Hyperbilirubinemia In Patients Research Articles

Su1015 Transient Severe Hyperbilirubinemia After Hepatic Arterial Infusion of Oxaliplatin in Patients With Liver Metastases

Purpose We have observed severe, but rapidly reversible, hyperbilirubinemia in patients receiving hepatic arterial infusion (HAI) of oxaliplatin. We performed a retrospective analysis to characterize this unusual phenomenon.

Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia

Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.

Albumin domain II mutant with high bilirubin binding affinity has a great potential as serum bilirubin excretion enhancer for hyperbilirubinemia treatment

Background4Z,15Z-bilirubin-IXα (BR), an endogenous toxic compound that is sparingly soluble in water, binds human serum albumin (HSA) with high affinity in a flexible manner. Our previous findings suggest that both Lys195 and Lys199 in subdomain IIA are important for the high-affinity binding of BR, and especially Lys199 in stand-alone domain II plays a prominent role in the renal elimination of BR. Our hypothesis is that HSA-domain II with high BR binding would be a useful therapeutic agent to treat hyperbilirubinemia in patients with impaired liver function. MethodsUnbound BR concentrations were determined using a modified HRP assay. To evaluate the effect of pan3_3-13 domain II mutant in promoting urinary BR excretion, the serum concentration and urinary excretion amount of BR were determined using bile duct ligation mice. ResultsAfter three or six rounds of panning, pan3_3-13 and pan6_4 were found to have a significantly higher affinity for BR than wild-type domain II. Administration of pan3_3-13 significantly reduced serum BR level and increased its urinary excretion in the disease model mice as compared to wild-type domain II treatment. ConclusionsThese results suggest that pan3_3-13 has great potential as a therapeutic agent that promotes urinary BR excretion in hyperbilirubinemia. General significanceThis is the first study to be applied to other HSA bound toxic compounds that are responsible for the progression of disease, thereby paving the way for the development of non-invasive and cost effective blood purification treatment methods.

Hyperbilirubinemia in Patients with Amoebic Liver Abscess: A Study of 75 Cases

Background: Hyperbilirubinemia is a frequent occurrence in patients with amoebic liver abscess (ALA). Despite this, the cause of jaundice has not been established. It is presumed to be either due to parenchymal destruction or due to cholestatis due to pressure on the intrahepatic bile ducts by the abscess cavity or a combination of both. Aim: The present study is designed to study the incidence and the cause of hyperbilirubinemia in patients with ALA. Settings and design: prospective randomized controlled study Methods and material: Study was performed in a tertiary care centre with high volume of patients of liver abscesses. We evaluated 75 patients of liver abscess from December 2008 to March 2010 and based on presence or absence of hyperbilirubinemia, divided into Group I (serum bilirubin ≥ 1 mg/dl) and Group II (serum bilirubin <1 mg/dl). After detailed evaluation, both the Groups were compared on basis of parameters like clinical symptoms (e.g. fever, pain), alcohol intake, leucocytosis, bilirubin levels, liver enzymes, size of cavity, and response to treatment. Statistical analysis used: Chi square test/ Fischer’s exact test was used for qualitative data, and for quantitative data, t-test/Mann Whitney test was used. Results: In this study, we found hyperbilirubinemia in 23 of total 75 ALA patients with incidence of 30.7%. Overall the serum bilirubin values ranged from 0.4 to 11.7 mg/dl (mean=1.551) whereas in group 1 it ranged from 1.3 to 11.7 mg/dl (mean=3.71). The high values of bilirubin were associated with elevated alkaline phosphatase enzyme in 21 of 23 cases (91.3%) however significant biliary radical dilatation could not be found. The Jaundice responded well to the drainage of abscess cavity. Conclusions: Hyperbilirubinemia occurs frequently in cases of amoebic liver abscess which seems to obstructive in nature and it can be treated by surgical drainage of the abscess cavity. Further large volume and more detailed studies are needed to confirm the findings.

