic stiffness index (AoSI) (1.99 ± 0.30 vs. 1.85 ± 0.26,p = 0.02) and elastic modulus (AoEM) (2.06 ± 0.83 vs. 1.73 ± 0.68, p = 0.03;the low and high bilirubin groups, respectively) higher in the low bilirubin group.Serum total bilirubin concentration correlated with hsCRP levels, AoD, AoSI and AoEM. In conclusion, left ventricular systolic and diastolic functions were similar between hypo- and hyperbilirubinemic subjects, but aortic elastic properties were impaired in subjects with lower serum bilirubin concentrations.

High Serum Bilirubin Concentrations Preserve Coronary Flow Reserve and Coronary Microvascular Functions

Elevated serum bilirubin concentrations protect against atherosclerotic diseases; however, it is not clear whether higher serum bilirubin concentrations in physiological ranges work in favor of the cardiovascular system in younger persons with no cardiovascular risk factors. Accordingly, we investigated the effects of high, intermediate, and low serum bilirubin concentrations on coronary flow reserve (CFR). Fifty-two healthy subjects with hyperbilirubinemia (total bilirubin 1.43+/-0.33 mg/dL; mean age 35.9+/-7.3), 55 subjects with intermediate bilirubin level (total bilirubin: 0.69+/-0.11 mg/dL; mean age: 36.4+/-6.8), and 53 healthy subjects with hypobilirubinemia (total bilirubin 0.37+/-0.08 mg/dL; mean age, 37.6+/-6.6) were studied. Transthoracic second harmonic Doppler echocardiography examination was performed using an Acuson Sequoia C256 Echocardiography System. Coronary diastolic peak flow velocities were measured at baseline and after dipyridamole infusion (0.84 mg/kg over 6 minutes). CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities. Demographic features, coronary risk factors, echocardiographic measurements, and biochemical measurements were similar among the 3 groups, except high-sensitivity C-reactive protein (hsCRP). CFR values were significantly higher in subjects with high bilirubin concentrations than those were in the intermediate and the low bilirubin groups (3.19+/-0.73; 2.75+/-0.42; 2.56+/-0.52, respectively; P<0.0001), and hsCRP levels were significantly lower in subjects with high bilirubin concentrations than those in both intermediate and low bilirubin groups (1.4+/-1.0, 2.0+/-1.7, 3.0+/-1.9 mg/L, respectively; P<0.001). hsCRP levels correlated with total bilirubin concentration and with CFR. Elevated serum bilirubin concentrations protect from CFR impairment, coronary microvascular dysfunction, and possibly coronary atherosclerosis.

Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women

Background Elevated levels of low-density lipoprotein (LDL) cholesterol and its oxidative modification have been described to be involved in the process of atherogenesis. Bilirubin, an antioxidant, prevents oxidative modification of LDL and therefore may protect from atherosclerosis and coronary heart disease (CHD). Impaired brachial artery flow-mediated dilatation (FMD), which means endothelial dysfunction (ED) and carotid intima-media thickness (IMT) are predictors for the development and progression of atherosclerosis. In the present study, FMD and IMT were studied in healthy subjects with lower and higher serum bilirubin concentrations in physiological ranges. Methods Ninety-one healthy subjects between 25 and 45 years of age (47 with lower and 44 with higher serum bilirubin concentrations) were included in this study. Carotid IMT and brachial artery flow-mediated dilatation was measured by means of high-resolution vascular ultrasound. FMD was assessed by establishing reactive hyperemia and endothelium-independent dilatation (EID) was determined by using sublingual isosorbide dinitrate. Results EDD in subjects with lower serum bilirubin concentrations was significantly worse than in those with higher serum bilirubin concentrations (11.6 ± 4.4% versus 7.2 ± 4.7%, respectively, p < 0.0001). EID measurements were not significantly different between the groups (16 ± 5.1% versus 16.8 ± 7%, respectively). In addition, carotid IMT was significantly greater in subjects with lower serum bilirubin concentrations (0.5 ± 0.13 mm versus 0.42 ± 0.07 mm, p < 0.0001). Furthermore, FMD in women with lower serum bilirubin concentrations was significantly lower than in women with higher serum bilirubin concentrations (11.5 ± 4.9% and 17.5 ± 4.7%, respectively, p < 0.001). Accordingly, men with lower serum bilirubin concentrations had significantly lower FMD as compared to hyperbilirubinemic ones (11.7 ± 3.6% versus16.7 ± 4.8%, respectively, p = 0.009). Conversely, carotid IMT was significantly greater in both women and men with lower serum bilirubin concentrations compared to the subjects with elevated serum bilirubin concentrations (0.51 ± 0.08 versus 0.41 ± 0.08, p < 0.001; 0.55 ± 0.12 versus 0.40 ± 0.07, p = 0.002, in women and men, respectively). Conclusion The healthy subjects with lower serum bilirubin concentrations show significant ED and increased carotid IMT, which are predictors for atherosclerosis.

Apoptosis in murine hepatoma hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin.

