intrahepatic cholestasis of pregnancy

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 μM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC...

Pregnancy is a particular period in womans life. It accompanies with plenty of adaptation changes include many on skin. Pathological morphofunctional changes form a group of pregnancy-specific dermatoses. The clinical case of bullous pemphigoid of pregnancy is presented in the article. The disease occurs during pregnancy or postpartum period. The incidence is estimated to be approximately 1 in 60,000 pregnancies. Clinically, PG is characterized by intense pruritus and polymorphic skin eruptions. Skin lesions develop including erythematous patches and plaques, followed by urticarial rash and blisters. Diagnosis of the disease is based on the features of the clinical picture, complex data of pathomorphological and immunological research methods, including direct or indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), immunohistochemical determination of a fragment of the complement component C4d and determination of serum antibodies to BP180. The most effective trea...

The traditional paradigm that prostaglandins (PGs) are of central importance in the initiation of labor has been challenged. A group of investigators has recently reported that the amniotic fluid concentrations of PGE2 and PGF2~ increase only late in the course of labor implying that 'the accumulation of prostaglandins in amniotic fluid is an after-effect of labor and not indicative of a role of these compounds in the initiation of human parturition'. The present study was conducted to determine whether amniotic fluid prostaglandin concentrations increase prior to the onset of human labor, the central question in this controversy. Three amniocenteses were performed in 17 women with intrahepatic cholestasis of pregnancy -the first two prior to the onset of labor and the third during early spontaneous labor. PGE~ and PGF2~ were measured with sensitive and specific radioimmunoassays. Amniotic fluid concentrations of PGE 2 and PGF2~ increased prior to the onset of spontaneous labor. An additional increase in the concentrations of PGE2 and PGF2~ was found in samples obtained in early labor. We conclude that an increase in prostaglandin bioavailability precedes the onset of spontaneous human parturition.

To determine whether estrogen production and excretion are impaired in gravidas with intrahepatic cholestasis. Methods: Plasma and urine samples were collected from 13 women from the United States and Chile at 35-38 weeks' gestation with mild (n ‫؍‬ ‫؍‬ ‫؍‬ 9) or severe (n ‫؍‬ ‫؍‬ ‫؍‬ 4) intrahepatic cholestasis of pregnancy. Urinary and plasma steroid levels from women with cholestasis were compared with levels from 27 normal pregnant women within the same gestational age range. Urinary concentrations of dehydroepiandrosterone (DHEA), estrone (E1), estradiol (E2), estriol (E3), estetrol, progesterone, and 16-hydroxy-pregnenolone were measured by gas chromatography mass spectrometry, and plasma concentrations of DHEA sulfate, progesterone, unconjugated E1, unconjugated E2, unconjugated E3, sulfated E3 derivatives, glucuronidated E3 derivatives, and total E3 were measured by radioimmunoassay. Results: Compared with normal pregnant women, women with cholestasis had significantly lower plasma levels of estrogens and DHEA sulfate, the precursor to placental estrogen production synthesized by the fetal adrenal gland (Hotelling-Lawley trace ‫؍‬ ‫؍‬ ‫؍‬ 0.81; F 4,19 ‫؍‬ ‫؍‬ ‫؍‬ 3.9; P ‫؍‬ ‫؍‬ ‫؍‬ .02). The mean plasma DHEA sulfate, unconjugated E2, unconjugated E3, and total E3 concentrations were 0.271, 10.21, 9.80, and 99.53 ng/mL, respectively, in women with cholestasis compared with 0.802, 18.98, 16.28, and 145.07 ng/mL for controls. Conclusion: Fetal adrenal production of DHEA sulfate, and in response, downstream placental production of estrogens, was compromised by intrahepatic cholestasis of preg

Background: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach.

