Normal Total Bilirubin Levels Research Articles

Diagnosing delta-beta thalassaemia in a resource poor setting

An eight-year-old girl presented with mild scleral icterus, pallor and hepatosplenomegaly. Her preliminary investigations revealed low haemo-globin (Hb) (94g/L), high reticulocyte count (3.5%), normal total bilirubin level and normal liver function tests. Her blood picture revealed evidence of chronic haemolysis. High perfor-mance liquid chromatography (HPLC) revealed markedly raised Hb-F (98.3%). Capillary electro-phoresis revealed Hb-F of 99.2%. Acid elution test (Kleihauer test) showed pan-cellular distribution of Hb-F. Her parents were first cousins. Her mother’s profile showed thalassaemic red cell indices with normal Hb-A2 and high Hb-F (13.3%). The father was not available for screening. The paternal grandmother’s HPLC showed normal Hb-A2 and high Hb-F (6.8%). Based on clinical and laboratory findings and family screening results, the child was diagnosed as homozygous delta-beta (αβ)-thalassaemia presenting as thalassaemia intermedia.

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

BackgroundEffective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator–activated receptor delta agonist, has potential benefits.MethodsIn this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).ResultsOf the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, −3.2 vs. −1.7; least-squares mean difference, −1.5; 95% CI, −2.5 to −0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.ConclusionsIn this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.)

Clinical Characterization of Hepatic Light Chain Amyloidosis in the Chinese Population: A Single-Center Retrospective Analysis

CONCLUSION Hepatic light chain amyloidosis is caused by malignant plasma cells that abnormally secrete immunoglobulin light chains, which undergo a conformational change to a β-pleated sheet configuration and are deposited in the liver. The amyloid fibrils are deposited mainly in the hepatic sinusoids, the space of Disse and the walls of blood vessels. Previous autopsy studies have shown that the proportion of systemic light chain amyloidosis with liver involvement is extremely high; however, there are fewer systematic analyses of the clinical features in the Chinese population. Therefore, this study retrospectively analysed the clinical data of patients with hepatic lightchain amyloidosis in our center to further explore the clinical characteristics of this disease. A total of 40 patients with hepatic light chain amyloidosis were included in the analysis from 2007 to 2022. Inclusion criteria were positive liver tissue biopsy or positive biopsy of other organs with alkaline phosphatase (AKP) greater than 1.5 times the upper limit of normal or total liver span &amp;gt;15 cm in the absence of heart failure. The median age of these patients was 58±10 years and 80% were male. Of these 40 patients, 66% had light-chain amyloidosis secondary to myeloma and the remainder had primary amyloidosis. The proportion of patients with symptoms related to liver injury as the initial clinical presentation was 33%. Symptoms included malaise, abdominal distention, or jaundice. 40% of patients with symptoms related to abnormal heart function, such as chest tightness, severe shortness of breath, and dizziness. 25% of the patients were first seen for symptoms related to impaired renal function, such as proteinuria with lower limb edema or hypourocrinia. κ-type was found in 28% of the patients and λ-type in 73%. All patients had other sites of involvement, 95% with cardiac involvement (72.9%, Mayo 2004 stage III) and 48% with renal involvement. AKP was elevated in 100% of patients, r-GT in 95%, liver enzymes in 33%, total bilirubin in 44%, and the maximum anteroposterior diameter of the right lobe of the liver was 16.6±1.7 cm (upper limit of normal was 10 cm). In this cohort of patients, 80% received a 2- to 3-drug combination regimen based on proteasome inhibitors and 5% received a 2-drug combination regimen based on melphalan, with a median survival time of 6.5±31.3 months, and patients with a normal total bilirubin level had an overall survival time 2.4 times longer than those with an elevated level (p&amp;lt; 0.05,Figure 1). Contrary to previous reports of hepatic light chain amyloidosis, λ light chain amyloidosis was predominant in our center; elevated total bilirubin was an independent risk factor for survival.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis

BackgroundPrimary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.MethodsIn this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).ResultsA total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (−1.93 vs. −1.15; difference, −0.78; 95% CI, −1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.ConclusionsTreatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.)

Transjugular Intrahepatic Portosystemic Shunt Benefits for Hepatic Sinusoidal Obstruction Syndrome Associated with Consumption of Gynura Segetum: a Propensity Score-Matched Analysis.

