Serum Bilirubin Levels In Patients Research Articles

The associations of psychopathology and metabolic parameters with serum bilirubin levels in patients with acute-episode and drug-free schizophrenia: a 5-year retrospective study using an electronic medical record system

BackgroundThe oxidative system plays an important role in the pathogenesis of schizophrenia. Inconsistent associations were found between hyperbilirubinemia and psychopathology as well as glycolipid metabolism in patients with schizophrenia at different episodes. This current study aimed to examine these associations in patients with acute-episode and drug-free (AEDF) schizophrenia.MethodsThis is a retrospective study using 5 years of data from May 2017 to May 2022 extracted from the electronic medical record system of Chaohu Hospital of Anhui Medical University. Healthy controls (HCs) from the local medical screening center during the same period were also included. Participants’ data of the bilirubin levels [total bilirubin (TB), conjugated bilirubin (CB), unconjugated bilirubin (UCB)], glycolipid metabolic parameters and the score of the Brief Psychiatric Rating Scale (BPRS) were collected.ResultsA total of 1468 case records were identified through the initial search. After screening, 89 AEDF patients and 100 HCs were included. Compared with HCs, patients had a higher CB level, and lower levels of glycolipid metabolic parameters excluding high density lipoprotein-cholesterol (HDL-C) (all P < 0.001). Binary logistic regression analyses revealed that high bilirubin levels in the patients were independently associated with higher total and resistance subscale scores of BPRS, a higher HDL-C level, and lower total cholesterol and triglyceride levels (all P < 0.05).ConclusionBilirubin levels are elevated in patients with AEDF schizophrenia. Patients with high bilirubin levels have more severe psychopathology and relatively optimized glycolipid metabolism. In clinical practice, regular monitoring of bilirubin levels in this patient population should be carried out.

Gene Therapy in Patients with the Crigler–Najjar Syndrome

BackgroundPatients with the Crigler–Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation.MethodsWe report the results of the dose-escalation portion of a phase 1–2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler–Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 μmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy.ResultsNo serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 μmol per liter. The patients who received the higher dose had bilirubin levels below 300 μmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 μmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 μmol per liter).ConclusionsNo serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.)

Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease.

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.

Plasma total bilirubin in patients with Alzheimer’s disease: An observational study

AbstractBackgroundBilirubin, the primary end product of the heme cleavage pathway, is currently regarded as a major physiologic antioxidant with important cytoprotective properties. Oxidative stress is a well established contributing factor in the development of Alzheimer's disease (AD). In the present study, we aimed to compare serum bilirubin levels in patients with AD and healthy elderly controls, and to analyze the potential relationship between serum total bilirubin levels and dementia severity in AD patients.MethodMeasures of fasting serum total bilirubin levels were studied in 68 patients with AD (34 women; mean age 71.4±5.8 years; range 60‐82) (DSM‐IV; NINCDS‐ADRDA criteria) from a private ambulatory of neurology, recruited in a community elderly in Skikda‐Algeria (2017‐2020); and in 68 elderly controls (34 women; mean age 70.4±6.3 years; range 58‐82). Dementia severity was assessed by the clinical dementia rating scale‐CDR global score.ResultThe mean (±SD) plasma total bilirubin level was 0.72±0.13 (Range 0.49–1.08) among AD group and 0.66±0.11 (range 0.48–1.02) mg/dL among control group; (p= 0.0029). By gender, plasma total bilirubin level was higher in cases compared to controls both in men 0.75±0.14 vs. 0.67±0.13 mg/dL respectively, (p= 0.027); and in women 0.70±0.12 vs. 0.64±0.10 mg/dL; (p= 0.040). Patients with mild AD (Mean age 68±3.7 years) showed significantly higher levels of plasma total bilirubin compared with patients with moderate AD (Mean age 77.4±3.6 years): 0.77±0.13 vs. 0.64±0.09 mg/dL respectively (one way ANOVA, p= 0.0001). Plasma total bilirubin level was significantly negatively correlated with dementia severity, r= ‐0.4503; (95% CI for rho: ‐0.621; ‐0.238), p= 0.0001. By gender r= ‐3564; (p= 0.038) for men; and r= ‐0.5481, (p= 0.0007) for women.ConclusionThese data indicate that plasma total bilirubin level is increased in AD compared to controls, and inversely correlates with dementia severity. Patients with mild AD have higher total bilirubin levels (Within clinical normal range) than patients with moderate AD. These results suggest that serum total bilirubin level may provide additional information for predicting development of AD. We speculate that a possible beneficial physiologic antioxidant role for bilirubin could be operating during earlier stages of AD and gradually fades with disease progression.

