Increase In Unconjugated Bilirubin Research Articles

Biliary sludge syndrome induced by cephalosporins in children: clinical and diagnostic markers, management

Biliary sludge can occur when taking medicines (oral contraceptives, cephalosporins, octreotide, furosemide, clofibrate, morphine, calcium preparations, etc.). In particular, 30–40 % of ceftriaxone, which is widely used in pediatric inpatient practice, is excreted with bile, 5–15 % of all side effects of the drug are due to biliary sludge. The mechanism of ceftriaxone-associated biliary sludge is due to the fact that ceftriaxone competes with bilirubin for albumin, which induces an increase in unconjugated bilirubin in the blood. The drug enters the bile in the form of a divalent anion, binds to calcium in ceftriaxone-calcium complexes with inclusions of cholesterol monohydrate crystals and bilirubinate granules. In patients taking cephalosporins, when complaints from the gastrointestinal tract appear, ultrasound screening is mandatory. Children with a family history of gallstone disease and risk factors should undergo ultrasound screening on the 10th day and 1 month after treatment with cephalosporins, even in the absence of complaints. The administration of ursodeoxycholic acid leads to a significant regression of clinical symptoms of biliary sludge and objective ultrasound signs in 2/3 of children after 2 months.

Care living instrument for neonatal infant connectivity solution (CliNicS) in smart environment

Hyperbilirubinemia or jaundice occurs in 60% of healthy babies and 80% of preterm infants because of an increase in unconjugated bilirubin in red blood cells. It is subjective to determine the severity of jaundice by visual assessment of the skin color of a newborn, and clinical judgement is dependent on the doctor’s knowledge. The paper explains the development of a non-invasive bilirubin detection technique called CliNicS, to check the bilirubin level of premature babies and report premature births and deaths to the health organization via an IOT network. CliNicS provides a noninvasive, transcutaneous bilirubin monitoring system using LED having a wavelength of 410 nm to 460 nm, and it also provides the treatment automatically by using LCT (LED Controlled Therapy) method. The level of bilirubin will be detected by using the photo detector, and the bilirubin measurement will be displayed on the LCD display. The bilirubin levels will be transmitted to doctors and health organizations via the IOT network. The proposed method helps to detect neonatal jaundice earlier, which reduces the risk of hyperbilirubinemia in newborns and makes it easier to measure total serum bilirubin levels than ever before.

НАСЛЕДСТВЕННАЯ НЕКОНЪЮГИРОВАННАЯ ГИПЕРБИЛИРУБИНЕМИЯ (СОЧЕТАНИЕ СИНДРОМА КРИГЛЕРА-НАЙЯРА II ТИПА И СИНДРОМА ЖИЛЬБЕРА)

Background. Enzymopathic jaundices are manifested by intermittent hyperbilirubinemia, no changes in the structure of the liver, no hemolysis, Rh-conflict as well as cholestasis being noted. These jaundices include Crigler-Najjar syndrome type I, Crigler-Najjar syndrome type II and Gilbert's syndrome. They are characterized by an autosomal recessive inheritance due to the presence of mutations and polymorphisms in uridine 5'-diphosphate-glucuronosyltransferase gene (UGT1A1) leading to a decrease of the enzyme activity or to its complete loss. Objective. To demonstrate the peculiarities of diagnosis and treatment of a rare case of hereditary unconjugated hyperbilirubinemia - a combination of Crigler-Najjar syndrome type II and Gilbert's syndrome. Material and methods. Clinical observation of a patient G. aged 19, who was examined and treated at the Department of gastroenterology of a multidisciplinary hospital in Moscow in January 2021. Results. The patient G. has had icteric sclerae and skin since birth; he occasionally suffers from easy fatigability and general malaise. Physical examination revealed no changes (except for icteric discoloration). An increase in unconjugated bilirubin up to 270 μmol/L (median - 170 μmol/L) was detected. The molecular genetic study of UGT1A1 gene identified mutations in exon 4 Val378Asp (2002) and Arg108Cys as well as polymorphism 6/7TA in the promoter region, confirming the diagnosis of autosomal recessive inherited disease – a combination of Crigler Najjar syndrome type II and Gilbert's syndrome (heterozygous state), complicated by the development of hepatic encephalopathy stage 2. There was noted a significant decrease in unconjugated bilirubin up to 170.5 μmol/L, as well as improvement in general condition – reduced fatigue and weakness during the treatment with microsomal enzyme inducer (phenobarbital) and hyperammonemia corrector (ornithine aspartate). Conclusions. The use of molecular genetic analysis allows tailoring strategies for patient-specific disease diagnostics, treatment and prevention. The preservation of quality of life within satisfactory level is achieved through elimination of adverse effects provoking the development of this syndrome and through control of risk factors.