Background: To determine the prevalence and outcomes of intrahepatic cholestasis of pregnancy. Methods: A review comparing intrahepatic cholestasis of pregnancy pregnancies to all other pregnancies in three tertiary care Australian hospitals over a 36-month period. Results: There were 43,876 pregnancies. The prevalence of intrahepatic cholestasis of pregnancies (n ¼ 319) was 0.7%. There were differences between intrahepatic cholestasis of pregnancy and non-intrahepatic cholestasis of pregnancy mothers including higher prevalence of South Asian (22.6% versus 3.1%, p < 0.001), Indigenous Australian (3.8% versus 1.8%, p < 0.05), and Asian ethnicity (8.4% versus 5.7%, p < 0.05), mothers with a body mass index >35 kg/m 2 (10.6% versus 5.5%, p < 0.001), those with diabetes mellitus (25.7% versus 9.8%, p < 0.001), and those with twin births (8.7% versus 2.2%, p < 0.001). The primary clinical outcomes of intrahepatic cholestasis of pregnancy included a median gestational age at delivery of 36.4 (SE 0.09) weeks compared to 38.6 (SE 0.01) weeks (p < 0.001), a lower birth weight (3.12 (SE 0.03) versus 3.31 kg (SE 0.03), p < 0.001), and an increase in special care nursery admissions (44.5% versus 15.3%, p < 0.001). Conclusion: Treated intrahepatic cholestasis of pregnancy in the population described here had similar mortality outcomes although increased special care nursery admission as compared to the general population.

CHILDREN IN THE PEDIATRIC INTENSIVE CARE UNIT (PICU) may suffer secondary complications related either to the disease process itself, treatment regimens and drug therapy, or opportunistic infections. Several factors may be responsible for the development of cholestasis and subsequent hepatic dysfunction, including hypoxia from hypoxemia or hypoperfusion, direct or metastatic infiltration of the liver, pharmacologic agents (including chemotherapeutic agents), and opportunistic infections that directly invade the liver or induce inflammatory changes resulting in hepatitis and/or cholestasis. Additionally, various factors may interfere with the ability to provide adequate enteral nutrition in the PICU patient, requiring the use of parenteral nutrition for varying periods of time until adequate enteral intake is tolerated. Parenteral nutrition and the lack of enteral feeding may cause or further aggravate cholestasis. The effects of one or a combination of these conditions can result in either intrahepatic or extrahepatic cholestasis. Patients with cholestatic liver disease may develop hepatotoxic injury from endogenous bile acids, resulting in progressive hepatic damage, hepatic failure, and, ultimately, death. 1,2 Treatment of these patients with orally administered exogenous bile acids, such as ursodeoxycholic acid (UDCA), can decrease intrahepatic cholestasis and potentially

CHILDREN IN THE PEDIATRIC INTENSIVE CARE UNIT (PICU) may suffer secondary complications related either to the disease process itself, treatment regimens and drug therapy, or opportunistic infections. Several factors may be responsible for the development of cholestasis and subsequent hepatic dysfunction, including hypoxia from hypoxemia or hypoperfusion, direct or metastatic infiltration of the liver, pharmacologic agents (including chemotherapeutic agents), and opportunistic infections that directly invade the liver or induce inflammatory changes resulting in hepatitis and/or cholestasis. Additionally, various factors may interfere with the ability to provide adequate enteral nutrition in the PICU patient, requiring the use of parenteral nutrition for varying periods of time until adequate enteral intake is tolerated. Parenteral nutrition and the lack of enteral feeding may cause or further aggravate cholestasis. The effects of one or a combination of these conditions can result in either intrahepatic or extrahepatic cholestasis. Patients with cholestatic liver disease may develop hepatotoxic injury from endogenous bile acids, resulting in progressive hepatic damage, hepatic failure, and, ultimately, death. 1,2 Treatment of these patients with orally administered exogenous bile acids, such as ursodeoxycholic acid (UDCA), can decrease intrahepatic cholestasis and potentially

Background: The diagnosis and treatment of intrahepatic cholestasis of pregnancy (ICP) has important implications on fetal health. The biochemical parameter commonly used in the diagnosis of ICP is the determination of the concentration of total serum bile acids (TSBA). However, bile acid profile, especially lithocholic acid (LCA) analysis is a more sensitive and specific biomarker for differential diagnosis of this pathology and also could be an alternative to evaluate the efficiency of ursodeoxycholic acid (UDCA) for ICP treatment. Methods: Serum bile acid (SBA) profiles including LCA determination, were studied in 28 ICP patients using a capillary electrophoresis method. The effects of UDCA treatment on bile acid profile, were analysed in 23 out of 28 ICP patients and the two samples obtained before and 15 days after treatment were compared. Two samples taken as controls were also obtained from each of five patients without therapy. Results: A dramatic decrease in LCA concentrations and maintenance of TSBA concentrations were found in all patients after UDCA therapy, whereas SBA profiles together with LCA values did not change in patients without therapy. Conclusion: We propose LCA as an alternative biomarker and a more sensitive parameter than TSBA to evaluate the effectiveness of UDCA treatment, at least in ICP patients from Argentina.