R-JaunLab: Automatic Multi-Class Recognition of Jaundice on Photos of Subjects with Region Annotation Networks.

Jaundice occurs as a symptom of various diseases, such as hepatitis, the liver cancer, gallbladder or pancreas. Therefore, clinical measurement with special equipment is a common method that is used to identify the total serum bilirubin level in patients. Fully automated multi-class recognition of jaundice combines two key issues: (1) the critical difficulties in multi-class recognition of jaundice approaches contrasting with the binary class and (2) the subtle difficulties in multi-class recognition of jaundice represent extensive individuals variability of high-resolution photos of subjects, huge coherency between healthy controls and occult jaundice, as well as broadly inhomogeneous color distribution. We introduce a novel approach for multi-class recognition of jaundice to detect occult jaundice, obvious jaundice and healthy controls. First, region annotation network is developed and trained to propose eye candidates. Subsequently, an efficient jaundice recognizer is proposed to learn similarities, context, localization features and globalization characteristics on photos of subjects. Finally, both networks are unified by using shared convolutional layer. Evaluation of the structured model in a comparative study resulted in a significant performance boost (categorical accuracy for mean 91.38%) over the independent human observer. Our work was exceeded against the state-of-the-art convolutional neural network (96.85% and 90.06% for training and validation subset, respectively) and showed a remarkable categorical result for mean 95.33% on testing subset. The proposed network makes a performance better than physicians. This work demonstrates the strength of our proposal to help bringing an efficient tool for multi-class recognition of jaundice into clinical practice.

Analysis of therapeutic effect of intermittent and continuous phototherapy on neonatal hemolytic jaundice.

Clinical efficacy and adverse reaction rates of ABO hemolytic jaundice in patients with continuous and intermittent blue light irradiation were compared, to provide reference for clinical treatment of neonatal ABO hemolytic jaundice. A retrospective analysis of 307 patients with neonatal hemolytic jaundice admitted to Qilu Hospital of Shandong University (Qingdao) from January 2010 to December 2017 was undertaken. A total of 165 cases of children with continuous blue light irradiation and 142 cases of intermittent blue light irradiation were analyzed. Also the serum bilirubin levels, phototherapy time and frequency, treatment efficiency and adverse reaction rates were compared between the groups. The phototherapy time of children in the continuous phototherapy group was significantly higher from the intermittent phototherapy group, and the difference was statistically significant (t=26.800, P<0.001). Before treatment, there was no significant difference in serum bilirubin levels between continuous and intermittent phototherapy groups (P>0.050). Serum bilirubin levels of patients in continuous and intermittent phototherapy groups were lower than both previous and before treatment period, and differences were statistically significant (P<0.001). The overall effective rate of the continuous phototherapy group was higher than that of the intermittent phototherapy group (P>0.050). The adverse reaction rates after treatment in the continuous phototherapy group was significantly higher than the intermittent phototherapy group (P<0.050). After the symptomatic treatment in children, the adverse reactions ceased. The therapeutic effect of intermittent blue light irradiation on neonatal ABO hemolytic jaundice was consistent with the continuous blue light irradiation treatment, and the intermittent blue light irradiation treatment has a low adverse reaction rate, and is worth promotion in clinical practice.

Serum Bilirubin Levels in Patients with COPD during Acute Exacerbation

Serum Bilirubin Levels in Patients with COPD during Acute Exacerbation

Hyperbilirubinaemia: its utility in non-perforated appendicitis.