Effect of Leaf Extract of Senna alata on Biochemical Indices of Wistar Rats Infected with Trypanosoma brucei brucei

This study was aimed at determining the effect of leaves of Senna alata extract on biochemical indices of Wistar rats infected with Trypanosoma brucei brucei. Phytochemical screening revealed the absence of steroids in all extracts, absence of saponins in chloroform extracts and the presence of free anthraquinones only in chloroform extract. Post-infection treatment of animals stirred the emergence of parasitaemia by Day 3. Only animals receiving 200 mg/kg b.wt. of chloroform extract survived by day 16. A significant (P<0.05) decrease in ALT for groups receiving methanol (400 mg/kg b.wt.), chloroform and aqueous extracts and significant (P<0.05) increase in unconjugated bilirubin in the group receiving methanol extract (200 mg/kg b.wt.) compared to infected not treated rats. Significant (P<0.05) decrease in potassium concentration in groups receiving methanol and chloroform, and a significant (P<0.05) increase in sodium concentration in the group receiving 400 mg/kg b.wt. of aqueous extract compared to the infected not treated rats. These results thereby demonstrate the ameliorative potential of Senna alata leaves against T. brucei brucei.

Isothiocyanates Activate the Constitutive Androstane Receptor in an Oxidative Stress Dependent Manner in hUGT1 Mice

Our laboratory has previously developed a humanized UDP‐glucuronosyltransferase 1 (hUGT1) mouse model, creating an in vivo model to examine UGT1A metabolism and gene regulation. Mirroring human development, neonatal hUGT1 mice experience a developmental delay in expression of UGT1A1, the sole enzyme capable of bilirubin glucuronidation, resulting in an increase in unconjugated bilirubin. The accumulation of total serum bilirubin (TSB) is readily quantifiable and creates an observable phenotype linked to the expression of UGT1A1. The UGT1A1 gene is regulated by a host of nuclear receptors allowing drugs to be examined in vivo for their effects on nuclear receptor activity. By examination of the relationship between oxidative stress and UGT1A1 expression, we discovered a novel association between the constitutive androstane receptor (CAR) and oxidative stress. In order to induce oxidative stress, hUGT1 mice were treated with phenylethyl isothiocyanate (PEITC), a natural pesticide found in cruciferous vegetables with known anticancer and antioxidant response properties. It is well established that PEITC reacts with glutathione, depleting a major cellular antioxidant, which then activates antioxidant response pathways in response to the change in the cells redox potential. Neonatal hUGT1 mice experienced a drastic decrease in TSB levels following oral PEITC treatment. Concurrently, a significant increase in hepatic and intestinal UGT1A1 expression was observed. In characterizing a mechanism responsible for UGT1A1 induction, we determined CAR to be the major contributor by examining nuclear receptor target genes. CAR's activation was observed by the significant induction CYP2B10, with the Cyp2b10 gene being a consensus CAR target. This suggested a novel association between CAR activation and oxidative stress. In order to confirm CAR's role in the induction of UGT1A1 and CYP2B10, we treated hUGT1/Car(−/−) and hUGT1/Car(+/−) mice orally with PEITC and demonstrated CAR dependence for intestinal and hepatic CYP2B10 induction. We further identified PEITC induction of UGT1A1 was significantly dependent on CAR in liver. PEITC's ability to directly activate CAR was examined using an in vitro transactivation assay, and determined that PEITC is incapable of directly activating CAR by binding to its ligand binding domain. To probe the role of oxidative stress on UGT1A1 induction/CAR activation, hUGT1 mice were pretreated with N‐acetyl cysteine (NAC), an antioxidant and precursor to glutathione. NAC effectively prevented PEITC induced oxidative stress and a concurrent drop in hepatic UGT1A1 and CYP2B10 induction was observed. This suggests a direct correlation between oxidative stress and CAR activation.Support or Funding InformationU.S. Public Health Service Grants ES010337, GM100481, GM086713 (R.H.T.) and R21‐ES024818 (S.C)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparison of Fibrotest and PGAA for the diagnosis of fibrosis stage in patients with alcoholic liver disease

