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PubMed2000

Pathogenesis of endotoxemia and multiple organ failure in case of mechanical jaundice and their aggravation after the relief of cholestasis.

PURPOSE: To clarify the mechanisms of systemic endotoxemia in extrahepatic cholestasis and the pathogenesis of aggravation of multiorgan failure after external biliary drainage (EBD)--for elaborating of the curative tactics. MATERIALS AND METHODS: The results of experimental studies performed on 208 Wistar rats and 90 dogs were implemented in the surgical clinic in treatment of 150 patients with cholestasis. In experiments--Histological, Transmission and Scanning Electron Microscopic, and Biochemical (Malonic Dialdehide--the end product of Peroxide Oxidation of Lipids of cell membrane) methods have been used. Perfect model of EBD in cholestasis was created. In clinic--the measurement of Mitochondrial ferments, Bilirubin concentration, Creatinin clearance and Psychometric tests were used for evaluation of liver, kidney and brain functions. RESULTS: Destruction of 7.2% and 8.1% of villi in 6 and 7 days cholestasis and 17.3% and 23.5% of villi consequently in 12-14 days cholestasis (compared with 1.1%-1.4% in control [P < 0.01]) resulted in denudation of lacteals was observed. Malonic Dialdehide concentration is significantly increased in plasma after EBD in cholestasis, especially under rapid decreasing of biliary pressure. CONCLUSION: Gut barrier failure in cholestasis "lets" gram-negative bacteria and their endotoxins to penetrate the systemic circulation via the lymphatic system avoiding the liver filter. This process, which is partially suppressed by bile salts existed in lymph due to bilio-lymphatic reflux, precipices just after EBD with all consequences. Aggravation of hepatic failure after one-stage rapid biliary decompression is also promoted by activation of Peroxide Oxidation of Lipids (caused by blood reflow into portal system under falling the pressure in bile compartment) injuring the liver cells. Administration of "Duphalac" ("Solvey Pharmaceuticals")--with antiendotoxic, and "Plapheron LB" (Georgian Industry)--with anti-free-radicals properties is suggested in cholestasis not only before the operation, but after the biliary drainage as well.

Animals↗
PubMed1992

[The clinico-pathogenetic variants of cholestasis in different liver diseases].

To base the clinico-pathogenetic nonuniformity of cholestasis in different liver diseases, 135 patients distributed into groups were examined. Group I was made up of 48 patients with chronic persistent hepatitis, group II of 34 patients with chronic active hepatitis, group III of 29 patients with liver cirrhosis, and group IV of 24 patients with primary and metastatic liver carcinoma. The data obtained suggest the existence of different forms of cholestasis: multicomponent cholestasis, partial bilirubin cholestasis, partial choleacid cholestasis. In the group I patients, the incidence of cholestasis was 8.3%, in group II 2.9%, in group III 3.4%. The incidence of partial choleacid cholestasis was 4.2% in group I, 2.9% in group II, and 6.9% in group III. The presence of partial cholestasis may be caused by the impairment of the assumed "personal" carrier for different bile components.

Adolescent↗
PubMed2005

Neonatal cholestasis in Thai infants.