Hyperbilirubinemia during therapy with atazanavir boosted with ritonavir in HIV-infected patients in Lodz region

BackgroundAtazanavir/r (ATV/r) is used in treatment-naïve HIV infected patients as a component of first antiretroviral combination or is a switch option for patients experiencing tolerability problems with other drugs. Material and methodsThis retrospective study included 64 patients who started ATV/r-based combination antiretroviral therapy (cART) from January 2004 to June 2011. The aim of this retrospective study was to evaluate hyperbilirubinemia in patients treated with ATV/r. Long-term maintenance and safety of the ATV/r-based antiretroviral (ARV) regiment were analysed. ResultsIn 38 ARV-experienced patients the main reason for switching to ATV/r was hyperlipidemia. During treatment with ATV/r hyperbilirubinemia was the most commonly reported adverse event. It was observed in 58.7% patients, however only in 2 patients was the reason for discontinuation of ATV/r-based therapy. Hyperbilirubinemia occurred more frequently in patients who started ATV/r treatment with CD4 count ≥200cells/μl and those who were treated longer. Hyperbilirubinemia was not associated with age, gender, HBV/HCV coinfection and aminotransferase level before ATV/r treatment. ConclusionATV/r-based regimen was well tolerated and we demonstrated long-term maintenance of this antiretroviral therapy. Hyperbilirubinemia occurred more frequently in patients with higher CD4 cells count and was a rare cause of discontinuation of this drug.

Unconjugated hyperbilirubinemia in patients with non-alcoholic fatty liver disease: A favorable endogenous response

The clinical significance of increased frequency of unconjugated hyperbilirubinemia in patients with non-alcoholic fatty liver disease (NAFLD) is unknown. Serum bilirubin is an endogenous anti-oxidant, and oxidative stress plays an important role in the pathogenesis of NAFLD. In this study, we have documented 25.4% prevalence of unconjugated hyperbilirubinemia in 204 consecutive NAFLD patients. These patients had a significantly less severe liver disease on histopathology and/or fibroScan which may be attributed to anti-oxidant effect of bilirubin.

Hepatobiliary transporter expression and post‐operative jaundice in patients undergoing partial hepatectomy

Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with high morbidity and mortality. Apart from different known factors responsible for the development of post-operative jaundice, little is known about the role of hepatobiliary transport systems in the pathogenesis of post-operative jaundice in humans after liver resection. Two liver tissue samples were taken from 14 patients undergoing liver resection before and after Pringle manoeuvre. Patients were retrospectively divided into two groups according to post-operative bilirubin serum levels. The two groups were analysed comparing the results of hepatobiliary transporter [Na-taurocholate cotransporter (NTCP); multidrug resistance gene/phospholipid export pump(MDR3); bile salt export pump (BSEP); canalicular bile salt export pump (MRP2)], heat shock protein 70 (HSP70) expression as well as the results of routinely taken post-operative liver chemistry tests. Patients with low post-operative bilirubin had lower levels of NTCP, MDR3 and BSEP mRNA compared to those with high bilirubin after Pringle manoeuvre. HSP70 levels were significantly higher after ischaemia-reperfusion (IR) injury in both groups resulting in 4.5-fold median increase. Baseline median mRNA expression of all four transporters prior to Pringle manoeuvre tended to be lower in the low bilirubin group whereas expression of HSP70 was higher in the low bilirubin group compared to the high bilirubin group. Higher mRNA levels of HSP70 in the low bilirubin group could indicate a possible protective effect of high HSP70 levels against IR injury. Although the exact role of hepatobiliary transport systems in the development of post-operative hyper bilirubinemia is not yet completely understood, this study provides new insights into the molecular aspects of post-operative jaundice after liver surgery.

Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab

Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome. Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables. Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10). Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent.

Compound Heterozygote of a Novel Missense Mutation (p.K402T) and a Double Missense Mutation (p.[G71R;Y486D]) in Type II Crigler‐Najjar Syndrome

362 C rigler-Najjar syndrome type II (CN-II; # Mendelian Inheritance in Man [MIM] 606785) is a moderate type of hereditary unconjugated hyperbilirubinemia caused by mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene UGT1A1 (1). Diagnosis of this syndrome is important in distinguishing it from the severe phenotype of hereditary unconjugated hyperbilirubinemia, known as Crigler-Najjar syndrome type I (CNI; MIM #218800). The serum bilirubin concentration of CN-I is more than 20 mg/dL (343mmol/L) and can reach 30 to 50 mg/dL (513–855mmol/L). Patients with CN-I are in danger of kernicterus and must receive daily phototherapy right from the neonatal period (2). They should undergo liver transplantation to avoid kernicterus. Hyperbilirubinemia in patients with CN-II is less severe than CN-I (1). The serum bilirubin concentration of CN-II is seldom harmful after the neonatal period. The serum bilirubin concentration of patients with CN-I or CN-II is often intermediate between the values specifying the 2 syndromes. Accurate diagnosis of the 2 syndromes is necessary for appropriate treatment. A phenobarbitalloading test is effective in differential diagnosis (3), but the results are not always clear, in which case genetic diagnosis is necessary. The cDNA of UGT1A1 was first cloned in 1991, and a large number of mutations have been found in patients with CN-I, CN-II, and Gilbert syndrome (GS; MIM #143500) (4,5). Mutations of UGT1A1 differ according to ethnic grouping. East Asians display many unique mutations; in particular, a major polymorphic mutation is c.211G>A: p.G71R in exon 1 of UGT1A1 (6). p.G71R reduces glucuronidation ability to less than 32% of wild type and is an important cause of Gilbert syndrome (7). One of the most important causes of CN-II in Asians is a double missense mutation, p.[G71R;Y486D] (8). This double mutation has hardly ever been detected in white and African populations.

Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis

Background Appendiceal perforation in patients with acute appendicitis may cause a variety of potentially life-threatening complications. Escherichia coli endotoxin has been shown to impact physiological bile flow in vivo. This had led to the theory that hyperbilirubinemia in patients with appendicitis may have a predictive potential for the preoperative diagnosis of appendiceal perforation. The aim of this retrospective study was to investigate the diagnostic value of hyperbilirubinemia as a preoperative laboratory marker for appendiceal perforation in patients with acute appendicitis. Methods We identified 538 patients (306 female; 232 male, mean age, 35.6 y) with histologically proved acute appendicitis who underwent laparoscopic or conventional appendectomy between January 2004 and December 2007 in a surgical department of an academic teaching hospital. A retrospective multiple chart review of the medical records including laboratory values and histologic results was conducted. Results The mean bilirubin level of all patients was .9 mg/dL (±.6 SD mg/dL; range, .1–4.3 mg/dL; median, .7 mg/dL). Patients with appendiceal perforation, however, had a mean bilirubin level of 1.5 mg/dL (±.9 SD mg/dL; range, .4–4.3 mg/dL; median, 1.4 mg/dL), which was significantly higher than those with a nonperforated appendicitis ( P < .05). The specificity of hyperbilirubinemia for appendiceal perforation was .86 compared with .55 for white blood count and .35 for C-reactive protein. Sensitivity was .7 compared with .81 for white blood count and .96 for C-reactive protein. Conclusions Patients with hyperbilirubinemia and clinical symptoms of appendicitis should be identified as having a higher probability of appendiceal perforation than those with normal bilirubin levels.

Primary biliary cirrhosis and coronary atherosclerosis: Protective antioxidant effect of bilirubin

Increased concentration of lipid peroxidation products in patients with primary biliary cirrhosis is related to elevation of serum lipid content, but not to activation of lipid peroxidation. Hyperbilirubinemia in patients with primary biliary cirrhosis is accompanied by a decrease in the concentration of lipid peroxidation products and increase in antioxidant activity of blood serum. Antioxidants play a major role in the prevention of atherosclerosis. We hypothesized that the absence of increased risk of atherosclerosis in patients with primary biliary cirrhosis is due to inhibition of lipid peroxidation in blood serum by antioxidant compound bilirubin.

Clinical factors causing hyperbilirubinemia in patients with Kawasaki disease

Purpose: Hyperbilirubinemia, jaundice and gallbladder hydrops are unusual manifestations of Kawasaki disease (KD). In this case, abdominal pain, anorexia and abdominal distension may follow eventfully. We reviewed the clinical and laboratory data to investigate the causative factors of hyperbilirubinemia in patients with KD. Methods: Two-hundred eighty two children diagnosed and hospitalized with KD were identified by searching patients' charts. Cases were included in the study if diagnosed between January 1997 and December 2004. We reviewed clinical data, age, sex, duration from the onset of fever to admission and duration from start of treatment to defervescence. Clinical and laboratory data were compared between normal (A) and hyperbilirubinemia (B) groups. Results: Thirteen patients (4.6 percent) showed hyperbilirubinemia. In the hyperbilirubinemia group, age and initial ALT value were higher than group A (P=0.003, 0.018 respectively). Duration from the onset of fever to admission and age were relative risk factors in hyperbilirubinemia (P=0.007, 0.003 respectively) in patients with KD. Conclusion: Shorter duration from the onset of fever to admission and older age group were relative risk factors of hyperbilirubinemia in patients with KD. (Korean J Pediatr 2007;50:52-55)