Pyrrolidine alkaloids-related hepatic sinusoidal obstruction syndrome (PA-HSOS) is associated with a high mortality rate without standardized therapy. The efficacy of transjugular intrahepatic portosystemic shunts (TIPS) remains controversial. The study aimed to explore the risk factors influencing the clinical response in patients with PA-HSOS related to Gynura segetum (GS) to assess the disease prognosis at an early stage and to evaluate the efficacy of TIPS in these patients. This study retrospectively enrolled patients diagnosed with PA-HSOS between January 2014 and June 2021 with a clear history of exposure to GS. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors influencing the clinical response in patients with PA-HSOS. Propensity score matched (PSM) was performed to compensate for differences in baseline characteristics between patients with and without TIPS. The primary outcome was the clinical response defined as the disappearance of ascites with normal total bilirubin levels and/or a reduction of elevated transaminase levels < 50% within 2weeks. A total of 67 patients were identified in our cohort with a clinical response rate of 58.2%. Of these, thirteen patients were assigned to the TIPS group and 54 to the conservative treatment group. Logistic regression analysis revealed that TIPS treatment (P = 0.047), serum globulin levels (P = 0.043), and prothrombin time (P = 0.001) were independent factors influencing clinical response. After PSM, there was a higher long-term survival rate of patients (92.3% vs. 51.3%, P = 0.021) and a shorter hospital stay (P = 0.043), but a high trend in hospital costs (P = 0.070) in the TIPS group. The 6-month survival probability in patients undergoing TIPS therapy was more than ninefold higher than in patients without receiving that treatment [hazard ratio (95% CI) = 9.304 (4.250, 13.262), P < 0.05]. TIPS therapy may be an effective treatment option for patients with GS-related PA-HSOS.

S3188 The Tale of an Ancient Herb: A Stress Reliever or a Liver Stressor

Introduction: Ashwagandha is found in several herbal products today. However, there is a paucity of literature regarding its safety. Our case serves to remind physicians about the potential liver toxicity of Ashwagandha and to illustrate how early recognition of drug-induced liver injury (DILI) and discontinuation of the offending substance can be lifesaving. Case Description/Methods: A 58-year-old man with a remote history of hepatitis B and C presented with nausea, vomiting, and right upper quadrant abdominal pain of one day duration. He reported using an herbal supplement called “Primal Male,” which contained Ashwagandha as a main ingredient, over the past two weeks. He was normotensive, tachycardic up to 120 beats per minute (bpm), and febrile. The initial laboratory studies were notable for elevated AST level of 954 U/L, ALT level of 860 U/L, and a normal alkaline phosphatase level of 101 U/L. He had a normal total bilirubin level and an international normalized ratio of 1.3. His complete blood count and renal function were unremarkable. His creatinine kinase (CK) level was also within the normal range. His drug test, alcohol level, and acetaminophen level were unremarkable. The viral panel did not suggest active viral infections. His autoimmune panel was negative. An abdominal CT scan did not reveal any acute abnormality. In the following days, his symptoms worsened, and he became more encephalopathic. His AST, ALT, total bilirubin, and INR levels continued to rise. He developed hypotension and received intravenous fluids and midodrine. He also completed a course of N-acetylcysteine treatment. On the fifth day of admission, he underwent a transjugular liver biopsy. Liver histology showed active lymphocytic hepatitis with moderate inflammation (primarily lymphocytes, abundant neutrophils, and occasionally eosinophils) around the portal tract. On the sixth day of hospitalization, he reported decreasing pain and was more hemodynamically stable. His liver enzymes also showed improvement. The cause of acute liver injury was suspected to be drug-induced liver injury from Ashwagandha use. He was counseled to avoid the use of the herbal supplement and other hepatotoxic products. One month later, his liver enzymes were in normal range. Discussion: DILI is a less common form of liver injury but is a leading cause of acute liver failure in the United States. Ashwagandha has been reported in a few cases of DILI. It is important to have an early suspicion of the offending agent and avoid further substance exposure.