The objective of this study was to study etiologies and outcome of neonatal cholestasis in Thai infants. The medical records of infants aged less than 3 months with the diagnosis of neonatal cholestasis in Department of Pediatrics, Siriraj Hospital from 1993 to 2004 were retrospectively reviewed. The etiologies were diagnosed by history, physical examination, and proper investigations. There were 252 infants, including 135 males (53.6%) and 117 females (46.4%). The etiologies of cholestasis were idiopathic neonatal hepatitis (INH) 23%, extrahepatic biliary atresia (EHBA) 22.2%, total parenteral nutrition (TPN)-related cholestasis 18.3%, infection 9.9%, endocrine causes 6%, choledochal cyst 5.6%, Down syndrome 4.4%, hemolytic anemia 1.6%, and miscellaneous causes 9.1%, respectively. TPN-related cholestasis was increasingly found due to advance management of critically ill premature infants. Inborn error of metabolism were suspected in 8 patients (3.21%). Seventeen cases (6.7%) developed cholestasis during the first week of life due to hemolytic anemia, intrauterine infection, hypoxia and others. During the 3 month follow-up period, 6 cases died of progressive dysfunction of liver and one case with idiopathic neonatal hepatitis died from intracranial bleeding from vitamin K deficiency. In conclusion, INH and EHBA are the most common causes of neonatal cholestasis. Due to advance management and nutritional support in critically ill premature infants, TPN-related cholestasis is found more often. Inborn error of metabolism related to neonatal cholestases is uncommon in Thai infants. Overall short-term prognosis of neonatal cholestases is good.

Biliary Atresia↗
PubMed2001

Clinical aspects on neonatal cholestasis based on observations at a Swedish tertiary referral centre.

UNLABELLED: The aim of the study was to investigate the clinical aspects of neonatal cholestasis. The medical records of 85 cholestatic infants were retrospectively reviewed. A majority of the patients were referred from other parts of the country. The most common diagnoses were extrahepatic biliary atresia (n = 30 patients), alpha1-antitrypsin deficiency (n = 11) and progressive familial intrahepatic cholestasis (n = 11). On presentation, the biliary atresia group had higher mean serum values of bilirubin, G-GT and cholesterol than the patients with intrahepatic cholestasis, with no significant differences noticed for any other biochemical parameter. A lack of excretion on hepatobiliary scintigraphy was noticed in all investigated patients with biliary atresia, but also in 9 of 34 patients with intrahepatic neonatal cholestasis. There was no statistical correlation between the age at portoenterostomy and the outcome in patients with biliary atresia. However, both the detection of a partial flow on perioperative cholangiogram and the establishment of a non-icteric phase within 6 mo after the portoenterostomy correlated to a good outcome. Eight of 11 patients with progressive familial intrahepatic cholestasis were treated with a biliary diversion procedure, five of eight experienced a sustained cholestatic remission. CONCLUSIONS: Progressive familial intrahepatic cholestasis may be a more common cause of neonatal cholestasis in Sweden than reported elsewhere and that the experience with biliary diversion is positive. While early referral in patients with extrahepatic biliary atresia remains important, a portoenterostomy should be attempted also in patients referred after 3 mo of age.

Blood Chemical Analysis↗
PubMed1993

Lithocholate-3-O-glucuronide-induced cholestasis. A study with congenital hyperbilirubinemic rats and effects of ursodeoxycholate conjugates.

The mechanism of lithocholate-3-O-glucuronide-induced cholestasis is unknown. In this study, we investigated the cholestatic effects of this agent in a congenital hyperbilirubinemic rat, EHBR. We also studied the effects of ursodeoxycholate-3-O-glucuronide and tauroursodeoxycholate on lithocholate-3-O-glucuronide-induced cholestasis in rats. Lithocholate-3-O-glucuronide, administered at the rate of 0.1 mumol/min/100 g for 40 min, a cholestatic dose in control rats, failed to cause cholestasis in EHBR, and biliary lithocholate-3-O-glucuronide excretion was delayed. Biliary concentrations of this agent did not correlate with the severity of cholestasis. Both tauroursodeoxycholate and ursodeoxycholate-3-O-glucuronide, infused at the rate of 0.2 mumol/min/100 g for 120 min, completely inhibited cholestasis induced by lithocholate-3-O-glucuronide administered at the rate of 0.1 mumol/min/100 g for 40 min. Only tauroursodeoxycholate enhanced biliary lithocholate-3-O-glucuronide excretion. These findings indicate that lithocholate-3-O-glucuronide-induced cholestasis is induced by damage at the level of the bile canalicular membrane. Ursodeoxycholate-3-O-glucuronide inhibits this cholestasis, possibly by inhibiting the access of lithocholate-3-O-glucuronide to the bile canalicular membrane.