The PGAA index was one of the first composite liver fibrosis markers. This study aims, prospectively, to confirm the diagnostic value of PGAA and Fibrotest in patients with alcoholic liver disease and to compare their diagnostic performances. We prospectively included 200 consecutive patients (159 men and 41 women; mean age: 51±0.7 years).The PGAA index was calculated by combining the results of four laboratory tests (prothrombin time, γ-glutamyl transpeptidase, apolipoprotein A1, and α-2-macroglobulin) scored on a 0-4 scale. The Fibrotest score was computed using the Biopredictive website. The overall diagnostic performances of scores were evaluated in terms of the area under the receiver operating characteristic (AUROC) curve. The Obuchowski measure was assessed taking into account the distribution of fibrosis stages observed in the cohort. For predicting F≥2 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.83±0.03 and 0.80±0.03, respectively. For predicting F4 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.87±0.03 and 0.86±0.03. There was no difference between the AUROC curves of PGAA and Fibrotest. The Obuchowski measure was 0.92±0.01 for PGAA and Fibrotest. For a value of 10, PGAA had 98% specificity and 97% positive predictive value for the detection of F≥2 fibrosis stage and 80% sensitivity and 92% negative predictive value for F4 stage fibrosis. We confirm the comparable diagnostic values of Fibrotest and PGAA. When Fibrotest use is constrained by an increase in unconjugated bilirubin or is not financially viable, PGAA may be an alternative.

Markedly Elevated Indirect Bilirubin in an 11-Year-Old African American Boy: Normal or Aberrant?

Patient: 11-year-old African American boy. History of Present Illness: The patient presented with a 1-week history of nausea and vomiting and a 1-day history of jaundice; he reported general fatigue. Past Medical History: The patient had a history of sickle cell disease (SS type) requiring seven blood transfusions in the past few years. Medications: Over-the-counter Motrin PRN (300 mg, Q8h). Physical Examination: Scleral icterus and yellow oral mucosa were observed. No hepatosplenomegaly or altered mental status was observed. Family History: Sickle cell trait. Social History: Unremarkable. Principle Laboratory Findings: Table 1 and Table 2 1. What are the most strikingly abnormal laboratory findings? 2. Are these abnormal laboratory findings reliable? 3. What may be causing the patient’s persistent hyperbilirubinemia? 4. What may have caused the discrepancy between the in-house laboratory and the reference laboratory bilirubin results? 5. What is your diagnosis? 1. The most striking laboratory finding is the markedly elevated total bilirubin level (74 mg/dL), consisting mostly of indirect (unconjugated) bilirubin and, to a lesser extent, direct (conjugated) bilirubin (Table 1). 2. The clinical and laboratory findings suggest a mixture of pre-, intra-, and posthepatic involvement. Under normal physiological conditions, indirect bilirubin approximates the amount of unconjugated bilirubin. A marked increase in unconjugated bilirubin, together with the patient’s history of sickle cell disease, and mildly elevated aspartate transaminase (AST) and alanine aminotransferase (ALT) enzymes, indicates a prehepatic injury due to red blood cell sickling and hemolysis or an intrahepatic injury due to sickle cell hepatopathy. …