Total Kadar Bilirubin Pada Pasien Tuberculosis (TB) Paru Setelah 5 Bulan Mengkonsumsi Obat Anti Tuberkulosis (OAT) di Rumah Sakit Tentara Kota Binjai

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis which attacks the lungs and bronchi. Anti-tuberculosis drugs consist of isoniazid, ethambutol, pyrazinamide, rifampicin and streptomycin which must be consumed for 6 months. OAT has side effects, especially disturbing liver function, one of which is bilirubin. Bilirubin is a yellow pigment derived from the heme reshuffle of hemoglobin in the process of erythrocyte breakdown by reticuloendothelial cells. This research is desktiptif. This study aims to describe the total bilirubin levels in pulmonary tuberculosis patients after 5 months of consuming anti-tuberculosis drugs in TK.IV.01.07.02 Binjai Army Hospital in May-June. This study was taken from 53 samples of total bilirubin levels in tuberculosis patients who had consumed OAT for 5 months. The results of the 53 samples found normal total bilirubin levels of (77.40%) and increased by (22.60%). Frequency distribution in male sex (56.6%) women (43.4%). Total bilirubin levels increased more in male patients (13.21%). The increase in total bilirubin occurred at&gt; 56 years of age. Total bilirubin levels increased more in female patients (9.43%).

Association between serum bilirubin levels and progression of albuminuria in Taiwanese with type 2 diabetes mellitus

BackgroundTo investigate the association between serum bilirubin (BIL) levels and the progression of albuminuria in type 2 diabetic Taiwanese. MethodsLongitudinal data from January 2001 to June 2015 were retrospectively reviewed from Chang Gung Memorial Hospital in Taiwan. A total of 2877 type 2 diabetic patients with normal total BIL levels were divided into 4 groups according to BIL, with the highest BIL in the fourth group. The urinary albumin/creatinine ratio (UACR) trend and progression, as well as other laboratory measurements, were evaluated among the four groups. The cumulative incidence and Cox proportional hazard model analysis were performed to examine the relationship between BIL and the risk of albuminuria progression (AUPr). ResultsThe mean duration of follow-up was 1.5 years (±1.37 years). The mean patient age, glycosylated hemoglobin level, and duration of diabetes were 62.52 years, 7.9%, and 3.94 years, respectively. A significant correlation was observed between BIL and both the UACR at baseline (P < 0.001) and the cumulative incidence of AUPr (log–rank test, P = 0.031). Hazard ratio (HR) analysis revealed that patients in the fourth BIL quartile had the lowest HR risk of AUPr among the four groups (adjusted HR = 0.70; 95% Confidence Interval = 0.56–0.89, P < 0.05). ConclusionsHigher serum BIL levels are associated with a lower risk of AUPr in type 2 diabetes patients in Taiwan.

Role of Hyperbilirubinemia as a Diagnostic Tool to Predict Gangrenous/Perforated Appendicitis: An Observational Study

Background: Elevation in serum bilirubin was reported recently, but the importance of the raised total bilirubin has not been stressed in acute appendicitis and appendicular perforation. The aim of the study was to establish the role of hyperbilirubinemia as a new diagnostic tool to predict gangrenous/perforated appendicitis. Subjects and Methods: This was a prospective observational study, which was conducted at the Gujarat Adani Institute of Medical Science, Bhuj, Kutch, Gujarat, India. A total of 100 patients clinically diagnosed as appendicitis from August 2018 to August 2019 at Gujarat Adani Institute of Medical Science, Bhuj, Kutch, Gujarat, India. Patients were clinically evaluated by detailed history, routine examination on initial contact with patients and the routine investigations as per surgery and anesthesia requirements with inclusion of serum total bilirubin. Based on histopathological examination patients will be categorized as positive (acute appendicitis with perforation and/or gangrene) and negative (acute appendicitis without perforation or gangrene). Results: Out of 100 patients, 20 were managed conservatively (mass formation) and was called for interval appendectomy after 6 weeks. In acute catarrhal appendicitis group 47 patients showed normal total bilirubin levels, whereas 8 patients showed increase in levels of total bilirubin. In gangrenous appendicitis group all 10 patients showed elevated serum total bilirubin levels In perforated appendicitis group consisted of 15, 11 patients showed elevated serum bilirubin levels and 4 patients showed normal total bilirubin levels. Conclusion: Serum bilirubin is easily available test and cheap and can be estimated from the sample of blood drawn for routine blood investigations.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) for Very Severe Veno-Occlusive Disease after Unmanipulated Haploidentical HSCT with Post-Transplant Cyclophosphamide