Animals↗
PubMed2005

The delta opioid receptor 1 is expressed by proliferating bile ductules in rats with cholestasis: implications for the study of liver regeneration and malignant transformation of biliary epithelium.

In sharp contrast with the normal adult liver, the fetal human and rat livers and the liver of rats with cholestasis secondary to bile duct resection express the preproenkephalin mRNA, which codes for the endogenous opioid peptide Met-enkephalin. Furthermore, Met-enkephalin immunoreactivity is detected in hepatocytes and in proliferating bile ductules in the cholestatic rat liver. These data suggest that in cholestasis endogenous opioids may have a local effect in the cholestatic liver. As endogenous opioids exert their effect by binding to opioid receptors, the presence of opioid receptors in the cholestatic livers would support the hypothesis that Met-enkephalin plays a role in situ. Preliminary data presented in this manuscript reveals the expression of the delta opioid receptor in the liver of rats with cholestasis. This finding suggests that there is a scenario in which Met-enkephalin can bind to opioid receptors in the liver in cholestasis to exert a local effect. In vivo studies in this model of cholestasis with the use of opioid agonist and antagonist will shed light on the possible role of opioidergic regulation of liver regeneration. Studies on the effect of opiate antagonists on the evolution of cholestasis in this animal model may provide insight into the mechanisms of liver regeneration. In addition, as some conditions associated with cholestasis and bile ductular proliferation can be complicated by malignancy, the expression of the delta opioid receptor in malignant tumors of the biliary tree merits research.

Animals↗
PubMed1987

Diagnostic utility of hepatobiliary scintigraphy with 99mTc-DISIDA in neonatal cholestasis.

We retrospectively evaluated the utility of hepatobiliary scintigraphy and various clinical factors in differentiating intrahepatic cholestasis from biliary atresia in 28 consecutive infants with neonatal cholestasis. One millicurie of technetium-labeled diisopropyliminodiacetic acid (DISIDA) was administered intravenously, and images were obtained for up to 24 hours or until gastrointestinal excretion was noted. Nine separate studies in seven infants with biliary atresia were correctly interpreted as showing no gastrointestinal excretion of radionuclide. Of the 21 patients with intrahepatic cholestasis, only nine had gastrointestinal excretion on the first study; in eight without excretion, a second study was done, and five of these showed gut excretion. All infants with either neonatal hepatitis (six) or inspissated bile syndrome (three) had demonstrable gastrointestinal excretion either on the first or second DISIDA study. However, five of six infants with paucity of intrahepatic bile ducts, two of six infants with cholestasis secondary to total parenteral nutrition, and one infant with cholangiolitis did not show evidence of gastrointestinal excretion. The mean birth weight, mean gestational age, and mean weight at study were significantly greater (P less than 0.005) for infants with biliary atresia without excretion than for infants with intrahepatic cholestasis without excretion. The mean direct bilirubin concentration was 6.0 mg/dL for both infants with biliary atresia and infants with intrahepatic cholestasis without excretion; however, infants with excretion had a significantly lower (P less than 0.02) mean direct bilirubin value of 3.4 mg/dL. Excretion was noted in four infants with total bilirubin values greater than 10.0 mg/dL. The absence of gut excretion on the first DISIDA study was 100% sensitive but only 43% specific for biliary atresia. In infants without gut excretion of DISIDA, birth weight greater than 2200 g was 100% sensitive and 92% specific for biliary atresia. We conclude that DISIDA scanning, together with clinical data, is useful in differentiating extrahepatic from intrahepatic cholestasis. The absence of gut excretion on the first DISIDA study does not necessarily indicate extrahepatic obstruction; the study should be repeated if the diagnosis is not clear.