Lenalidomide-induced elevated bilirubin

Lenalidomide is an immunomodulator used to treat 5q-myelodysplastic syndrome, myelofibrosis, and multiple myeloma. We describe a 55-year-old male who was started on lenalidomide 10 mg daily for 21 days followed by 7 days off therapy for the treatment of early stage post-polycythemia vera myelofibrosis. Following initiation of lenalidomide, the patient was noted to have an asymptomatic increase in unconjugated bilirubin. Alkaline phosphatase, aspartate transaminase, and alanine aminotransferase were normal. During the 7 days off of lenalidomide, bilirubin began to trend down. Re-challenge with lenalidomide in subsequent cycles results in an asymptomatic elevation in unconjugated bilirubin followed by improvement during the 7-day lenalidomide-free period. The patient is a heterozygote for the TA7 allele which can decrease expression of uridine diphosphate glycuronosyl transferase 1A1, the enzyme responsible for conjugation of bilirubin. Therapy with lenalidomide may have unmasked Gilbert's syndrome in the patient.

Time (again) for a Randomized Trial of Pharmacogenetics of Antiretroviral Therapy

Last year, I managed to attain funding for the same grant rejected by several agencies. The reason was clearly stated: it is premature to run a pharmacogenetics-driven randomized trial on the basis of current knowledge on the genetics of toxicity to a number of antiretroviral agents, and it is too expensive. This reasonable rejection should not lead to questioning the research goals in the field: the identification of genetic markers, their association with an intermediate phenotype (the immediate biological effect of a variant gene, for example, an increase in unconjugated bilirubin), and the final correla tion with a clinical end point – such as severe toxicity, or treatment discontinuation. A clinical trial should formalize the ana lysis and provide the basis for translating it into medical economic terms: the cost–effectiveness of a new test. Let’s go down this list.

Accumulation of unconjugated bilirubin in cholesterol pellets implanted in swine gallbladders

BACKGROUND & AIMS: Most cholesterol gallstones have a pigmented center, but it is unclear whether its presence is primary or secondary. This study was performed to determine if bilirubin would accumulate in a gallstone model consisting of cholesterol pellets. METHODS: Cholesterol was compressed into pellets at 2500 psi, producing a pellet that behaved like human cholesterol gallstones in regard to penetration of solutes into the stone. Pellets were implanted into gallbladders of pigs and harvested after 4 weeks. Bilirubin species were measured by high-performance liquid chromatography. RESULTS: The proportions of bilirubin species in bile were not changed by the presence of pellets, i.e., diconjugates (mean +/- SD, 1.9% +/- 1.0% vs. 0.7% +/- 0.8%), monoconjugates (83.8% +/- 5.5% vs. 87.8% +/- 6.6%), and unconjugated bilirubin (14.2% +/- 5.3% vs. 11.5% +/- 5.6%) were similar at the time of implantation and removal. The cut surfaces of the pellets were pigmented. Pellets contained 5.46 +/- 1.38 micrograms bilirubin/g sample at harvesting, and 98.6% +/- 2.3% of bilirubin in pellets was unconjugated. In in vitro studies, there was a large increase in unconjugated bilirubin in the bile. Pellets also became pigmented in vitro, but there was considerable variability in the bilirubin species present in the pellets. CONCLUSIONS: Unconjugated bilirubin accumulates in cholesterol pellets and pigments them. This provides a mechanism by which cholesterol gallstones could become secondarily pigmented. (Gastroenterology 1996 Feb;110(2):607-13)