Background: The use of unmanipulated Haploidentical HSCT (Haplo-HSCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Veno-occlusive disease (VOD) is a threatening complication after both autologous and allogeneic HSCT, with high mortality rates despite early medical treatment, including the use of defibrotide. The objective of this study was to describe characteristics and outcomes of patients with refractory very severe VOD after Haplo-HSCT with PT-Cy, treated with TIPS as salvage procedure. Methods: We retrospectively analysed 176 Haplo-HSCT with Cy-post consecutively performed between 2011 and May 2019 in a single centre. VOD was defined according to modified Seattle, Baltimore or revised EBMT criteria. Severity was retrospectively graded according to revised EBMT severity criteria into four categories: mild, moderate, severe and very severe. Complete response (CR) was defined as a normal total bilirubin level (&lt;2 mg/dL) or, in patients with normal bilirubin or alternative causes of hyperbilirubinemia, as normalized renal function, reduction of elevated transaminase level &lt;50%, tense ascites resolution, and no need for oxygen supplement in the absence of alternative hypoxemia causes. Results: Sixteen patients (9.1%) met the modified Seattle, Baltimore or revised EBMT diagnostic criteria for VOD. Ultrasound with Doppler ultrasonography was performed in all patients, and at least indirect signs of VOD were found in all cases. Based on revised EBMT severity criteria, there were 2 mild (12.5%), 2 moderate (12.5%), 2 severe (12.5%) and 10 very severe (62.5%) grade VOD. Twelve patients (75%) were treated with defibrotide, including all patients with very severe VOD, except one with CNS hemorrhage (Patient 1). Six patients with very severe VOD, were treated with TIPS due to rapid clinical or analytical deterioration or refractory hepatorenal syndrome, despite medical treatment including defibrotide (Table 1). All were male patients, with a median age of 31 years (range 22-36), all transplanted with myeloablative conditioning regimen. TIPS insertion was performed on a median time since VOD diagnosis of 5 days (range 1-28) without technical complications in any case. Median total bilirubin, ALT, creatinine and INR the day of procedure were 3 mg/dL (range 2.2-11.2), 1120 UI/L (range 10-2595), 2.45 mg/dL (range 2.06-3.58) and 1.96 (range 1.1-4) respectively. Median hepatic venous pressure gradient (HVPG) prior to and after TIPS was 22.5 (range 14-29) and 6.5 (range 2-10) mmHg respectively, with a median drop of 16.5 mmHg (range 9-19). Following TIPS, all patients showed clinical improvement with hepatomegaly, ascites and renal failure resolution, and all showed analytical improvement with bilirubin, creatinine and ALT values reduction, except for patient 2, whose TIPS indication was refractory hepatorenal syndrome with normal ALT levels (Figure 1). The 5 patients who had iniciated defibrotide before TIPS, completed 21 days of treatment. All patients met criteria for CR in a median of 8 days after TIPS insertion (range 2-82). The 100-day overall survival (OS) was 100%. Five patients were alive with normal liver and renal function at last follow up, and one patient died due to infection 7 months after Haplo-HSCT, with VOD in complete resolution. Conclusions: Incidence of VOD after Haplo-HSCT with PT-Cy is comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe VOD according to revised EBMT severity criteria. For patients with rapid progressive VOD, early TIPS insertion allowed completion of defibrotide therapy. The use of TIPS together with defibrotide resulted in complete response and no associated complications with a 0% of VOD associated mortality in spite of high severity. ALT values may be the best predictor of CR after TIPS procedure. In our experience, timely and individualized use of TIPS significantly improves outcome of very severe VOD after Haplo-HSCT. Therefore, TIPS should be promptly considered in rapid progressive cases. Disclosures No relevant conflicts of interest to declare.

Clinical presentation and prognostic analysis of Chinese patients with systemic light chain amyloidosis with liver involvement

To summarize the clinical characteristics and prognostic factors of Chinese patients with systemic light chain amyloidosis with liver involvement. We retrospectively analyzed the clinical features and natural history data of 102 patients diagnosed with systemic light chain amyloidosis with liver involvement at Peking Union Medical College Hospital between March 2007 and May 2018. More than 95% of patients showed the involvement of other organs. Kidney and heart were the most frequently involved organs, accounting for 71.6% and 68.6% of cases, respectively. Hepatomegaly was the most frequently observed physical sign, accounting for 67.6% of cases. Elevated levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were frequently observed, accounting for 85.3% and 88.2% of cases, respectively. A significantly better prognosis was observed in patients with normal total bilirubin levels, as compared with those with elevated levels of total bilirubin. Patients in the normal total bilirubin group showed a significantly better progression-free survival (PFS) (38 months) as compared the elevated total bilirubin group (4 months; P < 0.001). The median overall survival (OS) in the normal total bilirubin group was not reached compared with the elevated total bilirubin group (4 months, P < 0.001). Notably, the early death rate was significantly lower in the normal total bilirubin group as compared to the elevated total bilirubin group (14.5% vs 48.5%, P < 0.001). In conclusion, the elevation of total bilirubin indicated an early death and worse PFS and OS. Early diagnosis is therefore essential, and requires appropriate treatment and intensive care.