Elevated serum and tissue bilirubin concentrations that occur in pathological conditions such as cholestasis, jaundice, and other liver diseases are known to stimulate cytotoxic responses. In preliminary studies, we noted that bilirubin seemed to cause apoptosis in murine hepatoma Hepa 1c1c7 wild-type (WT) cells. Consequently, we investigated apoptosis caused by bilirubin in WT, mutant C12 [aryl hydrocarbon receptor (AHR)-deficient], and C4 (AHR nuclear translocator-deficient) Hepa 1c1c7 cells. Three independent measures of apoptosis were used to quantify the effects of exogenous bilirubin (0, 1, 10, 25, 50, or 100 microM). Caspase-3 activity and cytochrome c release from mitochondria increased at 3 h post-treatment, before increased caspase-8 activity at 6 h, and nuclear condensation by 24 h after treatment with bilirubin. No differences in whole-cell lipid peroxidation were observed between the cell types; however, intracellular reactive oxygen species (ROS) production was greater in WT cells than C12 or C4 cells 3 h after bilirubin exposure. Pretreatment of cells for 1 h with 1 or 10 microM alpha-naphthoflavone, an AHR antagonist, before bilirubin exposure resulted in decreased caspase-3 activity at 6 h and nuclear condensation at 24 h in WT cells. These results indicate that bilirubin, a potential AHR ligand, causes apoptosis in murine Hepa 1c1c7 WT cells by a mechanism(s) partially involving the AHR, disruption of membrane integrity, and increased intracellular ROS production.

JAUNDICE AND BREASTFEEDING

Optimal management of breastfeeding does not eliminate neonatal jaundice and elevated serum bilirubin concentrations. Rather, it leads to a pattern of hyperbilirubinemia that is normal and, possibly, beneficial to infants. Excessive frequency of exaggerated jaundice in a hospital or community population of breastfed infants may be a warning that breastfeeding policies and support are not ideal for the establishment of good breastfeeding practices. The challenge to clinicians is to differentiate normal patterns of jaundice and hyperbilirubinemia from those that indicate an abnormality or place an infant at risk.

A primer on continuous renal replacement therapy for critically ill patients.

To characterize the multiple continuous renal replacement therapy (CRRT) techniques available for the management of critically ill adults, and to review the indications for and complications of use, principles of drug removal during CRRT, drug dosage individualization guidelines, and the influence of CRRT on patient outcomes. MEDLINE (January 1981-December 1996) was searched for appropriate publications by using terms such as hemofiltration, ultrafiltration, hemodialysis, hemodiafiltration, medications, and pharmacokinetics; selected articles were cross-referenced. References selected were those considered to enhance the reader's knowledge of the principles of CRRT, and to provide adequate therapies on drug disposition. CRRTs use filtration/convection and in some cases diffusion to treat hemodynamically unstable patients with fluid overload and/or acute renal failure. Recent data suggest that positive outcomes may also be attained in patients with other medical conditions such as septic shock, multiple organ dysfunction syndrome, and hepatic failure. Age, ventilator support, inotropic support, reduced urine volume, and elevated serum bilirubin concentrations have been associated with poor outcomes. Complications associated with CRRT include bleeding due to excessive anticoagulation and line disconnections, fluid and electrolyte imbalance, and filter and venous clotting. CRRT can complicate the medication regimens of patients for whom it is important to maintain drug plasma concentrations within a narrow therapeutic range. Since the physicochemical characteristics of a drug and procedure-specific factors can alter drug removal, a thorough assessment of all factors needs to be considered before dosage regimens are revised. In addition, an algorithm for drug dosing considerations based on drug and CRRT characteristics, as well as standard pharmacokinetic equations, is proposed. The use of CRRT has expanded to encompass the treatment of disease states other than just acute renal failure. Since there is great variability among treatment centers, it is premature to conclude that there is enhanced survival in CRRT-treated patients compared with those who received conventional hemodialysis. This primer may help clinicians understand the need to individualize these therapies and to prospectively optimize the pharmacotherapy of their patients receiving CRRT.

Study of Hepatic Functions and Prevalence of Hepatitis-B Surface Antigenaemia in Omani Children with Sickle Cell Disease

The prevalence of persistent hepatitis-B surface (HBS) antigenaemia and hepatic functions have been determined in 125 children with sickle cell disease (SCD) as well as in 100 age-matched healthy children. Hepatic functions and the presence of HBS antigenaemia have been followed for 1 year in six children with SCD and 10 normal children following acute hepatitis-B infection. The prevalence of chronic HBS antigenaemia (3 per cent) in children with SCD is not higher than in normal children (11 per cent). The significant elevation of serum alanine transferase (ALT) and bilirubin concentrations in sickle cell children denotes a process of mild hepatocellular dysfunction which is unrelated to hepatitis-B viral antigenaemia. The high incidence of chronic HBS antigenaemia accompanied by elevated serum ALT and bilirubin concentrations in sickle cell children following acute hepatitis-B infection, in addition to the significant impairment of hepatic functions in sicklers with chronic HBS antigenaemia compared to those without the antigenaemia, point out to the high risk of continual parenchymal hepatic damage in these children following acute hepatitis-B infection. Vaccination against hepatitis-B virus should eliminate this risk.

The effect of fasting on total serum bilirubin concentrations.

Thirty-seven healthy volunteers, 19 of whom had consistently elevated total serum bilirubin (TSB) concentrations, took part in an open, randomised cross-over study to determine the effect of fasting on TSB concentrations. The study comprised of two treatments. During one treatment period volunteers ate a standard supper but fasted for 24 h thereafter. During the other treatment period volunteers ate a standard supper, snacks, breakfast and lunch. TSB concentrations were measured at regular intervals. In both the normal and high bilirubin groups, minimum TSB values were recorded 4 h after the supper. A 24 h fast more than doubled TSB concentration from baseline values in both the normal and high bilirubin groups. A clinically relevant rise in TSB took place after 12 h into the fasting period (TSB of 17.3 mumol l-1 in the fasted group vs 14.0 mumol l-1 in the non-fasted group). When designing a clinical trial, selecting volunteers, or judging the tolerance of a new drug, the rise in TSB caused by fasting must therefore be taken into account, particularly in trials where volunteers or patients fast before entering the study.