Hyperbilirubinemia after extracorporeal circulation surgery: A recent and prospective study

To clarify the incidence and nature of postoperative hyperbilirubinemia in patients after modern extracorporeal circulation, to analyze possible perioperative risk factors, and to elucidate the clinical significance of postoperative hyperbilirubinemia associated mortality and morbidity. Between March 2005 and May 2006, three hundred and eighty six consecutive patients undergoing extracorporeal circulation surgery due to a variety of cardiac lesions were investigated prospectively. The incidence of postoperative hyperbilirubinemia was defined as a serum total bilirubin concentration of more than 51 micromol/L. Several perioperative parameters were compared by logistic regression between hyperbilirubinemia and non-hyperbilirubinemia patients to determine possible risk factors contributing to postoperative hyperbilirubinemia and mortality. Overall incidence of postoperative hyperbilirubinemia was 25.3% (98/386). In patients with postoperative hyperbilirubinemia, 56.2% reached peak total bilirubin concentration on the first postoperative day, 33.5% on the second day, and 10.3% on the seventh day. Eighty percent of the increase of total bilirubin resulted from an increase of both conjugated and unconjugated bilirubin. Development of postoperative hyperbilirubinemia was associated with a higher mortality (P<0.01), longer duration of mechanical ventilation (P<0.05) and longer ICU stay time (P<0.05). Preoperative total bilirubin concentration, preoperative right atrium pressure, numbers of valves replaced and of blood transfusion requirement were identified as important predictors for postoperative hyperbilirubinemia. Early postoperative hyperbilirubinemia after modern extracorporeal circulation is mainly caused by an increase in both conjugated and unconjugated bilirubin, and is associated with a high mortality. Important contributing factors are the preoperative total bilirubin concentration, preoperative severity of right atrial pressure, numbers of valve replacement procedures, and the amount of blood transfusion requirement during and shortly after surgery. We suggest that postoperative hyperbilirubinemia is a multifactorial process, which is caused by both the impaired liver function of bilirubin transport and the increased production of bilirubin from haemolysis.

MTHFR-A1298C Polymorphism Is Associated with Veno-Occlusive Disease (VOD) and Liver Toxicity after Busulfan/Cyclophosphamide Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Purpose: The aim of our study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) and glutathione S-transferases (GST) on liver toxicities seen in patients receiving busulfan and cyclophoshamide conditioning followed by allogeneic HSCT.Background: Polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) have been shown to potentially influence toxicity (e.g. mucositis) in HSCT. Additionally, many chemotherapeutics that have been linked to veno-occlusive disease (VOD) and liver toxicity (e.g. Busulfan) are metabolised by glutathione S-transferases (GST). Little is known about the impact of gene polymorphisms of MTHFR and various GSTs on VOD and liver toxicity in allogeneic HSCT.Methods: 84 adult patients were enrolled in this retrospective study. The majority of the patients had chronic myelogenous leukemia (CML) in 1st chronic phase (94%). 2 patients suffered from acute myelogenous leukemia (AML-M4), 2 from myelodysplastic syndrome (MDS) and 1 patients from Farber's disease. DNA was isolated from leucocytes of stem cell recipients collected prior to HSCT. Common gene polymorphisms of glutathione S-transferases (GSTP1-Ile105Val, GSTA1*A/B, GSTM1, GSTT1) and methylene-tetrahydofolate-reductase (MTHFR-C677T, MTHFR-A1298C) were detected by PCR-RFLP. All patients were treated with busulfan/cyclophosphamide as conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. 67 patients (80%) received additionally anti-thymocyte globulin (ATG). Assessment of liver toxicities was based on appearance of VOD according to the Baltimore criteria, maximum bilirubin levels within 20 days after HSCT and duration of hyperbilirubinaemia > 2 mg/dl.Results: Analyses revealed statistical significant association between the MTHFR-A1298C polymorphism and liver toxicities. There was significant higher incidence of VOD in patients that are homozygous for the C allele (p = 0,04). Independently of VOD, patients carrying the MTHFR-1298CC genotype demonstrated higher median maximum levels of bilirubin with 6.8 mg/dl than MTHFR-1298AC and MTHFR-1298AA patients (3,0 mg/dl and 3,4 mg/dl) (p = 0,004). Furthermore, elevation of bilirubin levels > 2 mg/dl lasted longer in MTHFR-1298CC patients with a median of 14 days compared to 3 and 6 days in patients harbouring the MTHFR-1298AC and MTHFR-1298AA genotype (p = 0,004). Interestingly, the common MTHFR-C677T polymorphism did not reach statistical significance in accordance to liver toxicity in our study population. No significant associations between GSTP1-Ile105Val, GSTA1*A/B, GSTM1 and GSTT1 polymorphisms and liver toxicity were found in this study.Conclusion: Our data suggest that the MTHFR-A1298C polymorphism is associated with VOD and hyperbilirubinaemia in patients treated with busulfan/cyclophosphamide as conditioning regimen followed by allogeneic HSCT. To the best of our knowledge this the first report linking the MTHFR-A1298C polymorphism to liver toxicity in patients receiving allogeneic HSCT.

Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer

Hyperbilirubinemia is a critical complication following hepatectomy for biliary cancer. Hepatic multidrug resistance protein 2 (MRP2), a bilirubin transporter, is shown to be down-regulated by acute biliary obstruction in rats. However, little is known about the effect of chronic obstruction by malignancy on the MRP2 expression in patients or the association of MRP2 expression with posthepatectomy hyperbilirubinemia. The MRP2 expression before hepatectomy was determined by immunostaining and Western blotting in patients with biliary cancer. To directly determine the effect of chronic bile duct obstruction on the MRP2 expression, the expression levels were compared between the cholestatic and noncholestatic lobes in each of seven patients. In another 39 patients, the correlation of the MRP2 expression of the anticipated remnant liver with the posthepatectomy severe hyperbilirubinemia, defined as a serum total bilirubin concentration>or=200 micromol/l, was evaluated. The MRP2 staining in the cholestatic lobes was weak and not restricted to the canalicular membrane, unlike the noncholestatic lobes. The expression levels in the cholestatic lobes were 45% of those in the noncholestatic lobes. Postoperative maximum bilirubin levels were significantly correlated with MRP2 expression of the anticipated remnant liver. The MRP2 expression had been already impaired before hepatectomy in all patients who eventually developed severe hyperbilirubinemia. Decreased MRP2 expression, caused by biliary obstruction due to cancer, is a possible risk factor for posthepatectomy severe hyperbilirubinemia.

RACIAL VARIABILITY IN HAPLOTYPE FREQUENCIES OF UGT1A1 AND GLUCURONIDATION ACTIVITY OF A NOVEL SINGLE NUCLEOTIDE POLYMORPHISM 686C&gt; T (P229L) FOUND IN AN AFRICAN-AMERICAN

Ethnic differences in genetic polymorphisms in UDP-glucuronosyltransferase 1A1 (UGT1A1) were investigated among African-Americans, Caucasians, and Japanese using samples obtained from 150 individuals for each population. Genotyping of -3279T>G in the phenobarbital-responsive enhancer module, TA repeats in the TATA box, 211G>A (G71R) and 686C>A (P229Q) in exon 1, and three single nucleotide polymorphisms (SNPs) (1813C> T, 1941C>G, and 2042C>G) in the 3'-untranslated region in exon 5 was performed. Eight haplotypes of block 1 (exon 1 and its 5'-flanking region) harboring the first four variations were assigned to each individual. The dominant haplotype for African-Americans was *28b (-3279G;TA(7); 211G;686C) (0.446), whereas that for the Japanese was *1a (-3279T; TA(6);211G;686C) (0.610). Frequencies of the two haplotypes *1a and *28b were comparable in Caucasians. Haplotype *6a (-3279T;TA(6); 211A;686C) was characteristic of the Japanese, whereas haplotypes *36b and *37b (-3279T;TA(5) and TA(8);211G;686C) were found mostly in African-Americans. Although the three SNPs in block 2 (exons 2-5) were in complete linkage in the Japanese, they were not completely linked in African-Americans or Caucasians. These differences in haplotype distribution patterns among the three populations suggest the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C>T (P229L), was found in an African-American. The intrinsic clearance of 7-ethyl-10-hydroxycamptothecin (SN-38) by P229L UGT1A1 expressed in COS-1 cells was about 3% of the wild type. The results of Western blotting and real-time reverse transcription-polymerase chain reaction suggest that the low glucuronidation activity of the variant was partly due to its low stability. The variation 686C>T may cause high toxicity during 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) therapy or hyperbilirubinemia in patients.