Aggressive Locoregional Treatment Improves the Outcome of Liver Metastases from Grade 3 Gastroenteropancreatic Neuroendocrine Tumors.

Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare, and there is no report specifically dealing with patients of liver metastases from G3 GEP NETs.From January 2004 to January 2014, 36 conservative patients with G3 GEP NET liver metastases were retrospectively identified from 3 hepatobiliary centers in China. The clinical features and treatment outcomes were analyzed.Aggressive locoregional treatments (LT, including cytoreductive surgery, radiofrequency ablation, and liver-directed intra-arterial intervention) and systemic therapy (ST) were introduced separately or combined, with 26 (72%) patients receiving resection of primary tumor and/or hepatic metastases, 12 patients receiving non-surgical locoregional interventions (NSLRIs), and 22 patients receiving certain kind of STs. Median overall survival (OS) was 20.0 months (95% confidence interval [CI]: 8.9–31.1 months) and survival rates were 62.6%, 30.1%, and 19.8%, at 1, 3, and 5 years, respectively. The median OS was 9.0 months (95%CI: 3.3–14.7 months) for patients receiving only STs (n = 6), 19 months (95%CI: 1.3–36.8 months) for patients receiving LT followed by STs (n = 16), and 101 months (95%CI: 0.0–210.2 months) for patients receiving only LT (n = 12). Moreover, compared with those receiving only ST or best supportive care, patients given certain types of LTs had higher rates of symptom alleviation (3/8 versus 20/23). On univariate analysis, positive prognostic factors of survival were pancreatic primary tumor (P = 0.013), normal total bilirubin level (P = 0.035), receiving surgery (P = 0.034), receiving NSLRI (P = 0.014), and sum of diameters of remnant tumor < 5 cm (P = 0.008). On multivariate analyses, pancreatic primary tumor (P = 0.015), normal total bilirubin level (P = 0.002), and sum of diameters of remnant tumor < 5 cm (P = 0.001) remained to be independent prognostic factors.For patients with G3 GEP NET liver metastases, aggressive LTs may improve clinical outcomes. Larger studies with prospective design are warranted to consolidate these results, and to discover the most appropriate seletion criteria for patients to undergo different kinds of aggressive LTs and to find the most effective combinations, with or without ST.

Cholangiocarcinoma: spectrum of appearances on Gd-EOB-DTPA-enhanced MR imaging and the effect of biliary function on signal intensity.

BackgroundTo describe the Gd-EOB-DTPA-enhanced MRI appearances of cholangiocarcinoma, and evaluate the relative signal intensities (RSIs) changes of major abdominal organs, and investigate the effect of total bilirubin (TB) levels on the RSI.Methods25 patients with pathologically-proven cholangiocarcinoma underwent Gd-EOB-DTPA-enhanced MRI. The visualization of the biliary system during biliary phase (BP) was observed. RSIs of the abdominal aorta (A), portal vein (V), liver (L), and spleen (S) were measured.ResultsOn hepatocellular phase (HP), exophytic tumors (n =10) and infiltrative tumors (n =10) were hypointense, polypoid tumors (n = 2) were hypointense, and combined type tumors (n = 3) had mixed appearances. While patients with normal TB levels (≤22 μmol/L, n = 12) had clear visualization of the biliary tree during BP, those with elevated TB levels (>22 μmol/L, n = 13) had obscured or no visualization. In addition, patients with normal TB levels had higher RSIA, RSIV and RSIS than those with elevated TB levels on all dynamic phases (P <0.001), and lower RSIA, RSIV and RSIS on HP and BP (P <0.001). Patients with normal TB levels had higher RSIL than those with elevated TB levels on all phases (P <0.001).ConclusionsRSIs of major abdominal organs reflected underlying biliary function. Cholangiocarcinoma patients with elevated TB levels had delayed excretion of Gd-EOB-DTPA compared with patients with normal TB levels.