Bile Ducts, Intrahepatic↗
PubMed1997

Elevation of the serum bilirubin diconjugate fraction provides an early marker for cholestasis in the rat.

AIMS/METHODS: During cholestasis, components normally excreted into bile, e.g. bilirubin, accumulate in liver cells and biliary passages. In order to assess the conjugation of bilirubin retained in the hepatocyte during cholestasis, we analyzed the pattern of bilirubin pigments in rat serum and bile, using reversed phase alkaline methanolysis-HPLC. Cholestasis was induced by bile flow interruption for 1 to 2 h. RESULTS: One hour after initiation of cholestasis, the serum concentration of total bilirubin rose 2-fold due to increases in bilirubin di- (BDC) and monoconjugate (BMC), while unconjugated bilirubin (UCB) decreased by 33%. As a result, the BDC/BMC ratio increased to 1.67+/-0.20 vs 0.60+/-0.10 in controls (p<0.01) and the BMC/UCB ratio to 1.0+/-0.2 vs 0.1+/-0.1 (p<0.01). After relief of biliary obstruction, biliary output rose to 8.0+/-0.5 vs 5.5+/-0.3 micromol x min(-1) x kg (p<0.01), and the biliary BDC/BMC ratio to 4.0+/-0.3 vs 1.5+/-0.2 (p<0.01). In contrast, the biliary BMC/UCB ratio remained unchanged throughout. Increasing the duration of obstruction to 2 h led to a further increase in the serum BMC/UCB ratio to 2.2+/-0.3 (p<0.01), but not in the BDC/BMC ratio. Serum aminotransferase activity and the concentration of total bile acids increased 3- and 100-fold above their respective control values. Alkaline phosphatase activity remained unaltered, and electron microscopical features of cholestasis became apparent only after 2 h of biliary obstruction. CONCLUSIONS: We suggest that one of the initial events of cholestasis is a more efficient conjugation of bilirubin retained in the hepatocyte. This results in a shift of the equilibrium among bilirubin pigments towards BDC, the end-product of conjugation. Such a shift provides an early marker for cholestasis.

Alkaline Phosphatase↗
PubMed2002

Obstetric cholestasis: outcome with active management.

OBJECTIVE: Conservative management of intrahepatic obstetric cholestasis is associated with a high stillbirth rate despite monitoring of fetal well-being with non-stress test and amniotic fluid volume assessment. Most cases of stillbirth are associated with meconium passage. We prospectively evaluated the effect of a management protocol inclusive of surveillance for presence of meconium and induction of labor at 37 weeks. STUDY DESIGN: Between January 1989 and December 1997, all women with obstetric cholestasis underwent transcervical amnioscopy after 36 weeks for assessment of amniotic fluid color, in addition to standard monitoring of fetal well-being (semi-weekly non-stress test and amniotic fluid volume determinations). Amniocentesis for fetal lung maturity and amniotic fluid color assessment was performed before 36 weeks in severe cases. Labor was induced at 37 weeks or earlier in the presence of non-reassuring fetal testing, meconium, or severe maternal symptoms unresponsive to therapy with mature fetal lungs. The obstetric outcome of the group with cholestasis was compared with that of the general obstetric population at our Institution during the study period. The rate of fetal death in the study group was compared with that of series published within the last 20 years, which used expectancy and conventional monitoring of fetal well-being. Statistical analysis utilized Fisher's exact test, Chi-square, and Student's t-test with P value <0.05 or an odds ratio (OR) with 95% confidence interval (CI) not inclusive of the unity considered significant. RESULTS: Obstetric cholestasis was diagnosed in 206/20,815 pregnant women (1%) at a median gestational age of 34 weeks (range 20-40). Delivery was prompted by non-reassuring fetal testing in four cases (2%). Meconium passage was documented in 33 cases (16%), in 11 of which before onset of labor and in 10 before 37 weeks. The rate of meconium passage before 37 weeks (17.9 versus 2.9%, OR=7.3; 95% CI 3.3, 16.0) was significantly higher in obstetric cholestasis than in the general obstetric population, whereas the cesarean section rate was similar in the two groups (15.1 versus 16.0%, OR=0.9; 95% CI 0.6, 1.4). The fetal death rate was significantly lower in the group managed with the current strategy than in the published series of obstetric cholestasis (0/218 versus 14/888, P=0.045). CONCLUSION: In pregnancies complicated by obstetric cholestasis, a protocol inclusive of search for meconium and elective delivery at 37 weeks, in addition to standard monitoring of fetal well-being, can significantly reduce the stillbirth rate without increasing the cesarean delivery rate.

