[Neonatal hyperbilirubinemia and molecular mechanisms of jaundice]. / Vrozené hyperbilirubinemie a molekulární mechanizmy zloutenky.

The introductory summarises the classical path of heme degradation and classification of jaundice. Subsequently, a description of neonatal types of jaundice is given, known as Crigler Najjar, Gilberts, DubinJohnson and Rotor syndromes, emphasising the explanation of the molecular mechanisms of these metabolic disorders. Special attention is given to a recently discovered molecular mechanism of the Rotor syndrome. The mechanism is based on the inability of the liver to retrospectively uptake the conjugated bilirubin fraction primarily excreted into the blood, not bile. A reduced ability of the liver to uptake the conjugated bilirubin contributes to the development of hyperbilirubinemia in common disorders of the liver and bile ducts and to the toxicity of xenobiotics and drugs using transport proteins for conjugated bilirubin.

Síntese e metabolismo da bilirrubina e fisiopatologia da hiperbilirrubinemia associados à Síndrome de Gilbert: revisão de literatura / Bilirubin synthesis and metabolism, and hyperbilirubinemia associated with Gilbert’s Syndrome: A review of the literature

A icterícia é sinal clínico comum a várias condições patológicas, podendo ser evidenciada em vários locais do organismo devido à grande capacidade de impregnação do pigmento biliar. A icterícia torna-se evidente quando a concentração plasmática encontra-se acima de 2,5 a 3,0 mg/dL. O presente trabalho retrata o metabolismo fisiológico dos pigmentos biliares concomitantemente com a síntese e metabolismo de bilirrubina, assim como processos fisiopatológicos causados pelo aumento da bilirrubina plasmática (hiperbilirrubinemia), como ocorre na síndrome de Gilbert, caracterizada pela deficiência enzimática, que se manifesta clinicamente como icterícia. Compreender os passos da formação e excreção da bilirrubina é fundamental para a compreensão das manifestações clínicas e que ocorrem na icterícia, facilitando o entendimento dos mecanismos fisiopatológicos da hiperbilirrubinemia, como ocorrem na síndrome de Gilbert.

Jaundice is a common clinical manifestation of several pathological conditions. It can be found in several parts of the body because of the high impregnation capacity of the bile pigment. Jaundice is evident when plasmatic concentration is higher than 2.5 ? 3.0 mg/dL. This paper describes the physiological metabolism of bile pigments concomitantly with bilirubin synthesis and metabolism, as well as the pathophysiological processes derived from increased plasmatic bilirubin (hyperbilirubinemia). This is a circumstance typical of the Gilbert?s syndrome, which causes enzymatic deficiency that is clinically manifested as jaundice. Knowledge of the steps of bilirubin formation and excretion is crucial to shed light into the clinical manifestations of jaundice and thus gain more understanding of the physiological mechanisms of hyperbilirubinema associated with Gilbert?s syndrome.

Síndrome ictérica / Icteric syndrome

O entendimento do metabolismo das bilirrubinas, desde sua formação quando da degradação das hemácias, passando por sua captação e conjugação nos hepatócitos até sua eliminação pelas vias biliares,é fundamental para os diversos diagnósticosque podem ser realizadosfrente uma síndrome ictérica. Classificando as síndromes ictéricas em dois grandes grupos, temos inicialmente aquelas devidas a hiperbilirrubinemia não-conjugada, como as doenças hemolíticas, as icterícias constitucionais e a icterícia do recém-nascido. Já as síndromes ictéricasdevidas a hiperbilirrubinemia conjugada também podem ser devidas a icterícias constitucionais, mas fundamentalmente a icterícias parenquimatosas com ausência de colestase ou colestases intra-hepáticas e extra-hepáticas. O trabalho clínico de coleta dos dados de história e exame físico é essen- I cial para os diferentes diagnósticos de icterícia, assim como a interpretação de exames laboratoriais e a correta indicação de exames complementares de imagem e/ou endoscópicos. Diferenciação entre as icterícias constitucionais, o diagnóstico etiológico das hepatites virais e os padrões mais freqüentes de icterícia encontrados na clínica são oferecidos em tabelas, assim como um algoritmo para a realização desse importante diagnóstico diferencial.

Optimal timing for living-related liver transplantation in children.

BACKGROUND: The pediatric end stage liver disease (PELD) score has been used widely to prioritize children awaiting cadaveric liver transplantation (LTx). To establish the objective parameter for optimal timing of living-related LTx (LRLTx), we have assessed our cases using the PELD score. METHODS: From 1997 to 2002, 24 children were evaluated 28 times for the indication of LRLTx. Among them, 15 were for jaundice and nine for growth failure, hepatopulmonary syndrome, and variceal bleeding. Nine of 24 children underwent LRLTx. They were divided into several groups according to their clinical course. The PELD score consisted of age, albumin, total bilirubin, prothrombine time-international ratio (INR) and growth failure. A cut-off value was obtained by the highest positive and negative predictive value. RESULTS: The PELD score in cases whose indication for LRLTx was approved was significantly higher compared with the cases who were not, and a cut-off value of 4 was obtained. The PELD score in cases who were alive after LRLTx was significantly lower compared with the cases who died after LRLTx or evaluation of the indication, and a cut-off value of 22 was established. CONCLUSION: LRLTx may be considered when the PELD score exceeds 4, and LRLTx may be required immediately when the PELD score exceeds 22.