Low Incidence of Hyperbilirubinemia Events With ABT-450/r-Ombitasvir and Dasabuvir With or Without Ribavirin in HCV Genotype-1 Infected Patients

Introduction: Ribavirin (RBV) is known to cause hemolytic anemia that can lead to hyperbilirubinemia. In addition, the NS3/NS4A protease inhibitor ABT-450 can increase unconjugated bilirubin levels due to transporter inhibition. We report the rate of hyperbilirubinemia in HCV genotype 1-infected patients treated with ABT-450/r-ombitasvir (formerly ABT-267) and dasabuvir (formerly ABT-333) (3D regimen) with or without RBV. Methods: Data from 910 patients randomized in 3 phase 3 trials (PEARL-II, PEARL-III, and PEARLIV), which examined the contribution of RBV to the safety and efficacy of the 3D regimen, were used to evaluate the incidence and severity of clinical events related to bilirubin (hyperbilirubinemia, jaundice) during 12 weeks of treatment. Total, direct, and indirect bilirubin were assessed at baseline and every 1-2 weeks per protocol. Results: Total bilirubin elevations of >3X ULN occurred in 23/401 (5.7%) 3D+RBV patients and in 2/509 (0.4%) patients receiving the RBV-free 3D regimen. The majority of patients in each group (>90%) had normal total bilirubin levels at the end of treatment. Mean total bilirubin levels were significantly higher at each treatment visit in the RBV-containing treatment groups. Mean total bilirubin peaked at week 1 in both treatment groups (predominantly indirect), and declined to baseline by week 2 in the RBV-free group. Events of hyperbilirubinemia and jaundice were mostly mild, occurred within the first 2 weeks of treatment and did not result in study drug discontinuation. One patient underwent RBV dose modification and one interrupted study drug due to hyperbilirubinemia; both patients achieved sustained virologic response 12 weeks post-treatment. Two patients receiving 3D+RBV experienced ALT ≥3X ULN and total bilirubin ≥2X ULN, however, the timing and predominance of indirect bilirubin were not consistent with drug induced liver injury. No serious adverse events related to hyperbilirubinemia were reported. Conclusion: Low rates of hyperbilirubinemia were observed with both 3D regiments but were less frequent in the RBV-free 3D regimens, suggesting that increases in bilirubin associated with ABT-450-containing regimens are enhanced by RBV-induced hemolysis. Bilirubin-related adverse events were infrequent with both regimens and did not affect treatment response. Disclosure - D Bernstein - Grant/Research Support: AbbVie, BMS, Gilead, Janssen, Vertex, Merck, Genentech; Consultant/Speaker’s Bureau: AbbVie, Gilead, Janssen, Vertex, Merck. N Tsai - Consultant/Advisory Board: AbbVie, Gilead, Janssen; Grant/Research Support: AbbVie, Janssen, Genentech-Roche, Vertex, BMS; Speaker’s Bureau: Gilead, Genentech-Roche, BMS, Vertex, Merck, Janssen. T Hassanein - Grant/Research Support: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Gilead Sciences, Janssen, Idenix, Ikaria, Mochida, Roche, Ocera, Taigen, Takeda, Salix, Sundise, Vertex. Speaker’s Bureau: Baxter, Bristol-Myers Squibb, Gilead, Salix; Advisory Board: AbbVie, Bristol-Myers Squibb. F Rodriguez-Perez - Advisory Board: AbbVie, Gilead, Janssen, Merck; Speaker’s Bureau: BMS, Merck. M Romero-Gomez - Advisory Board/Speaker’s Bureau: AbbVie, Roche, Gilead Sciences, MSD, Janssen, Merz, BMS, Boehringer Ingelheim, GSK. R Marinho - Advisory Board/Speaker’s Bureau: AbbVie, Gilead, BMS, Roche, Merck, Janssen. R Planas Vila - Advisory Board: Roche, MSD, BMS, Gilead, Janssen; Speaker’s Bureau: Roche, MSD, BMS, Gilead, Janssen, Boehringer Ingelheim; Grant/Research Support: Roche, MSD, BMS, Gilead, Janssen. M Colombo - Grant/Research Support: Merck, Roche, BMS, Gilead; Advisory committee; AbbVie, Merck, Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, Abbott, Boehringer Ingelheim, GSK, GenSpera; Speaker’s Bureau: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Sciences, Vertex. M Pedrosa - Employee/Stockholder: AbbVie. S Lovell - Employee/Stockholder: AbbVie. J Enejosa - Employee/Stockholder: AbbVie. Y Luo - Employee/Stockholder: AbbVie. D Cohen - Employee/Stockholder: AbbVie. KR Reddy - Ad-Hoc Advisory Board: AbbVie, BMS, Gilead, Vertex, Janssen, Merck, Genentech-Roche, Idenix; Grant/Research Support: AbbVie, BMS, Gilead, Vertex, Janssen, Merck, Genentech-Roche, Genfit. This research was supported by an industry grant from AbbVie.Table 1