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Summary: In clinical practice, hepatologists frequently encounter patients with abdominal swelling. Typically, this is caused by the accumulation of fluid in the abdomen, most frequently (&gt; 80%) as a manifestation of decompensated cirrhosis. Still, there are other, extrahepatic diseases, occurring with abdominal swelling. Sometimes it’s the giant ovarian cysts, and the process of diagnosis can be difficult. Instrumental non-invasive examination methods are not always sufficiently informative, and surgical methods may be needed (laparoscopy, laparotomy). The article presents a clinical case of a patient with abdominal swelling caused by a huge ovarian cyst with a breakthrough content in the abdominal cavity. The combined pathology, controversial clinical data have made the process of diagnosis quite difficult, and the final diagnosis was made only at laparotomy.Резюме: В клинической практике врача-гепатолога достаточно часто встречаются больные с патологическим увеличением объема ...

Ultrasonic measurement of the gallbladder volume was taken in 8 nonpregnant, healthy women, in 7 women with normal pregnancies and in 7 women whose pregnancies were complicated by intrahepatic cholestasis of pregnancy, in the fasting state and 30, 60, 120 and 180 min after a test meal. At the same time the serum concentrations of cholic acid and chenodeoxycholic acid were measured. The fasting and ejection vohnnes of the gallbladder in cholestasis of pregnancy were greater than in normal pregnancy. The fasting volume of the gallbladder was greater, but the ejection volume smaller in normal pregnancy than in nonpregnant women. No difference in the ultrasonic appearence of the intra-and extrahepatic bile ducts was found between the groups. Serum bile acids were increased in cholestasis of pregnancy and did not display any decreasing tendency after the postprandial rise during the following 3 h. The results indicate that in cholestasis of pregnancy the gallbladder function and the enterohepatic circulation of bile acids are different from normal pregnancy. This may be associated with the great tendency to gallstones in these women. The large size of the gallbladder in cholestasis of pregnancy has differential diagnostic importance in the ultrasonic evaluation of a pregnant woman with liver disease..

SummaryTwo primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), and one secondary bile acid, deoxycholic acid (DCA), were measured by radioimmuno‐assay in pregnancy serum from 30 healthy women, 49 women with itching and 45 with intrahepatic cholestasis of pregnancy. All subjects were studied serially from between 16 and 20 weeks gestation until 35–60 days post partum. In healthy pregnant women, serum CA and DCA levels did not change significantly at any time. The mean CDCA level rose significantly towards term. In women with intrahepatic cholestasis, serum levels of CA and CDCA were increased ten‐ and five‐fold, respectively, at the time of appearance of clinical Symptoms and the CA/CDCA ratio rose from l/l to 2/1; there was also a moderate increase in the serum concentration of DCA. In 4 of 8 women studied prospectively an increase in serum bile acid levels preceded the appearance of Symptoms or other laboratory evidence of intrahepatic cholestasis. Nine of the wo...

Objetivo: identificar la expresividad clínica, bioquímica y los result ados perinatales en pacientes con colestasis intrahepática del embarazo. Método: estudio observacional descriptivo prospectivo, de marzo de 2012 a febrero de 2014 en el Hospital Vladimir Ilich Lenin, de Holguín, Cuba. De 68 pacientes ingresadas con sospec ha de afección hepatobiliar, 43 con colestasis del embarazo clasificaron bajo criterios de selección muestral. Los datos procedieron del interrogatorio, examen físico e historias clínicas. Se emplearon los estadígrafos U de Mann-Whitney y Test de Fisher. La clínica se especificó como de mayor o menor severidad y el desenlace perinatal, favorable o desfavorable. Resultados: 58,1% fueron recién nacidos pretérmino; 25,6% con bajo peso al nacer y 23,3% con bajo Apgar. La alaninoaminotransferasa y aspartatoaminotransferasa fueron los analitos con mayor aumento promedio, con 3,2 y 2,2 veces por encima del límite superior normal, respectivamente. Las cifras de alaninoaminotransferasa, aspartatoaminotransferasa, la bilirrubina y el tiempo de protrombina fueron significativamente mayores en el grupo con mayor severidad del cuadro clínico para un 37,2% de la muestra de bilirrubina y triglicéridos, en el grupo con desenlace perinatal desfavorable en un 74,4%. Se produjo una asociación significativa (p = 0,003) entre la severidad de cuadro clínico y el desenlace perinatal. Conclusiones: los resultados de este estudio abren las puertas a futuras investigaciones de diseño más riguroso, con vistas a identificar predictores clínicos y bioquímicos, de peor pronóstico fetal en nuestro medio.