Adult↗
PubMed2000

Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats.

The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17beta(beta-D-glucuronide) (E(2)17G). Administration of ¿(3)HE(2)17G (18 nmol/g body weight) gave a similar degree of cholestasis and biliary excretion of E(2)17G-equivalents in wild-type and Mdr1a(-/-)/1b(-/-) mice. When expressed in Sf9 cells, Bsep-mediated adenosine triphosphate (ATP)-dependent transport of taurocholate (TC, 1 micromol/L) in membrane vesicles was 110% +/- 12.5% and 108% +/- 17.3% of control in the presence of 10 and 50 micromol/L E(2)17G, respectively, whereas in rat canalicular membrane, both E(2)17G and the choleretic estradiol-3-beta-D-glucuronide (E(2)3G) inhibited ATP-dependent transport of TC to the same extent. Infusion of ¿(3)HE(2)17G (24 micromol) did not induce cholestasis in Mrp2-deficient TR(-) rats whereas 2 micromol of ¿(3)HE(2)17G inhibited bile flow by 51% in control Wistar rats. The maximal biliary concentration of E(2)17G was 3.5 and 2.5 mmol/L in control and TR(-) rats, respectively. However, 2.2 mmol/L of E(2)17G in bile is associated with inhibition of bile flow in control rats. These data show that (1) Mdr1a/1b are not essential for E(2)17G-mediated cholestasis, (2) direct inhibition of Bsep-mediated bile acid transport is not the mechanism for E(2)17G cholestasis, and (3) accumulation of E(2)17G in bile alone is not sufficient to induce cholestasis. These data indicate that the process of Mrp2-mediated transport of high concentrations of E(2)17G is essential for its induction of cholestasis.

ATP-Binding Cassette Transporters↗
PubMed2002

Cholestatic effect of large bilirubin loads and cholestasis protection conferred by cholic acid co-infusion: a molecular and ultrastructural study.

BACKGROUND: Large intravenous bilirubin loads block biliary phospholipid secretion, produce canalicular membrane lesions and cause canalicular cholestasis. Cholic acid co-infusion forestalls these untoward effects. The aim of this study was first to determine whether bilirubin overload causes cholestasis through reducing the activity or the hepatic expression of the bile salt export pump (bsep) or Na-taurocholate co-transporting polypeptide (ntcp) and, secondly, whether cholic acid co-infusion forestalls cholestasis by upregulating bsep, ntcp or phosphoglycoprotein 3 (pgp3) expressions or activities. A further aim was to determine whether large bilirubin infusions also produce ultrastructural changes inside hepatocytes. METHODS: The effects of intravenous infusion of 2 g bilirubin over 150 min on hepatic expression of bsep, ntcp and pgp3 were studied in bile acid-depleted and cholic acid co-infused pigs, and related to canalicular bile acid transport and bile secretion. Effects on hepatocyte ultrastructural morphology were analysed by electron microscopy. RESULTS: Bilirubin-induced cholestasis reflected marked diminution of bsep and pgp3 transport activities and not reduced hepatic expression of these transporters. Hepatocyte ultrastructural abnormalities were predominantly confined to the hepatocyte canalicular membrane in cholestatic livers. Cholic acid co-infusion with bilirubin conferred complete cholestasis protection through enhancing pgp3 and bsep transporter activities and not through upregulating their expression. Bilirubin infusion did not change ntcp expression. CONCLUSION: Bilirubin-induced cholestasis is due to markedly impaired activity of the membrane-embedded bsep transporter consequent upon ultrastructural injury to the canalicular membrane. Cholic acid co-infusion with bilirubin enhances bsep and pgp3 activities and confers protection against canalicular membrane injury and bilirubin-induced cholestasis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