Hyperbilirubinemia after cardiac operation

Three hundred and two consecutive patients who had undergone cardiac operation for various cardiac lesions were studied prospectively to evaluate the incidence, risk factors, and the associated mortality of postoperative hyperbilirubinemia after cardiopulmonary bypass. Concentrations of the serum total (conjugated and unconjugated) bilirubin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, albumin, globulin, and serum haptoglobin were measured before the operation and again on the first, second, and seventh postoperative days. Postoperative hyperbilirubinemia was defined as occurrence of a serum total bilirubin concentration of more than 3 mg/dl in any measurement during the postoperative period. Logistic regression was done to identify possible risk factors for postoperative hyperbilirubinemia. Overall incidence of postoperative hyperbilirubinemia was 35.1%; the incidence of postoperative hyperbilirubinemia was higher in patients whose valves were replaced with mechanical prostheses than in those without prostheses (p < 0.00001). In patients with postoperative hyperbilirubinemia, 70% of the increase of total bilirubin on the first postoperative day came about from an increase in unconjugated bilirubin. Serum haptoglobin decreased significantly at the same time (p < 0.01). Development of the postoperative hyperbilirubinemia was associated with a higher mortality (5.6% versus 0.5%, p < 0.01) and higher frequency of use of intraaortic balloon counterpulsation, especially for patients in whom the highest postoperative total bilirubin occurred after the first 2 days. The numbers of valves replaced, preoperative right atrial pressure, and preoperative total bilirubin concentration are the significant risk factors that, in combination, correctly predict the occurrence of postoperative hyperbilirubinemia in 80% of the patients. We concluded that postoperative hyperbilirubinemia results mainly from an increase in unconjugated bilirubin and is associated with higher mortality, especially for patients in whom highest postoperative total bilirubin occurred late after operation. Patients with the higher preoperative right atrial pressure and total bilirubin level who then underwent multiple valve replacement procedures are at greater risk for development of postoperative hyperbilirubinemia.

New mutation causing jaundice in mice.

A new mutant causing jaundice in mice is reported. Allelism tests indicate that it is not allelic with known hemolytic anemia mutants in mice [hemolytic anemia (sphha), jaundiced (ja), normoblastic anemia (nb), and spherocytosis (sph and sph2Be)]. The jaundiced condition appears in young mice at about 24 hours postpartum and is due to a major increase in unconjugated bilirubin in serum compared to normal controls. Adult mutant mice are not jaundiced and bilirubin levels do not differ from normal mice. Adult male mutants have reduced testes size and no viable sperm. Female mutants are fertile but overall maternal performance is reduced as indicated by increased mortality and reduced growth rate of pups. Genetic tests indicate that a single autosomal recessive gene is responsible for the condition. We propose that the mutant be designated hyper-unconjugated bilirubinemia, with the gene symbol hub.

An unusual case of Crigler-Najjar disease in the adult: Classification into types I and II revisited

We present the case of a 25-year-old man with Crigler-Najjar disease who had since birth a marked unconjugated hyperbilirubinemia without bilirubin overproduction, without any neurological involvement and in whom phenobarbital administration failed to produce any effect. Analysis of his biliary bile pigments on two occasions showed (i) a decrease excretion of bilirubin, as indirectly suggested by a high ratio of biliary bile acids over total bilirubin; (ii) an increase in unconjugated bilirubin IX alpha quantitated by thin-layer chromatography (TLC) following alkaline methanolysis and by direct extraction and TLC of the tetrapyrroles; (iii) a high proportion of bilirubin monoconjugates whereas the excretion of diconjugates was very low. Classification of the present patient into Crigler-Najjar disease type I or II was not possible. The most striking and practical difference among the various cases of Crigler-Najjar disease remains the response to phenobarbital. Among cases of Crigler-Najjar disease which respond to enzyme induction and Gilbert's syndrome, the continuous spectrum suggests a common defect.

Composition of bile pigment in gallstones and bile and their etiological significance.

Abstract In order to gain further information on the etiology of bile pigment-calcium stones, gallstone samples from 37 patients were visually classified as cholesterol stones (19 subjects), bile pigment-calcium stones (10 subjects), and pure-pigment stones (eight subjects). Bile from each gallstone case was analyzed with ethyl anthranilate and p -iodoaniline diazo reagent. The mean concentration of bilirubin in gallbladder bile from each gallstone case was significantly lower than that of the controls, regardless of their type. Unconjugated and monoconjugated bilirubin was significantly increased in all stone types, particularly with bile pigment-calcium stones, and the difference between each group was significant except between cholesterol and pure-pigment stones. A significant decrease of glucuronide (δ-azopigment) was noted in the bile pigment-calcium stone and pure-pigment stone cases; the latter also had a considerable increase in isomeric glucuronides (β- and γ-azopigment). Bacteriological study suggested a close relationship between the increase in unconjugated bilirubin and the over-all infection rates of the bile. Gallstone analysis revealed that the proportion of conjugated bilirubin was significantly lower in the bile pigment-calcium stones than in cholesterol and pure-pigment stones. These findings all agree with the general belief that during the formation of bile pigment-calcium stone, bacterially mediated hydrolysis of bilirubin conjugates occurs, leading to the formation of monoconjugate and further to unconjugated bilirubin, which in turn precipitates as calcium bilirubinate, thus resulting in stone formation.

