Initial assessment of the infant with neonatal cholestasis-Is this biliary atresia?

INTRODUCTION: Optimizing outcome in biliary atresia (BA) requires timely diagnosis. Cholestasis is a presenting feature of BA, as well as other diagnoses (Non-BA). Identification of clinical features of neonatal cholestasis that would expedite decisions to pursue subsequent invasive testing to correctly diagnose or exclude BA would enhance outcomes. The analytical goal was to develop a predictive model for BA using data available at initial presentation. METHODS: Infants at presentation with neonatal cholestasis (direct/conjugated bilirubin >2 mg/dl [34.2 µM]) were enrolled prior to surgical exploration in a prospective observational multi-centered study (PROBE-NCT00061828). Clinical features (physical findings, laboratory results, gallbladder sonography) at enrollment were analyzed. Initially, 19 features were selected as candidate predictors. Two approaches were used to build models for diagnosis prediction: a hierarchical classification and regression decision tree (CART) and a logistic regression model using a stepwise selection strategy. RESULTS: In PROBE April 2004-February 2014, 401 infants met criteria for BA and 259 for Non-BA. Univariate analysis identified 13 features that were significantly different between BA and Non-BA. Using a CART predictive model of BA versus Non-BA (significant factors: gamma-glutamyl transpeptidase, acholic stools, weight), the receiver operating characteristic area under the curve (ROC AUC) was 0.83. Twelve percent of BA infants were misclassified as Non-BA; 17% of Non-BA infants were misclassified as BA. Stepwise logistic regression identified seven factors in a predictive model (ROC AUC 0.89). Using this model, a predicted probability of >0.8 (n = 357) yielded an 81% true positive rate for BA; <0.2 (n = 120) yielded an 11% false negative rate. CONCLUSION: Despite the relatively good accuracy of our optimized prediction models, the high precision required for differentiating BA from Non-BA was not achieved. Accurate identification of BA in infants with neonatal cholestasis requires further evaluation, and BA should not be excluded based only on presenting clinical features.

Avaliação e suporte nutricional na criança com colestase / Nutrition assessment and support of children with cholestasis

A colestase acomete 65% dos pacientes pediátricos com hepatopatia, sendo responsável por várias consequências clínicas, como: retenção hepática de substâncias excretadas pela bile, lesão hepática progressiva, má-absorção intestinal de gorduras e vitaminas lipossolúveis, anorexia e esteatorreia. Há risco subestimado de desnutrição nesses pacientes, que está associada a grande morbidade. Para classificar os pacientes quanto ao estado nutricional, usam-se os índices de avaliação do crescimento. Porém, considerando a condição clínica do paciente, que pode incluir visceromegalias e ascite, os índices que utilizam o peso na análise podem ser imprecisos. Nesses casos, o uso das medidas de pregas cutâneas e da circunferência braquial leva a avaliações mais fidedignas. O paciente com colestase exige suporte nutricional para compensar a má-absorção e possível desnutrição. Esse suporte inclui: aporte calórico elevado,ingestão proteica em níveis que não se induza hiperamonemia, oferta de ácidos graxos majoritariamente de cadeia média, suplementação de vitaminas lipossolúveis (A,D, E e K) e alguns minerais. Adequado suporte nutricional pode evitar a progressão rápida da doença hepática, facilitar o processo de cicatrização, aumentar a função imunológica, além de prevenir várias consequências da deficiência de uma variedade de micro ou macronutrientes que pode ocorrer na colestase...

Cholestasis affects 65% of pediatric patients with liver disease and it is responsible for several clinical consequences such as liver retention of substances excreted in bile, progressive liver damage, intestinal malabsorption of fats and fat-soluble vitamins, anorexia, and steatorrhea. There is an underestimated risk of malnutrition in these patients, whichis associated with high morbidity. Indexes of growth evaluation are used to classify patients according to their nutritional status. However, considering the clinical condition of the patient, which may include increase of some organs?s size and ascites, the indices that use weight in the analysis may be inaccurate. In these cases, the use of measures of skinfold thickness and arm circumference leads to more reliable evaluations. The patient with cholestasis requires nutritional support to compensate the malabsorption and possible malnutrition. This support includes: caloric intake higher than usual, protein intake at levels which do not induce hyperammonemia, an offer of fatty acids predominantly mediumchain (absorbed independently from the action of micellar bile acids), supplementation of fat-soluble vitamins (A, D, E and K) and some minerals. An adequate nutritional support can avoid the fast progression of liver disease, facilitate the healing process, and enhance immune function, besides of preventing many consequences from the deficiency of a variety of micro or macronutrients which may happens in cholestasis...