The diagnosis of acute appendicitis is made using clinical findings and investigations. Recent studies have suggested that serum bilirubin, a cheap and simple biochemical test, is a positive predictor in the diagnosis of appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC). The aim of this study was to investigate the utility of the serum bilirubin level in patients with suspected acute but non-perforative appendicitis. A retrospective chart review of 213 patients who presented with suspected appendicitis in a 6-month period to Nambour General Hospital was performed. Serum bilirubin, WCC and CRP were recorded and analysed as to their utility in relation to the final diagnosis. A total of 196 patients underwent an appendicectomy and 41 of these were negative. The specificity of hyperbilirubinaemia for appendicitis overall was 0.83 with a positive predictive value (PPV) of 0.86, compared with CRP (specificity 0.40, PPV 0.75) and WCC (specificity 0.67, PPV 0.85). The area under the receiver operating characteristic curve for bilirubin was 0.6289 compared to 0.6171 for CRP and 0.7219 for WCC. A subgroup analysis of those with complicated appendicitis demonstrated a PPV for bilirubin of 0.66 compared to 0.58 for WCC and 0.34 for CRP in agreement with the literature. Subgroup analysis of hyperbilirubinaemia in simple appendicitis demonstrated a PPV of 0.81 compared to CRP (0.71) and WCC (0.82). Bilirubin had a higher specificity than CRP and WCC overall in patients with appendicitis. Hyperbilirubinaemia had a high PPV in patients with simple appendicitis.

The duration of diabetes is inversely associated with the physiological serum bilirubin levels in patients with type 2 diabetes.

The aim of this study was to assess the relationship between the duration of diabetes and the physiological serum bilirubin concentration in association with antioxidant properties in patients with type 2 diabetes. A total of 1,746 patients with type 2 diabetes were investigated in this cross-sectional study. An analysis of covariance was performed after adjusting for other covariates. Simple correlation analyses and a multivariate regression model were used to assess the association between the duration of diabetes and the serum bilirubin concentration. The mean total bilirubin value differed significantly according to the tertile of diabetes duration (<5 years, 12.38 μmol/L, 95% confidence interval (CI) 12.02-12.76; 5-11.9 years, 12.33 μmol/L, 95% CI 11.97-12.69; ≥12 years, 11.73 μmol/L, 95% CI 11.35-12.11; p for trend =0.033), after adjustment for other covariates. In addition, an inverse correlation was found between the serum bilirubin concentration and diabetes duration (ρ=-0.211, p<0.001). According to a multivariate model, the association between the diabetes duration and serum bilirubin concentration remained significant, even after adjustment for confounding factors (β=-0.074, p=0.008). The duration of diabetes is inversely associated with a serum bilirubin concentration within the physiologic range in patients with type 2 diabetes.

Relationship between serum bilirubin levels and optic neuritis

Background Bilirubin is the end product of heme catabolism and has strong antioxidant properties. Serum bilirubin levels are reported to be reduced in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). The pathophysiology of optic neuritis (ON) resembles that of MS; however, the role of endogenous bilirubin in ON is unclear. The aim of this study is to measure serum bilirubin levels in patients with ON, and to investigate the correlation between ON and serum antioxidant status of bilirubin. Methods Serum levels of bilirubin were measured in 42 patients with ON, 50 patients with multiple sclerosis (MS), 48 patients with neuromyelitis optica (NMO) and 48 healthy control subjects. Results Serum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) levels in patients with ON were significantly lower than those in the healthy controls. However, no statistical significance was found between levels in the ON and MS, ON and NMO, and MS and NMO groups. In patients with ON, serum Tbil, Dbil, and Ibil levels were lower in those with recurrence or those with ON for a longer duration (≥1 year). Moreover, Tbil, Dbil, and Ibil concentrations were lower in patients with papillitis than in those with retrobulbar type ON, but the differences were not statistically significant. Conclusions Low antioxidant status may exist in patients with ON. But serum levels of Tbil, Dbil, and Ibil did not correlate with clinical presentations, such as recurrence, duration of disease and subtypes of ON. Low antioxidant status already existed in MS or NMO patients before systemic symptoms appeared.