Effect of glutathione depletion and hydrophilic bile acids on hepatic acute phase reaction in rats with extrahepatic cholestasis.

BACKGROUND: Extrahepatic cholestasis by biliary obstruction induces an acute phase reaction in the liver. It is a complex process involving cytokines, hormones and growth factors. To determine whether the regulation of acute phase proteins (APP) in cholestasis depends on glutathione (GSH), the effect of buthionine sulfoximine-induced (BSO-induced) GSH depletion on the expression of various APP was studied. In addition, we determined the influence of hepatoprotective bile acids on hepatic APP and underlying cytokine events. METHODS: Liver samples of bile-duct-ligated or sham-operated rats were examined. mRNA expression was quantified by densitometric analysis of Northern blots. RESULTS: Expression of APP increased 2-5-fold in bile-duct-ligated rats as compared to sham-operated controls. This acute phase reaction remained similar independently of whether cholestasis occurred for 5 days or 3 weeks. In contrast to alpha2-macroglobulin and tissue inhibitor of metalloproteinases-1 (TIMP-1), mRNA levels of both beta-fibrinogen and haptoglobin were significantly up-regulated after GSH depletion by BSO in cholestasis. Feeding of ursodeoxycholic and iso-ursodeoxycholic acid markedly down-regulated alpha2-macroglobulin and TIMP-1 expression in cholestasis but did not affect overexpression of beta-fibrinogen and haptoglobin. Cholestasis leads to an increased APP expression accompanied by an increased expression of inflammatory cytokines (IL-6, TNF-alpha). After feeding of hydrophilic bile acids, increases in inflammatory cytokines were abrogated. CONCLUSIONS: We show that GSH is involved in the acute phase reaction during obstructive cholestasis. In addition, bile acids might selectively ameliorate the acute phase response by reducing expression of the APP not affected by GSH depletion (alpha2-macroglobulin and TIMP-1).

Acute-Phase Proteins↗
PubMed1986

Pharmacokinetics and pharmacodynamics of vecuronium in patients with cholestasis.

The pharmacokinetics and pharmacodynamics of vecuronium were studied in nine surgical patients with cholestasis, and in 14 patients without hepatic or renal disease. After the administration of vecuronium 0.2 mg kg-1 the plasma concentration of vecuronium and the degree of neuromuscular blockade were measured. The plasma clearance of vecuronium was decreased significantly (P less than 0.01) from 4.30 +/- 1.56 ml min-1 kg-1 (mean +/- SD) in normal patients to 2.36 +/- 0.80 ml min-1 kg-1 in patients with cholestasis. The elimination half-life was of 58 +/- 22 min in normal patients and was prolonged to 98 +/- 57 min (P less than 0.05) in patients with cholestasis. The total apparent volume of distribution was unchanged in patients with cholestasis. A prolonged neuromuscular blockade induced by vecuronium was observed in patients with cholestasis: the duration of effect from injection to 75% recovery of the twitch height was prolonged from 74 +/- 19 min in normal patients to 111 +/- 13 min in patients with cholestasis. The plasma concentration corresponding to 50% recovery from paralysis did not differ significantly between the two groups. Vecuronium has a prolonged effect in patients with cholestasis which is caused by a delay in its elimination.

Adult↗
PubMed1997

Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis.