Hyperbilirubinemia in Lapatinib Treated Patients Is Associated with Gilbert's Syndrome UGT1A1 Polymorphism.

Abstract Background: Lapatinib, an oral EGFR/HER2 tyrosine kinase inhibitor, is approved in combination with capecitabine for the treatment of patients with advanced or metastatic HER2-positive breast cancer who have been treated previously with an anthracycline, taxane and trastuzumab. Treatment associated elevations in transaminases and bilirubin have been observed in lapatinib clinical trials. A common TA repeat polymorphism in the promoter region of uridine diphosphoglucuronyl transferase (UGT1A1*28, TA7 allele) reduces UGT1A1 enzyme levels and has been associated with hyperbilirubinemia for a range of drugs. We sought to determine the effect of the UGT1A1*28 variant on bilirubin elevation in lapatinib treated patients.Patients and Methods: Association between the UGT1A1 TA repeat polymorphism and total bilirubin levels (TBL) was examined in lapatinib treated patients using data pooled from 12 trials in advanced and metastatic breast cancer. A total of 899 lapatinib treated (as monotherapy or combined with chemotherapy) patients provided a germline DNA sample and were available for this analysis. UGT1A1 TA repeat genotype was determined by PCR amplification and sequencing. For case-control analysis, patients were defined as having normal TBL at baseline, with on-treatment TBL ≥1.5 and ≤1 times upper limit of normal for cases and controls, respectively, and at least 13 weeks of treatment for controls.Results: The UGT1A1 TA repeat polymorphism strongly correlated with lapatinib associated hyperbilirubinemia. A significant association (P=1.03x10-5, 60 cases and 396 controls) was observed. For hyperbilirubinemia cases, 21/60 (35%) were carriers of two TA7 alleles and 28/60 (47%) were carriers of one TA7 allele. Overall, when compared with other genotypes, the odds ratio (95% confidence interval) of the TA7/TA7 genotype for developing hyperbilirubinemia was 10.7 (5.3-21.6).Conclusion: These data suggest that UGT1A1*28 accounts for the major proportion of total bilirubin elevation observed during lapatinib treatment. This is consistent with an underlying predisposition to Gilbert's syndrome. Given the life-threatening nature of advanced and metastatic breast cancer and the benign clinical course of Gilbert's syndrome, these data support treatment continuation with lapatinib for patients with mild to moderate, isolated, indirect bilirubin elevation, when accompanied by appropriate ongoing safety evaluation (eg, bilirubin fractionation, ALT evaluation) to exclude liver injury risk in these patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1112.