The interaction between high ammonia diet and bile duct ligation in developing rats: assessment by spatial memory and asymmetric dimethylarginine.

Bile duct ligation (BDL) in developing rats causes cholestasis, impaired liver function and cognition. Because both nitric oxide (NO) and ammonia are implicated in hepatic encephalopathy (HE), we hypothesized that asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, and ammonia affect cognition in young rats with BDL. Four groups of young male Sprague-Dawley rats ages 17 days were used: rat underwent laparotomy (SC group), rat underwent laparotomy plus a 30% ammonium acetate diet (SC+HA group), rat underwent BDL (BDL group), rats underwent BDL plus high ammonia diet (BDL+HA group). Spatial memory was assessed by Morris water maze task. Plasma was collected for biochemical and ADMA analyses. Liver and brain cortex were collected for determination of protein arginine methyltransferase-1 (PRMT1, ADMA-synthesizing enzyme) and dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme). We found BDL group had significantly higher plasma direct/total bilirubin, aspartate aminotransferase, alanine aminotransferase, ADMA, liver p22(phox), and worse spatial performance as compared with SC group. High ammonia diet increased plasma ammonia and ADMA concentration, and aggravated spatial deficit in the presence of BDL-induced cholestasis. We conclude plasma ADMA plays a role in BDL-induced spatial deficit. High ammonia aggravated the spatial deficits encountered in cholestatic young rats.

Ultrasonographic assessment of gallbladder bile exchanges in healthy subjects and in gallstone patients.

Impaired gallbladder motility may contribute to gallstone pathogenesis by providing time for nucleation and aggregation of cholesterol crystals. Simultaneous scintigraphic-ultrasonographic techniques have been proposed to assess alternating phases of gallbladder emptying and filling. To evaluate patterns of gallbladder motility and of postprandial bile flow by means of a single ultrasonographic technique, 12 healthy volunteers and 20 gallstone patients underwent minute-by-minute gallbladder ultrasonography for 3 h postprandially. Mathematical analysis of volume measurements was used to estimate hepatic and cholecystic bile flux through the gallbladder. Compared to controls, gallstone patients showed greater amounts of unexchanged cholecystic-to-hepatic bile (11% vs. 1%, p <.001) and most of them showed impaired gallbladder washout efficacy. Utrasonographic values of bile exchanges were similar to those derived from scintigraphic-sonographic studies in comparable groups of subjects. This study provides new ultrasonographic variables, which better express gallbladder bile retention in gallstone patients and strongly discriminate gallstone patients from controls.

Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: hemodynamic and hormonal assessment.

OBJECTIVE: To investigate myocardial function in patients with obstructive jaundice before and after internal biliary drainage. SUMMARY BACKGROUND DATA: Increased plasma levels of atrial natriuretic peptide (ANP) have been found in patients with biliary obstruction. METHODS: Thirteen patients with newly diagnosed obstructive jaundice and no previous heart, lung, or renal disease were studied using a Swan-Ganz catheter. Hemodynamic measurements were taken before and 4 days after internal biliary drainage. Levels of ANP and brain natriuretic peptide (BNP) were obtained and liver function tests were also determined. RESULTS: Plasma levels of ANP and BNP were increased twofold to fourfold in the basal state and declined after biliary drainage. Independent variables predicting left ventricular systolic work were total bilirubin concentrations, duration of jaundice, and BNP. In addition, bilirubin concentrations correlated with pulmonary vascular resistance, mean arterial pulmonary pressure, and right ventricular systolic work. Internal biliary drainage resulted in an improvement in left ventricular systolic work. A correlation was found between decreasing ANP concentrations and increasing cardiac output. CONCLUSIONS: Increased plasma levels of natriuretic peptides in patients with obstructive jaundice may reflect a subclinical myocardial dysfunction correlating with the degree of jaundice. After internal biliary drainage, there is a measurable improvement of cardiac function.

Reliability and validity of the NIDDK-QA instrument in the assessment of quality of life in ambulatory patients with cholestatic liver disease.