Large-cell change of hepatocytes (LCC), also called liver cell dysplasia of large-cell type, is a set of cytologic changes comprising nuclear and cytoplasmic enlargement, nuclear pleomorphism, and multinucleation. This entity is encountered frequently on histologic or cytologic examination of specimens obtained from livers with a variety of chronic diseases and originally was thought to have a premalignant nature. Accumulating evidence, however, now suggests that LCC is merely a reactive change. Having often observed LCC in liver specimens with chronic biliary tract disease, that is, in livers where cholestasis preceded hepatocyte injury, we surmised that LCC may be a result of prolonged cholestasis. To determine whether there was any association between LCC and cholestasis, we examined microscopically a series of 400 nodules from 40 consecutive adult cirrhotic livers, resected on transplantation, and graded LCC and cholestasis semiquantitatively. LCC was present diffusely in cirrhotic nodules of 25 specimens (62.5%). Nine additional specimens (22.5%) had focal mild LCC. Usually, LCC and cholestasis occurred together, in the same cirrhotic nodules and in the same areas of nodules. There was a statistically significant association between the presence and grade of LCC and those of cholestasis (p < 0.0001; chi-square test). Within etiological categories of cirrhosis (chronic hepatitis; n = 28; alcoholic liver disease; n = 6; biliary disease: n = 6), the significance was maintained. We conclude that, in cirrhosis of different etiologies, LCC may represent a reactive change that results from prolonged cytoplasmic cholestasis.

Adult↗
PubMed1999

The use of hepatocyte extraction fraction to evaluate neonatal cholestasis.

PURPOSE: Hepatobiliary scintigraphy is used routinely to evaluate infants with neonatal cholestasis. Hepatobiliary scintigraphy determines biliary patency by detecting radioactivity in the bowel on imaging, in duodenal and gastric aspirates, or all of these. During hepatobiliary scintigraphy, the hepatocyte extraction fraction (HEF) is calculated by deconvolution analysis. Normal values of HEF are more than 90%. It is believed that HEF may predict hepatic dysfunction, because, during hepatobiliary scintigraphy, the radiopharmaceutical used in this test is extracted by the hepatocytes from the blood stream. Therefore, a low value of HEF is seen with more severe hepatocellular disease. The goal of this study was to determine whether HEF has any correlation with synthetic liver function, whether HEF can differentiate obstructive from nonobstructive lesions that cause neonatal cholestasis, and whether HEF can predict the outcome of the different causes of neonatal cholestasis. METHODS: A retrospective analysis of 68 hepatobiliary scintigraphy results was done in patients with neonatal cholestasis for a period covering 6 years. RESULTS: The HEF was available in 67 of these 68 patients, with a median value of 25% (range, 3.3% to 100%). The results of synthetic liver function tests (i.e., albumin and prothrombin time) were normal in all infants with neonatal cholestasis. No significant correlation was detected between HEF and the serum levels of total and direct bilirubin, albumin, alkaline phosphatase, and prothrombin time by exploratory data analysis (R = 0.08; small, P > 0.2). The HEF values in different causes of neonatal cholestasis were compared: extrahepatic biliary atresia, neonatal hepatitis, and a miscellaneous category consisting of alpha1-antitrypsin deficiency, ischemic hepatitis, paucity of bile ducts, and others. The outcomes of these diseases were assessed as resolution, continuing disease, transplantation, or death, but no predictive correlation was found with HEF. CONCLUSIONS: A single determination of HEF is of no value in assessing synthetic liver function (as assessed by albumin and prothrombin time), specific diagnoses, and outcomes in patients with neonatal cholestasis. Therefore, a low isolated value of HEF should not be considered suggestive of poor prognosis and outcome in these patients.

Biliary Tract↗
PubMed2002

Niemann-pick disease type C in neonatal cholestasis at a North American Center.