Argatroban Therapy in Heparin-Induced Thrombocytopenia With Hepatic Dysfunction

We evaluated the dosing requirements in argatroban-treated patients with heparin-induced thrombocytopenia (HIT) and hepatic dysfunction, and compared efficacy and safety outcomes with historical control patients. Retrospective analysis. Inpatient setting. Patients with hepatic dysfunction, defined as total bilirubin > 25.5 micromol/L (1.5 mg/dL), aspartate aminotransferase >100 IU/L, and/or alanine aminotransferase >100 IU/L, were identified from previous multicenter, historical-controlled studies of argatroban therapy in HIT. Argatroban, adjusted to maintain activated partial thromboplastin times (aPTTs) 1.5 to 3 times baseline in the experimental group, vs no direct thrombin inhibition in the historical control patients. The analysis population included 82 argatroban patients and 34 historical control patients with hepatic impairment, of whom approximately 50% in each group had renal dysfunction (defined as a serum creatinine level > 1.3 mg/dL). The argatroban dosage was 1.6 +/- 1.1 microg/kg/min (mean +/- SD) over a mean 5-day course of therapy. Significantly lower doses were used in patients with elevated vs normal total bilirubin levels (0.8 +/- 0.6 microg/kg/min vs 1.7 +/- 0.8 microg/kg/min, p = 0.0063) and in patients with hepatic/renal dysfunction vs hepatic dysfunction alone (1.2 +/- 1.1 microg/kg/min vs 2.0 +/- 1.1 microg/kg/min, p < 0.001). The aPTT 24 h after argatroban initiation was 69 +/- 22 s, with 80% of patients having a therapeutic level of anticoagulation. Thirty-four argatroban-treated patients (41.5%) and 17 control patients (50.0%) experienced the 37-day composite end point of death, amputation, or new thrombosis (p = 0.32). Argatroban significantly reduced new thrombosis (8.5% vs 26.5%, p = 0.012). Major bleeding was similar between treatment groups (4.9% vs 2.9%, p = 0.684). Hepatic dysfunction affects argatroban dosing, with reduced doses required particularly in patients with serum total bilirubin levels > 25.5 micromol/L (1.5 mg/dL) or combined hepatic/renal dysfunction. Individual mean aPTT-adjusted doses typically remain > or = 0.5 microg/kg/min, supporting the recommendation of 0.5 microg/kg/min as a conservative initial dose for most patients with hepatic impairment. Argatroban, with proper initial dosing and monitoring, can provide safe and effective antithrombotic therapy in patients with HIT and hepatic impairment.

Efficacy of using total bilirubin values as a guide for screening direct bilirubin requests.

Two divergent laboratory approaches to the determination of direct bilirubin were assessed. The first approach, assaying direct bilirubin (DB) on all total bilirubin (TB) requests regardless of TB values, resulted in a true negative rate (normal TB level less than 1.0 mg/dL [less than 17 mumol/L], and DB level, less than 0.4 mg/dL [less than 6.8 mumol/L]) of 98.7% (984/997 specimens) and a low false negative (normal TB level, abnormal DB level) rate of 1.3% (13 of 997). The second approach, assaying DB on physician request and only if the TB level was greater than or equal to 1.0 mg/dL (1.7 mumol/L), resulted in a true negative rate (normal TB level, no liver disease) of 87.7% (150%) of 171 patients) and a relatively low false negative rate (normal TB level, liver disease) of 12.3% (21 of 171) patients. Medical chart review revealed that, with either approach, none of the patients with false negative results with hepatobiliary disease would have been missed clinically, even if the DB assay had not been done. It is possible to screen DB requests using a TB of 1.0 mg/dL (17 mumol/L) as a means to determine whether DB should be assayed.

Clinical value of serum bilirubin subfractionation by high-performance liquid chromatography and conventional methods in patients with primary biliary cirrhosis

The clinical value of serum bilirubin subfractionation, using high-performance liquid chromatography (HPLC), was studied in 26 patients with primary biliary cirrhosis (PBC) from whom 59 serum samples were obtained. Total bilirubin (TB) levels were determined by alkaline methanolysis and HPLC (TBHPLC) as well as by the conventional diazo method (TB diazo). The correlation between TBHPLC and TBdiazo was significant (P less than 0.001) but bilirubin concentrations measured by HPLC amounted to only about 30% of those by diazo method. This difference is probably caused by tightly albumin-bound bilirubin, so called 'delta bilirubin' or 'bilirubin-albumin', which is measured by the diazo but not by the HPLC method. Bilirubin conjugates were present in 16 sera of 26 patients; 14 of these had normal total bilirubin levels. There was an excellent correlation between bilirubin conjugates (BcHPLC) and TB diazo (P less than 0.001). In all conjugate-containing samples, mono- and diconjugates were present in about equal proportions. Our results suggest that the biochemical methods of choice in the follow-up of patients with primary biliary cirrhosis are determination of total serum bilirubin by conventional diazo technique and determination of serum alkaline phosphatase activity. Both are simple methods which correlate well with liver histology. For the detection of patients with liver disease, such as asymptomatic PBC, the more elaborate HPLC technique has the distinct advantage of being a reliable method to detect bilirubin conjugates at normal total bilirubin levels. However, one should realize that with the presently used HPLC method only free conjugates are measured whereas covalently bound 'bilirubin-albumin' may represent up to 70% of all bilirubin species in cholestatic serum. Both free conjugates and 'bilirubin-albumin' start to appear in serum at total bilirubin levels as low as 5 mumol/l. The presence of bilirubin conjugates and 'bilirubin-albumin' in serum suggests liver disease. Reliable methods to quantify 'bilirubin-albumin' are needed.