Experimental bovine anaplasmosis: clinico-pathological and nutritional studies

Groups of Brahman-cross steers maintained on two nutritional planes were infected intravenously with a stabilate of Anaplasma marginale. In general, animals on the higher plane of nutrition were more severely affected. Fever was the first clinical sign of anaplasmosis but, like anaemia, was absent in the mildest cases. When present anaemia appeared two to three weeks after infection. There was a corresponding increase in erythrocyte sedimentation rates when read after 24 h but not at 1 h. The haemolytic nature of the anaemia was indicated by a significant increase in unconjugated bilirubin during the acute phase. Some visceral damage was suggested by a significant increase of serum aspartate amino-transferase (GOT) especially in severely affected animals of the 'high' nutrition group but no significant change occurred in levels of alanine amino-transferase (GPT).

Prolonged Survival in Three Brothers with Severe Type 2 Crigler-Najjar Syndrome

Three brothers with severe type 2 Crigler-Najjar syndrome for over 50 years have been studied. Although the plasma unconjugated bilirubin (UCB) concentrations were in excess of 19 mg per 100 ml, no abnormal neurological signs were evident. Prolonged exposure to severe unconjugated hyperbilirubinemia does not therefore necessarily increase morbidity. Electron microscopy of liver tissue obtained from 2 patients before phenobarbital therapy showed hypertrophy and hyperplasia of smooth endoplasmic reticulum with unusual prominence of the Golgi apparatus and focal modification of the cell surface membranes. These changes may reflect the reactive state of the hepatocyte to high levels of unconjugated bilirubin. Phenobarbital therapy resulted in a marked reduction in UCB concentration and was accompanied by further hypertrophy of the smooth endoplasmic reticulum and minor changes in bile canaliculi. Dietary restriction to 400 cal daily for 3 days produced a dramatic increase in UCB. The addition of 2400 cal by the intravenous administration of 50% dextrose did not reduce the elevated UCB. In contrast, 2400 cal fed as a normal diet rapidly returned the UCB to basal levels. While on phenobarbital therapy, a similar response to caloric withdrawal and parenteral feeding was observed. These findings indicate that the hyperbilirubinemia of fasting does not depend on caloric deficiency per se, and suggest that either the route of caloric administration or the type of nutrient may influence the level of unconjugated hyperbilirubinemia.

Diagnosis of Gilbert's syndrome: role of reduced caloric intake test.

Reduction in caloric intake to 400 a day for 72 hours resulted in a significant increase in the plasma bilirubin concentration in patients with Gilbert's syndrome and in normal subjects. This was due to an increase in unconjugated pigment. There was no significant increase in the bilirubin concentration in patients with liver disease or haemolytic anaemia.The increase in unconjugated bilirubin was signficantly greater in Gilbert's syndrome than in normals but only when the initial bilirubin concentration was raised. It was usually seen within 24 hours of reducing the caloric intake. An increase of 100% or more suggests that unconjugated hyperbilirubinaemia is due to Gilbert's syndrome. In the normal subjects the unconjugated bilirubin level did not exceed 1.0 mg/100 ml.The increase in unconjugated bilirubin concentration on reducing the caloric intake may be due to decreased hepatic bilirubin uridine diphosphate glucuronyl transferase activity, which was shown to be present in seven rats starved for 72 hours. The effect of a 400 calorie diet for 24 hours on the unconjugated bilirubin level may distinguish Gilbert's syndrome from other causes of unconjugated hyperbilirubinaemia.