The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy.

BACKGROUND: The benefit of preoperative biliary drainage in jaundiced patients undergoing pancreaticoduodenectomy for a suspected malignancy of the periampullary region is still under debate. This study evaluated preoperative biliary drainage in relation to postoperative outcomes. STUDY DESIGN: At the Academic Medical Center, Amsterdam, the Netherlands, a cohort of 311 patients undergoing pancreaticoduodenectomy from June 1992 up to and including December 1999 was studied. Of this cohort 21 patients with external or surgical biliary drainage were excluded and 232 patients who had received preoperative internal biliary drainage were divided into three groups corresponding with severity of jaundice according to preoperative plasma bilirubin levels: < 40 microM (n = 177), 40 to 100 microM (n = 32), and > 100 microM (n = 23) were designated as groups 1, 2, and 3, respectively. These groups were compared with patients who underwent immediate surgery (n = 58) without preoperative drainage. RESULTS: The median number of stent (re)placements was 2 (range 1 to 6) with a median drainage duration of 41 days (range 2 to 182 days) and a stent dysfunction rate of 33%. Although patients in group 1 were better drained than patients in groups 2 and 3 (median reduction of bilirubin levels 82%, 57%, and 37%, respectively, p < 0.01), there was no difference in overall morbidity among the drained groups (50%, 50%, and 52%, respectively). There was no significant difference in overall morbidity between patients with and without preoperative biliary drainage (50% and 55%, respectively). CONCLUSIONS: Preoperative biliary drainage did not influence the incidence of postoperative complications, and although it can be performed safely in jaundiced patients it should not be used routinely.

Postoperative jaundice.

Postoperative jaundice is often multifactorial (Fig. 2). A precipitating or causative factor may be identified but seldom can a specific therapy be offered. A systematic approach will help eliminate a hepatotoxic drug or identify a biliary tract problem. Treatment involves discontinuation of an offending drug; however, the drug, such as an anesthetic agent, may not be in use when the jaundice is detected. Recognition of an anesthetic-induced injury would certainly warn the physician not to repeat its use in future surgery for that patient. Hyperalimentation may contribute to jaundice, but patients developing postoperative jaundice are generally very ill and require nutrition. Extrahepatic biliary tract disease should be readily recognized and treated. The physician should be alert to the possibility of acalculous cholecystitis so that it can be appropriately diagnosed and treated.

Differentiation and diagnosis of jaundice.

Bilirubin metabolism is a complex and fascinating example of the body's ability to discard, renew, and recycle vital elements. Jaundice is the warning sign for derangements in this system. As is true of pain, jaundice is a powerful impetus for visiting a healthcare provider. Usually associated with hepatitis by a nonclinician, the origins of jaundice can range from benign to fatally malignant. Patients may have any number of idiopathic or nosocomial conditions that can contribute to an icteric state. This review delineates the steps of bilirubin metabolism, enumerates the sources of bilirubin derangement, and examines elements of patient condition and therapeutics that can contribute to hyperbilirubinemia and jaundice.

[Euricterus. A European database on icterus with emphasis on the Danish contribution]. / Euricterus. En europaeisk icterusdatabase med fokus på den danske andel.

Clinical and biochemical data were collected prospectively from 8032 jaundiced patients to form a database as part of a EU-supported project on computer-aided diagnosis. Patients were recruited prospectively from centres in all EU-countries and some other countries as well. Five hundred and twenty-eight jaundiced patients were collected from four centres in Denmark. Alcoholic cirrhosis, acute alcoholic liver disease and malignancy of the pancreas or the biliary tract were more common in the Danish data base: 49% of cases in Denmark as compared to 30% of cases in the international database. Viral hepatitis was underrepresented in Denmark, 16% as compared to 23% in the international group. A crude Bayesian diagnostic programme on the total database with 17 diagnostic groups achieved 63% accuracy. For the 528 Danish cases the diagnostic accuracy was 64% when the European data base was used, whereas it increased to 81% when only the Danish data base was taken as basis for the calculations. In conclusion, we found a drop in diagnostic accuracy for the Danish patients when using the large European data base instead of the national one.

A performance evaluation of the expert system 'Jaundice' in comparison with that of three hepatologists.