The NIDDK-QA instrument, developed and widely used in liver transplant recipients, assesses quality of life (QOL) in four domains, including liver disease symptoms, physical function, health satisfaction, and overall well-being. We investigated whether the instrument may be used as a disease-specific instrument in ambulatory patients with cholestatic liver disease. The NIDDK-QA instrument was administered in 96 patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) seen at the Mayo Clinic. The SF-36, a well-established generic instrument, was also administered. Standard measures for test-retest reliability, internal consistency, and discriminant and concurrent validity were examined. All patients were ambulatory with mostly normal levels of serum bilirubin and albumin concentrations. The reliability of the NIDDK-QA, as measured by test-retest correlation (Pearson coefficients: 0.82-0.99, P <.01) and by internal consistency (Cronbach's alpha: 0.87-0.94) exceeded conventional acceptability criteria. The correlation between domain scores of the NIDDK-QA and SF-36 was clear and logical in that the physical function domain of NIDDK-QA strongly correlated with the physical component summary score of SF-36 (r = 0.86, P <.01). The overall well-being domain of the NIDDK-QA was closely associated with the mental summary score of SF-36 (r = 0.69, P <.01). Among PBC patients, there was a modest yet significant correlation between the Mayo risk score and overall well-being (r = -0.26, P =.03). In the assessment of QOL in patients with cholestatic liver disease, NIDDK-QA is found reliable and valid. These data, combined with our previous study, demonstrate its applicability in a wide spectrum of disease severity, ranging from early, ambulatory-phase disease to decompensated cirrhosis necessitating liver transplantation.

Renal effects of experimental obstructive jaundice: morphological and functional assessment.

BACKGROUND: The pathophysiology of renal impairments occurring in obstructive jaundice has been extensively studied, but the underlying mechanism of these derangements remains unclear. The aim of the present study was to investigate the time-related morphological and functional changes occurring in the kidneys of rats undergoing obstructive jaundice. METHODS: Histological examination, renal function assessment and determination of (Na + K)-ATPase activity were performed in the kidneys of rats 7, 14, and 21 days following bile duct ligation (BDL) or sham operation (sham). RESULTS: Glomerular filtration rate was unaffected by BDL throughout the period of the study. Tubular effects occurred at days 7 and 14, being more marked at day 7, and consisted of an increase of about twice in the fractional excretion of sodium and chloride, paralleled by a decreased proximal and distal tubular reabsorption of sodium of about 50 and 40%, respectively. Natriuresis was consistent with augmentation of osmolar clearance but it was not associated with changes in the activity of renal (Na+ + K+)-ATPase. The ability to dilute urine was impaired at days 14 and 21 after BDL. Additionally, these effects were accompanied by decreased tubulointerstitial fibrosis and vasodilation of inner medullary capillaries. At day 21, the parameters of tubular function in BDL and sham groups were not significantly different. CONCLUSIONS: These data support the view that raised natriuresis taking place in the initial 2 weeks following BDL is due mainly to tubular effects. The contribution of hemodynamic, paracrine and humoral mediators is discussed.

Nutritional assessment of patients with benign and malignant obstructions of the biliary tract.

OBJECTIVES: the aim of this study was to assess the severity and type of nutritional deficiencies observed in patients with benign and malignant obstructive jaundice (OJ). METHOD: in this prospective cross-sectional study 51 patients with OJ (21 with benign and with 30 malignant obstruction) were investigated. Nutritional status was assessed by anthropometric parameters (ideal body weight, midarm muscle area and skinfold thickness), visceral proteins, creatinine height index and total lymphocyte count. Observed values in patients with OJ were normalized to the percentage value of the lower limit of normal (obtained from 17 healthy subjects matched for age and sex) and averaged to obtain a total score for protein-energy malnutrition. RESULTS: forty-two (82%) patients with OJ had protein-calorie malnutrition (PCM). Malnutrition was mild in 55%, moderate in 35% and severe in 10%. Severity of PCM was associated with intensity (p < 0.05) and duration of jaundice (p < 0.01). Kwashiorkor (74%) was the dominant type of malnutrition. PCM was common in benign (71%) as well as in malignant obstruction (90%), but the total score (92 +/- 20 vs 80 +/- 19; p < 0.05) and the proportion of mild PCM in patients with benign obstruction (80% vs 41%, p < 0.01) was significantly higher than in patients with malignant tumors. CONCLUSIONS: a high percentage of patients with OJ had PCM. The degree of nutritional alteration was associated with the intensity of jaundice. Malnutrition was equally prevalent among patients with benign obstructions and patients with malignant causes of biliary obstruction, although it was more severe in the latter. Acute malnutrition (kwashiorkor) was the dominant type of malnutrition in both groups of patients.