Objetivo: identificar la expresividad clínica, bioquímica y los result ados perinatales en pacientes con colestasis intrahepática del embarazo. Método: estudio observacional descriptivo prospectivo, de marzo de 2012 a febrero de 2014 en el Hospital Vladimir Ilich Lenin, de Holguín, Cuba. De 68 pacientes ingresadas con sospec ha de afección hepatobiliar, 43 con colestasis del embarazo clasificaron bajo criterios de selección muestral. Los datos procedieron del interrogatorio, examen físico e historias clínicas. Se emplearon los estadígrafos U de Mann-Whitney y Test de Fisher. La clínica se especificó como de mayor o menor severidad y el desenlace perinatal, favorable o desfavorable. Resultados: 58,1% fueron recién nacidos pretérmino; 25,6% con bajo peso al nacer y 23,3% con bajo Apgar. La alaninoaminotransferasa y aspartatoaminotransferasa fueron los analitos con mayor aumento promedio, con 3,2 y 2,2 veces por encima del límite superior normal, respectivamente. Las cifras de alaninoaminotransferasa, aspartatoaminotransferasa, la bilirrubina y el tiempo de protrombina fueron significativamente mayores en el grupo con mayor severidad del cuadro clínico para un 37,2% de la muestra de bilirrubina y triglicéridos, en el grupo con desenlace perinatal desfavorable en un 74,4%. Se produjo una asociación significativa (p = 0,003) entre la severidad de cuadro clínico y el desenlace perinatal. Conclusiones: los resultados de este estudio abren las puertas a futuras investigaciones de diseño más riguroso, con vistas a identificar predictores clínicos y bioquímicos, de peor pronóstico fetal en nuestro medio.

Increased gastrointestinal permeability has been demonstrated in several liver diseases. It may facilitate the absorption of gut-derived endotoxin-stimulating Kupffer cells to release proinflammatory cytokines or other potentially hepatotoxic compounds. We examined gastrointestinal permeability, plasma levels of anti-lipopolysacharides (anti-LPS), and four proinflammatory cytokines in 20 patients with intrahepatic cholestasis of pregnancy (ICP) compared with 22 normal pregnant and 29 non-pregnant women. Urinary excretion of sucrose and the urinary lactulose/mannitol (L/M) ratio after a standard oral load were used to assess gastrointestinal permeability. Anti-LPS (IgA, IgM, and IgG) were measured in peripheral blood by Human EndoCAb test kit; TNF-␣, IL-1␤, IL-6, and IL-10 by Quantikine HS human immunoassays. Sucrose urinary excretion was similar in the three groups, indicating normal gastric permeability. The urinary L/M ratio was significantly higher in ICP than in the other groups [median (interquartile range): 0.018% (0.011-0.023) in ICP, 0.012% (0.009-0.016) in normal pregnancies, and 0.009% (0.008-0.012) in non-pregnant women, P < .01]. No significant differences were found in anti-LPS or cytokines plasma levels except slightly higher levels of IL-6 in ICP patients than in non-pregnant women (P < .05). Four of five women with abnormal urinary L/M ratio during ICP continued to show abnormalities in tests up to 2 years after delivery. In conclusion, an increased intestinal permeability was detected in ICP patients during and after pregnancy. A "leaky gut" may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts.

A 26-year-old gravida 3 para 1+1 was referred for antenatal care. In her last pregnancy she had a early spontaneous preterm delivery at 32 weeks and 2 days complicated by intra hepatic cholestasis of pregnancy. She had a strong family history of ischemic heart and combined hyperlipidaemia. In view of her past obstetric history a baseline liver function test and fasting bile acid assay was carried out. Upto 21 week her Bile acids were normal but at 22 weeks her fasting bile acid assay increased to the upper limit of normal (9 µmol/L). Ursodeoxycholic acid was started from 28 weeks gestation on a dosage of 500 mg b.i.d., which was subsequently increased to 500 mg t.d.s. at 32 weeks. At 34 weeks she gave a history of occasional right upper quadrant abdominal pain and her biochemistry revealed raised serum aspartate transaminase ,alanine transaminase, fasting serum triglyceride and cholesterol levels 58 IU,79 IU/L,18.37 mmol/L and 25.7 mmol/L respectively. The triglyceride level was too high to calculate the low density lipoprotein cholesterol. A diagnosis of severe intrahepatic cholestasis of pregnancy in a patient with background familial combined hyperlipidaemia was made. Ultrasound abdomen and cardiotocography was normal. She had normal delivery. In cases of early onset cholestasis of pregnancy we suggest that lipid profiles are checked in these patients to rule out hyperlipidaemia and its attendant short term and long-term risks. More research will be required to ascertain if there is a link between these 2 disorders.