Oxidative Stress and Some Liver Functions Parameters in Patients with Symptomatic Cholelithiasis

Background : Gallstone disease is one of a common surgical problem and one of the most common gastrointestinal diseases throughout the world but its pathogenesis remains unclear. Many theories have been put forward to explain the mechanism of stone formation. The living organism has enzymatic and non-enzymatic antioxidant systems neutralizing the harmful effects of the endogenous oxygen free radicals products. Under certain conditions, the oxidative or anti-oxidative balance shifts towards the oxidative status as a result of increase in oxygen free radicals and/or impairment in antioxidant mechanism.&#x0D; Objective :To evaluate the oxidative stress markers (total antioxidants capacity and malondialdehyde) and some liver functions parameters (aspartate aminotransefrerase , alanin aminotranseferase , alkaline phosphatase , total serum bilirubin )in serum of patients with gallstone disease and in control group.&#x0D; Patients &amp; Methods : The study group included 75 patient with gallstone disease and 33 age- and sex-matched healthy volunteers as control group. Antioxidative status of serum was evaluated by measuring total antioxidant capacity . serum: malondialdehde , aspartate aminotranseferase , alanine aminotransferase , alkaline phosphatase, and total bilirubin, were all measured in serum of patients with gallstones and controls.&#x0D; Results : There was a significant increase(P&lt;0.05) in serum: malondialdehyde, alkaline phosphatase , alanin aminotranseferase ,aspartate aminotransefrerase , total serum bilirubin levels in patients with symtomatic gallstones compared to healthy controls. The study also showed that there was a significant decrease in serum total antioxidant capasity (P&lt;0.05) in the patients compared to control group .&#x0D; Conclusion : The present study results indicated that patients with gallstones may have been exposed to oxidative stress . change in liver functions parameters was also seen in serum of patients compared to controls . these findings may provides insights and helps in understanding the various biochemical alterations undergoing in the gallbladder responsible for stone formation and would be helpful in developing strategies for the treatment and prevention of gallstones.

Prognostic Value of Total Bilirubin in Patients With ST-Segment Elevation Acute Myocardial Infarction Undergoing Primary Coronary Intervention

Previous studies have shown that the serum total bilirubin (TB) concentration was inversely related with stable coronary artery disease, diabetes mellitus, hypertension, and metabolic syndromes. The relation between TB levels and in-hospital and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI) is not known. Data from 1,624 consecutive patients with STEMI who underwent primary PCI were evaluated. TB was measured after primary PCI, and the study population was divided into tertiles. The high TB group (n=450) was defined as a value in the upper third tertile (>0.9 mg/dl) and the low TB group (n= 1,174) as any value in the lower 2 tertiles (≤0.9 mg/dl). The in-hospital mortality rate was significantly greater in the high TB group than in the low TB group (4% vs 1.5%, p= 0.003). In the multivariate analyses, a significant association was noted between high TB levels and the adjusted risk of in-hospital cardiovascular mortality (odds ratio 3.24, 95% confidence interval 1.27 to 8.27, p= 0.014). In the receiver operating characteristic curve analysis, TB >0.90 mg/dl was identified as an effective cutpoint in patients with STEMI for in-hospital cardiovascular mortality (area under the curve 0.66, 95% confidence interval 0.55 to 0.76, p= 0.001). The mean follow-up period was 26.2 months. No differences wereseen in the long-term mortality rates between the 2 groups. In conclusion, high TBisindependently associated with in-hospital adverse outcomes in patients with STEMIwhoundergo primary PCI. However, no association was found with long-term mortality.

Characterization of autoantibodies against uridine-diphosphate glucuronosyltransferase in patients with inflammatory liver diseases.

Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver-kidney microsomal autoantibodies and was termed LKM-3. To evaluate the nature of LKM-3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and 1 of 27 of the HCV patients. The anti-UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT-isoform involved in the bilirubin glucuronidation. Additionally, these sera were able to block UGT-mediated substrate glucuronidation in vitro. The prevalence for UGT1A1 was shown by 2 independent techniques: (1) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT-isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation. In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT-mediated glucuronidation in vitro, but it is unlikely that anti-UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range.

Correlation of mutational analysis to clinical features in Taiwanese patients with Gilbert’s syndrome

OBJECTIVES: Mutations in the promoter as well as in the coding region of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) have been found to be associated with Gilbert’s syndrome. However, the genetic basis of Gilbert’s syndrome in our population and correlation of these mutations to fasting serum bilirubin levels in patients with Gilbert’s syndrome remain to be clarified. METHODS: We applied polymerase chain reaction–based direct-sequencing assays to examine mutations in UGT1A1 gene in 20 unrelated Gilbert’s patients and in a family with Gilbert’s syndrome. RESULTS: We studied three mutations that were previously reported to be associated with Gilbert’s syndrome ( i.e., the TATAA-box mutation, Gly71Arg, and Pro229Gln) in 20 patients with Gilbert’s syndrome. Of the patients, 16, five, and six were found to have the TATAA-box, Gly71Arg and Pro229Gln mutations, respectively. Seven patients had simultaneous mutations both in the TATAA box and in the coding region. Of note, all six patients with Pro229Gln also had the TATAA-box mutation. Localization of Pro229Gln on the allele containing the TATAA-box mutation was demonstrated in a family with Gilbert’s syndrome. The patients simultaneously heterozygous for both the TATAA-box mutation and Gly71Arg usually had serum bilirubin levels similar to those found in the patients homozygous for the TATAA-box mutation, but usually higher than those found in the patients heterozygous for the TATAA-box mutation alone. On the other hand, concurrence of Pro229Gln in patients with TATAA-box mutation or with Gly71Arg did not significantly affect serum bilirubin levels. CONCLUSIONS: The TATAA-box mutation and Gly71Arg are the major causes for Gilbert’s syndrome in our population. Concurrence of mutations of Gly71Arg and TATAA-box usually exerts a synergistic effect on hyperbilirubinemia. Pro229Gln, which is regularly linked to the TATAA-box mutation, may not have a significant effect on serum bilirubin levels.

The utility of rifampin in diagnosing Gilbert’s syndrome

OBJECTIVE: The aim of this study was to evaluate the effect of rifampin (the “rifampin test”) on serum bilirubin in patients with and without Gilbert’s syndrome. METHODS: We conducted a clinical trial in which the effect of rifampin on serum bilirubin level in 15 patients with Gilbert’s syndrome was compared with 10 patients without Gilbert’s syndrome (controls) in a General Internal Medicine/Primary Care clinic of a Veterans Affairs medical center. Each participant underwent a “rifampin test,” i.e., bilirubin measurement at baseline and 2, 4, and 6 h after the administration of 900 mg of rifampin. Measurements included complete blood count, blood chemistry including liver panel tests (ALP, AST, LDH, and albumin) along with total serum bilirubin levels. Ten patients with Gilbert’s and nine control patients had haptoglobin level measured at baseline and 6 h after the administration of rifampin. RESULTS: While fasting, the mean rise in total serum bilirubin at 2, 4, and 6 h after the administration of rifampin, respectively, was 0.5, 0.7, and 0.7 mg/dl (analysis of variance, p < 0.001) in control patients and 0.6, 1.0, and 1.1 mg/dl ( p < 0.001) in the study patients. In 15 fed subjects (six control and nine study), the mean rise in total serum bilirubin at 2, 4, and 6 h, respectively, was 0.3, 0.5, and 0.6 mg/dl ( p < 0.001) in controls and 0.5, 1.0, and 1.2 mg/dl ( p < 0.001) in study subjects. In the fasting state, rise in total serum bilirubin to >1.9 mg/dl distinguished patients with Gilbert’s syndrome from those without at 2, 4, and 6 h (sensitivity 100%, 93%, and 93%; specificity 100%, 100%, and 100% at 2, 4, and 6 h, respectively). In the nonfasting state, rise in total serum bilirubin to >1.5 mg/dl at 4 and 6 h after rifampin administration distinguished the two groups (sensitivity 90% and 100%; specificity 100% and 100%, respectively). CONCLUSIONS: Rifampin increases total serum bilirubin levels in patients with and without Gilbert’s syndrome. On fasting for 12 to 24 h, an absolute increase of bilirubin to >1.9 mg/dl 2 to 6 h after the administration of 900 mg of rifampin distinguishes patients with Gilbert’s syndrome from those without it. In the nonfasting state, an increase in total serum bilirubin to >1.5 mg/dl 4 to 6 h after the administration of rifampin distinguishes persons with Gilbert’s syndrome from those without it.