Renal effects of experimental obstructive jaundice: morphological and functional assessment

Background. The pathophysiology of renal impairments occurring in obstructive jaundice has been extensively studied, but underlying mechanism of these derangements remains unclear. The aim of the present study was to investigate the time-related morphological and functional changes occurring in the kidneys of rats undergoing obstructive jaundice. Methods. Histological examination, renal function assessment and determination of (Na + K)-ATPase activity were performed in the kidneys of rats 7, 14, and 21 days following bile duct ligation (BDL) or sham operation (sham). Results. Glomerular filtration rate was unaffected by BDL throughout the period of the study. Tubular effects occurred at days 7 ant 14, being more marked at day 7, and consisted of an increase of about twice in the fractional excretion of sodium and chloride, paralleled by a decreased proximal and distal tubular reabsorption of sodium of about 50 and 40 percent, respectively. Natriuresis was consistent with augmentation of osmolar clearance but it was not associated with changes in the acivity of renal (Na+ + K+)-ATPase. The ability to dilute urine was imparied at days 14 and 21 after BDL. Additionally, these effects were accompanied by decreased tubulointerstitial fibrosis and vasodilation of inner medullary capillaries. At day 21, the parameters of tubular function in BDL and sham groups were not significantly different. Conclusions. These data support the view that rasied natriuresis taking place in the initial 2 weeks following BDL is due mainly to tubular effects. The contribution of hemodynamic, paracrine and humoral mediators is discussed

Noninvasive assessment of hepatobiliary and renal elimination of cysteinyl leukotrienes by positron emission tomography.

N-Acetyl-leukotriene E4 has been identified as an endogenous, biologically less active cysteinyl leukotriene metabolite in rodents and humans. To evaluate the ratio of hepatobiliary to renal elimination of leukotrienes noninvasively by positron emission tomography (PET), we synthesized N-[11C]acetyl-leukotriene E4 by chemical N-acetylation of leukotriene E4. After the intravenous injection of N-[11C]acetyl-leukotriene E4 in normal rats and monkey, uptake by the liver and subsequent excretion into bile were largely responsible for its rapid elimination from blood. In the Cynomolgus monkey, renal excretion of the leukotriene into urine was of additional quantitative importance. Kinetic modeling indicated a mean transit time through the liver of 17 minutes and 34 minutes in rat and monkey, respectively; the corresponding hepatic excretion half-times amounted to 8.5 minutes and 16 minutes. In a mutant rat strain deficient in the hepatobiliary excretion of cysteinyl leukotrienes across the canalicular membrane, the apparent mean liver transit time was 54 minutes, and the hepatic excretion half-time was 29 minutes, indicating prolonged organ storage and metabolism. After transport from the liver back into the circulating blood of omega-oxidized and beta-oxidized metabolites of N-[11C]acetyl-leukotriene E4, renal excretion compensated for the impairment of hepatobiliary elimination in the transport mutant. Metabolite analyses in urine after intravenous injection of N-[3H]acetyl-leukotriene E4 indicated the extensive inactivation of N-acetyl-leukotriene E4 by beta-oxidation from the omega-end in the mutants. A similar shift from hepatobiliary to renal cysteinyl leukotriene elimination was monitored in rats with cholestasis due to bile duct obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

[The comprehensive assessment of the degree of severity of their condition in patients with mechanical jaundice]. / Kompleksnaia otsenka stepeni tiazhesti sostoianiia bol'nykh s mekhanicheskoi zheltukhoi.

The authors examined 42 patients with obstructive jaundice of various severity. Comparison of the findings of radiohepatography with intoxication values according to the medium-weight molecule test and the biochemical parameters revealed statistically significant differences of some quantitative indices depending of the severity of jaundice. The results of the study made it possible to recommend the use of the values of blood clearance, time of maximum accumulation of a radiopharmacological agent in the liver, hepatic and blood retention index, and the medium-weight molecule test for objective quantitative appraisal of the severity of obstructive jaundice. Study of the time course of changes of the above parameters showed that normalization of hepatic function in resolving jaundice begins only from the second week after decompression of the biliary tract, which must be borne in mind in choosing the optimal time for the operation.

Use of a microcomputer in the assessment of diagnosis and risk in obstructive jaundice.

A series of multivariate analyses have been carried out in 49 patients with obstructive jaundice and three indices have been derived which help in the assessment of risk and the planning of investigation and management. The k-value, a measure of endogenous bilirubin clearance, is affected by cholangitis, alanine aminotransferase, pre-intervention bilirubin levels and the patient's sex. It has similar strength to the antipyrine clearance test in predicting morbidity and mortality. The mortality discriminant index is obtained from creatinine level, serum albumin and a score for cholangitis, and has an overall accuracy of 95%. The malignancy discriminant index depends on age, cholangitis score, creatinine level and gamma glutamyl transferase, and has an accuracy of 84%. All three indices have been programmed into a commercially available spreadsheet on a small microcomputer, and are automatically and rapidly available as soon as standard biochemical and clinical measurements have been entered.