The diagnostic performance of an Expert System (Jaundice) designed to discriminate between different causes of jaundice was evaluated in a test sample of 200 consecutive in-patients with serum bilirubin greater than or equal to 51 mumol/l. The average probability assigned to true diagnosis, the non-error rate and the overall accuracy were, respectively, 55%, 77% and 70%. The Expert System's discriminatory ability in probabilistic prediction, assessed by a method based on continuous functions of the diagnostic probabilities (Brier score) was good. We also compared the ability of our Expert System to that of three experienced hepatologists, who were required to give a diagnosis in 20 cases following the same protocol used by computer (i.e., by asking only clinical and laboratory items). Both the hepatologists and Jaundice achieved a correct diagnosis in 70% of 20 cases, but the Expert System asked a significantly higher average number of questions during each consultation. Analysis of the reasoning pathway made by an external referee showed a high agreement between the diagnostic strategies of the Expert System and the physicians. We conclude that Jaundice can be a useful tool to support a physician with insufficient clinical experience in this field to generate correct diagnostic hypotheses.

[Differential diagnosis of jaundice]. / Diferentsialna diagnoza na zhultenitsite.

Patients with jaundice and hyperbilirubinemia over 34 mumol/l have been examined by different methods in order to assess the diagnostic value of the methods. 340 patients were examined clinically and by laparoscopy, 168 patients and 92 healthy persons were examined by 10 laboratory indices, 639 patients--by ultrasonography, 95 patients--by scintigraphy, 116 patients--by computer tomography, 83 patients--by endoscopic retrograde cholangio-pancreatography (ERCPG), 17 patients--by percutaneous transhepatic cholangiography (PTC), 70 patients--by directed liver biopsy. In the patients with cholestasis the 5'-nucleotidase, alkaline phosphatase, glutamyl transpeptidase (lipoprotein X is positive in 92% of the patients) and cholesterol are increased most. The extrahepatic obstructions are diagnosed by ultrasonography in 94.8% of the patients (the biliary ducts are dilated), in 88.7% of the patients the localization of the obstruction and in 74.7% of the patients the cause of the obstruction are found. In parenchymal jaundice the sonography reveals the disease which has caused jaundice in 62.1% of the patients. The scintigraphy gives correct diagnosis in 50% of the patients with hepatitis and jaundice, in 78% of the patients with cirrhosis and jaundice and in 87.5% of the patients with liver cancer. The computer tomography reveals the obstructive jaundice in 94.7% of the patients and the focal processes in the liver in 96.7% of the patients. The ERCPG gives a clear picture of the biliary ducts in 72.28% and of the pancreatic duct in 83.13% of the patients with jaundice, simultaneously the biliary and the pancreatic ducts--in 45.78% of the patients and correct diagnosis in 83.1% of the patients examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithmic diagnosis of jaundice.

Extensive clinical and clinical chemical information was collected from 1002 jaundiced patients. By applying Bayes' theorem and logistic discriminant analysis, a diagnostic algorithm was developed based upon 21 of the 107 variables collected. This algorithm permitted a probabilistic classification of jaundiced patients into four diagnostic categories: acute non-obstructive, chronic non-obstructive, benign obstructive and malignant obstructive jaundice. Of the 985 patients with a final diagnosis a correct probabilistic diagnosis (obstruction vs. non-obstruction) was suggested by the algorithm in 867 patients (88%). Adopting a probability limit of 0.80, 683 patients (69%) were correctly classified, 34 patients (3.5%) were wrongly so, and 268 patients (27%) could not be classified with a probability above 0.80 (doubtful cases). The algorithm was also tested in a further series of 110 jaundiced patients and found to perform equally well: 88 patients classified, 22 patients remaining doubtful. Patients with doubtful diagnoses should be referred to a non-invasive test such as ultrasound examination, whereas patients with definite diagnoses can be referred to invasive tests (liver biopsy, direct cholangiography) as appropriate. The diagnostic algorithm seems to be a valuable aid for the preliminary differential diagnosis of the jaundiced patient and can be used in the planning of a diagnostic strategy for the individual patient.

Mecanismos de hiperbilirrubinemia y clasificación de las ictericias / Mechanisms of hyperbilirubinemia and classification of jaundice

Se definen los términos ictericia y colestasis. Luego se mencionan los posibles mecanismos por los cuales se puede alterar la vía normal de transporte, conjugación y eliminación de la bilirrubina para que pueda producirse una ictericia. Así desde un punto de vista didáctico, mencionaremos nueve mecanismos cuya alteración puede producir ictericia: excesiva producción de bilirrubina; dificultad en atravesar la membrana del hepatocito; dificultad de ser transportada hasta el microsoma; alteraciones del microsoma; dificultad del transporte de la bilirrubina ya conjugada hasta el capilar biliar; dificultad de atravesar la membrana del capilar biliar; dificultad de la bilirrubina (y de toda la bilis) en circular por el árbol biliar intrahepático; dificultad en la circulación de la bilis por el árbol biliar extrahepático; reabsorción tisular de bilirrubina. Consecuentemente, clasificaremos a las ictericias en: 1) premicrosomales, las cuales son todas a predominio de bilirrubina no conjugada; 2) posmicrosomales, con hiperbilirrubinemia a predominio conjugada. A su vez las premicrosomales las subdividiremos en prehepáticas y hepáticas, y las posmicrosomales en hepáticas y poshepáticas (o subhepáticas)