Correlation of mutational analysis to clinical features in Taiwanese patients with Gilbert's syndrome.

Mutations in the promoter as well as in the coding region of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) have been found to be associated with Gilbert's syndrome. However, the genetic basis of Gilbert's syndrome in our population and correlation of these mutations to fasting serum bilirubin levels in patients with Gilbert's syndrome remain to be clarified. We applied polymerase chain reaction-based direct-sequencing assays to examine mutations in UGT1A1 gene in 20 unrelated Gilbert's patients and in a family with Gilbert's syndrome. We studied three mutations that were previously reported to be associated with Gilbert's syndrome (i.e., the TATAA-box mutation, Gly71Arg, and Pro229Gln) in 20 patients with Gilbert's syndrome. Of the patients, 16, five, and six were found to have the TATAA-box, Gly71Arg and Pro229Gln mutations, respectively. Seven patients had simultaneous mutations both in the TATAA box and in the coding region. Of note, all six patients with Pro229Gln also had the TATAA-box mutation. Localization of Pro229Gln on the allele containing the TATAA-box mutation was demonstrated in a family with Gilbert's syndrome. The patients simultaneously heterozygous for both the TATAA-box mutation and Gly71Arg usually had serum bilirubin levels similar to those found in the patients homozygous for the TATAA-box mutation, but usually higher than those found in the patients heterozygous for the TATAA-box mutation alone. On the other hand, concurrence of Pro229Gln in patients with TATAA-box mutation or with Gly71Arg did not significantly affect serum bilirubin levels. The TATAA-box mutation and Gly71Arg are the major causes for Gilbert's syndrome in our population. Concurrence of mutations of Gly71Arg and TATAA-box usually exerts a synergistic effect on hyperbilirubinemia. Pro229Gln, which is regularly linked to the TATAA-box mutation, may not have a significant effect on serum bilirubin levels.

Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis.

Thirty-one patients with sclerosing cholangitis underwent reconstruction of their hepatic duct bifurcation and long-term stenting between 1980 and 1987. Indications for surgery were persistent jaundice in 29 and recurrent cholangitis in two. The mean serum bilirubin level before surgery was 10.4 mg/dl. Liver biopsy revealed that 26 patients had varying degrees of hepatic fibrosis, and five patients had progressed to secondary biliary cirrhosis. In 29 patients the major obstructive duct disease was at or near the hepatic duct bifurcation, and in two patients it was in the distal common duct. The operative procedure consisted of: (1) excision of the hepatic duct bifurcation and extrahepatic biliary tree, (2) dilatation of the intrahepatic ducts, (3) insertion of Silastic transhepatic biliary stents, and (4) bilateral hepaticojejunostomies. Two of the five patients (40%) with cirrhosis died after surgery. In contrast, only one of 26 patients (3.9%) with hepatic fibrosis died after operation. The 1-, 3-, and 5-year actuarial survival rates for patients with cirrhosis were 20%, 20%, and 20%, respectively. The only long-term survivor underwent a liver transplant. The 1-, 3-, and 5-year actuarial survival rates for patients with hepatic fibrosis were 92%, 87%, and 71%, respectively. In addition, the mean serum bilirubin levels of patients with hepatic fibrosis at 1, 2, 3, 4, and 5 years were 3.4 mg/dl, 2.9 mg/dl, 4.0 mg/dl, 5.4 mg/dl, and 4.3 mg/dl, respectively. Two of the long-term survivors subsequently underwent a liver transplant. Patients with sclerosing cholangitis, persistent jaundice, and biliary cirrhosis should be referred for consideration of liver transplantation. However, in the absence of biliary cirrhosis, if the major obstructive disease is at the hepatic duct bifurcation, primary biliary reconstruction and long-term stenting should be considered.