Application of bilirubin adsorption with HB-H-6 resin plasma perfusion in preoperative for pancreatic cancer with severe obstructive jaundice

目的 探讨HB-H-6树脂血浆灌流吸附胆红素用于恶性梗阻性黄疸病人先期减黄的有效性和安全性.方法对2例胰头癌伴重度黄疸病人用HB-H-6树脂进行血浆灌流减黄,1 d后行胰十二指肠切除术.结果病例1胆红素由533 μmol/L降至347 μmol/L,病例2由454 μmol/L降至367 μmol/L,红细胞、白细胞及血小板下降不明显,血钾、钙、镁有明显降低,但用复方电解质液提前预充冲洗灌流装置可有效减少降低.结论 HB-H-6树脂血浆灌流可以清除胆红素,有望成为恶性梗阻性黄疸先期减黄的新方法。

A novel approach to the management of late-onset liver failure in biliary atresia

Purpose Late-onset hyperbilirubinemia in patients who have undergone a successful portoenterostomy (PE) for biliary atresia (BA) is usually considered evidence of ongoing severe liver failure. The authors recently have treated 2 patients who had acute hyperbilirubinemia years and months after a successful PE and had dilated intrahepatic cysts. A combined operative and percutaneous approach reestablished drainage and a reduction in their bilirubin levels. Methods Data from 2 cases of BA and late-onset hyperbilirubinemia from obstruction were reviewed and analyzed. Results Two patients (15-year-old boy and a 2.5-year-old girl) presented with increasing serum bilirubin after a PE for BA in infancy. Both had extensive preoperative workup, which showed intrahepatic biliary dilatation in one and a large bile lake in the other. They underwent attempted percutaneous transhepatic cholangiography and stenting, followed by an intraoperative transhepatic approach in which the dilated ducts were connected to the PE. A rapid and sustained reduction in the serum bilirubin level was noted in these patients. Conclusions When patients with BA after a successful PE present with sudden onset of hyperbilirubinemia, imaging for biliary obstruction should be carried out. If biliary dilatation is found, then a combined radiologic and operative approach may help improve the bile flow and delay the need for liver transplant.

Orlistat treatment increases fecal bilirubin excretion and decreases plasma bilirubin concentrations in hyperbilirubinemic Gunn rats

ObjectiveTo determine whether serum levels of unconjugated bilirubin (UCB) can be decreased by enhancing fecal fat excretion. Study designGunn rats were fed a high-fat diet (control) or the same diet mixed with the lipase inhibitor orlistat. At regular intervals, plasma UCB concentrations were determined and 72-hour fat balances were performed. ResultsOrlistat treatment decreased plasma UCB concentrations (at 3 weeks; 100 mg/kg, −33%±8%, P<.05; 200 mg/kg, −46%±10%, P<.01). Within days of treatment, orlistat treatment increased fecal excretion of UCB (at day 3; +220%, P<.05). During 24 weeks of orlistat treatment (200 mg/kg diet), the plasma bilirubin concentrations were continuously ≈35% lower than in control rats. Plasma UCB concentrations were inversely correlated with the amount of fecal fat excretion (n=12, r=−0.87, P<.001). ConclusionsIn Gunn rats, orlistat treatment increases the fecal excretion of fat and enhances the disposal of UCB. This approach could lead to novel strategies for prevention and treatment of unconjugated hyperbilirubinemia in patients.

Unusual hyperbilirubinemia associated with bacterial pneumonia and acute myeloid leukemia

A 77-year-old man with pneumonia associated with acute myeloid leukemia was introduced to the hepatology unit at our hospital for hyperbilirubinemia. He had been suffering from a high fever because of pneumonia. He was icteric and his serum concentrations of total and direct bilirubin were 13.1 and 7.9 mg/dl, respectively. However, the other standard biochemical examinations for hepatic function, such as serum concentrations of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase were normal except for lactate dehydrogenase. Lactate dehydrogenase isoenzyme analysis revealed that the high concentration was derived from leukemia cells. Ultrasonography of the abdomen revealed no abnormality in the liver or biliary tract. Administration of antibiotics for pneumonia decreased the serum bilirubin concentration, however, he died because of respiratory failure caused by the progression of pneumonia at 33 days after the admission. It was suggested that a disturbance in the bilirubin metabolism without hepatocyte necrosis or mechanical cholestasis might be involved in the pathogenesis of hyperbilirubinemia in patients with infectious diseases.