OBJECTIVE: To determine the frequency of Niemann-Pick disease type C (NPC) among children being evaluated for neonatal cholestasis during a 2-year period. METHODS: Medical records were reviewed from all infants with cholestasis and all patients with NPC evaluated at our center from January 1997 through December 1998. RESULTS: Forty neonates with cholestasis were evaluated, including three patients diagnosed with NPC (age at diagnosis, 5-21 months) who were originally labeled as having idiopathic neonatal cholestasis (INH). Two adolescents (ages 14 and 16 years) were also diagnosed with NPC during this period, one who originally had neonatal hepatitis and cirrhosis, and the other who had hepatosplenomegaly throughout childhood. Three of the patients with NPC were Hispanic. At time of NPC diagnosis, infants had mildly delayed motor development and persistent splenomegaly with or without hepatomegaly, and the adolescents had ataxia, dysarthria, hepatosplenomegaly, and paresis of vertical gaze. The diagnosis of NPC was established by demonstrating defective cellular cholesterol esterification in cultured skin fibroblasts in three patients and a specific genetic mutation in three patients. Niemann-Pick disease type C was found in 27% of infants initially diagnosed with INH and 8% of all infants evaluated for cholestasis. CONCLUSION: Niemann-Pick disease type C should be considered in all infants with cholestasis, particularly those with splenomegaly or who are of Hispanic descent. Electron microscopy and lipid analysis of liver biopsy specimens obtained during the evaluation of neonatal cholestasis may suggest this diagnosis.

Adolescent↗
PubMed2006

Early treatment with ursodeoxycholic acid for cholestasis in children on parenteral nutrition because of primary intestinal failure.

BACKGROUND: There is conflicting evidence as to whether ursodeoxycholic acid (UDCA) reduces the incidence of parenteral nutrition-associated cholestasis. AIM: To investigate the efficacy of UDCA on parenteral nutrition-associated cholestasis in children with intestinal failure due to short bowel syndrome or to other causes. METHODS: Children with cholestasis received 30 mg/kg/day UDCA. Improvement or normalization of parenteral nutrition-associated cholestasis was evaluated at 6 months of therapy and at the last follow-up. In a subgroup of children, serum UDCA levels were measured while receiving UDCA and after 4 weeks withdrawal. RESULTS: Twelve children were treated with UDCA. Full remission or partial improvement of parenteral nutrition-associated cholestasis occurred in 11 of 12 children. In three of four children, withdrawal of UDCA was associated with a rebound rise of cholestasis. Only one of 12 treated children showed no improvement and in this patient, in contrast to four other patients, plasma levels of UDCA did not increase during treatment. CONCLUSIONS: Ursodeoxycholic acid was effective in controlling parenteral nutrition-associated cholestasis. The efficacy of UDCA also in children with short bowel is related to intestinal absorption.

Cholagogues and Choleretics↗
PubMed1995

Beta-hexosaminidase in bile and plasma from patients with cholestasis.

beta-Hexosaminidase (Hex) activity was determined in bile from 18 patients with cholestasis, six patients without cholestasis and in ten normal liver biopsies. The difference in the mean activities in bile from patients with and without cholestasis was not significant. Only about 0.5 promille of total liver Hex activity was lost per day via the bile flow. Gel chromatography showed that enzyme forms present in bile had higher molecular weights than the forms present in liver tissue, indicating that the biliary enzyme was not routed through the lysosomes before release into the bile. In 32 patients with cholestasis, plasma Hex was increased compared to controls, and correlated to bilirubin. The activity was significantly higher in patients with severe cholestasis than in patients with less severe forms of cholestasis, but no significant difference in Hex activity was observed between patients with benign or malignant biliary obstruction. No significant difference was noted between patients with cholestasis for less than 1 week compared to those whose illness had lasted more than 1.5 weeks. The impact of biliary obstruction on plasma Hex is further illustrated by the observation that decompression lowered plasma Hex as well as bilirubin and alkaline phosphatase.

Aged↗