The effects of diseases of the liver on serum 25-hydroxyvitamin D and on the serum binding protein for vitamin D and its metabolites.

Abstract The effects of liver damage on the serum levels of 25-OH-D and DBP were examined in patients with acute hepatitis, chronic hepatitis, and cirrhosis. Serum DBP levels were moderately decreased in patients with chronic hepatitis and markedly decreased in patients with early acute hepatitis and cirrhosis. Serum DBP levels in patients with acute hepatitis increased to normal values as the disease improved. Vitamin D 2 supplementation did not affect serum DBP levels. Serum DBP levels correlated positively with serum albumin levels and negatively with serum billirubin levels, both in patients with acute hepatitis and in patients with chronic hepatitis and cirrhosis. Serum DBP levels correlated negatively with serum GOT levels in patients with acute hepatitis. Without vitamin D 2 supplementation, serum 25-OH-D levels in patients with chronic hepatitis did not differ from those in normal subjects, but serum 25-OH-D levels in patients with cirrhosis were decreased. Serum 25-OH-D levels correlated positively with serum DBP and albumin levels and negatively with serum bilirubin levels in patients with chronic hepatitis and cirrhosis. On vitamin D 2 supplementation, serum 25-OH-D levels were increased in both patients with chronic hepatitis and those with cirrhosis and correlated positively with serum DBP and albumin levels. Thus the serum levels of DBP and 25-OH-D and the response of serum 25-OH-D to vitamin D 2 supplementation reflect the functional status of the liver and the severity of the disease.

AHF activity and AHF-like antigen in liver diseases

The procoagulant activity of antihemophilic factor (AHF-Ac) and AHF-like antigen (AHF-Ag) level in liver diseases have not been well studied, although it has already been shown that the level of vitamin K dependent clotting factors such as prothrombin, factors VII, IX and X is a very sensitive parameter of liver function.We studied AHF-Ac and AHF-Ag in 13 patients with acute hepatitis (AH), 15 with chronic active hepatitis (CAH), 20 with compensated liver cirrhosis (CLC) and 16 with decompen-sated liver cirrhosis (DCL). Also were performed coagulation studies in the same patients, such as hepaplastintest, prothrombin time, kaolin-activated PTT and assays of fibrinogen, prothrombin, factors V and IX.Hepaplastintest was normal in the majority of patients with AH, whilst many cirrhotic patients showed abnormal value. Prothrombin time and APTT were also within normal limits in the majority of cases of AH, CAH and CLC. Level of prothrombin and factor IX was proved to be a good parameter of liver function, although that of fibrinogen and factor V was insensitive to liver damage.AHF-Ac and AHF-Ag were both increased in almost all patients with the hepatic disorders mentioned above. The mean values of the AHF-Ac were 257±139% in AH, 124±53% in CAH, 104±30% in CLC and 189±74% in DLC, whilst those of AHF-Ag were 190±89%, 189±50%, 207±56% and 344±191% respectively.AHF-Ac in cirrhotic patients correlated well with serum γ-globulin level (p<0.01) and also was there close correlation between AHF-Ac and serum bilirubin level in patients with AH, but not statistically significant.The AHF-Ac/AHF-Ag ratio in patients with AH was 1.53±0.94, in contrast to 0.70±0.31 in CAH, 0.54±0. 24 in CLC and 0.63±0.27 in DLC, which showed higher level of AHF-Ac than that of AHF-Ag in AH.The cause of increased level of AHF in hepatic disorders still remains unknown, although increased extrahepatic production of AHF due to stress states and delayed inactivation and clearance of this factor in the liver may be playing a main role.