Background/Aims and Methods: The etiology of intrahepatic cholestasis of pregnancy (ICP) is unknown. We have performed comprehensive chromatographic and mass spectrometric analyses of progesterone metabolites and bile acids in serum and urine of six patients in order to characterize changes that might be of importance for the development of the disease. Results: Conjugated bile acids were increased in serum and urine of patients with ICP while the levels of unconjugated bile acids were similar in healthy pregnancies and ICI? Unconjugated and conjugated 7a,l2a-dihydroxy-3-oxo-4-cholenoic acid was excreted in urine both in healthy pregnancies and in ICP, possibly indicating a rate limitation of 3-oxo-d4-steroid 5/l-reductase in pregnancy. The serum levels and urinary excretion of total sulfated progesterone metabolites were increased in ICP while the glucuronides were unchanged or low. Confirming previous results, the fraction of metabolites with 3a-hydroxy-So(H)

Background/Aims: Low blood Se levels have been previously shown in normal pregnancies (third trimester) and significantly lower levels in patients with intrahepatic cholestasis of pregnancy (ICP), in Finland and in Chile, suggesting that a low or marginal dietary availability of Se may contribute to the pathogenesis of this disease. The aim of this study was to investigate whether a temporal change in plasma concentration of Se, and seasonal fluctuations in plasma concentrations of Se, Zn and Cu, could coincide with changes in the prevalence of ICE Methods: A cross-sectional cohort study was done including 21 ICP patients, 98 women in the third trimester of a normal pregnancy, 29 non-pregnant women, and also 13 individuals (seven non-pregnant women and six men) who had been studied 9 years before. Plasma Se, Zn and Cu were measured by atomic spectroscopy. Plasma Se levels in the present study were compared to the results obtained 5 to 7 years before, employing identical methodology in similar population samples. parison to non-pregnant women, normal pregnancies near term had lower plasma levels of Se: 1.08kO.25 pmolll; ~~0.01, and Zn: 17.90k3.61 pmolll vs 19.7123.21; p<O.O5, but higher plasma levels of Cu: 34.3527.12 pmolll vs 20.62k3.34;p<O.O1. In normal pregnancies, plasma Se concentration was significantly higher in summer (1.34kO.19 pmol/l) than in the other seasons, while Zn and Cu diminished. Similar to previous studies, ICP patients had significantly lower Se plasma levels than normal pregnancies: 0.9420.12 pmol/l, ~~0.05, and Cu levels were significantly higher: 50.8Ok7.02 pmol/l, pcO.01. Cu plasma levels correlated with the biochemical severity of the disease. Zn did not change in ICI? Conclusions: The present study shows that the decrease in the prevalence of ICP in Chile during the last decade coincides with an increase in plasma Se levels. Its lower incidence during summer coincides with a higher plasma Se concentration in summer than in other seasons, as observed in normal pregnancies.

Background/Aims and Methods: The mechanism(s) behind the effects of ursodeoxycholic acid on serum steroid sulphate profiles in patients with intrahepatic cholestasis of pregnancy is not clear. Conjugated progesterone metabolites and bile acids have therefore been analysed in serum and mine of patients with intrahepatic cholestasis of pregnancy before and during treatment with ursodeoxycholic acid using chromatographic and mass spectrometric methods. Results: The concentration of glycine-/taurine-conjugated bile acids decreased from 8.923 pmol/I (mean* SEM) before treatment to 1.8&0.6/rmol/l during treatment with ursodeoxycholic acid. The total bile acid excretion in urine decreased from 56&14 to 32k5.6 mol/g creatinine. The proportion of cholic acid in serum and urine, and of l/l-, 2p-and 6a-hydroxylated cholic acids in urine decreased markedly during ursodeoxycholic acid while the percentages of 3a,l2a-dihydroxy-3-oxo+cholenoic acid and chenodeoxycholic acid were unchanged. The levels in serum and excretion in urine of sulphated steroids decreased during ursodeoxycholic acid, by 499% for disulphates and 33-35% for monosulphates. The ratios of 3a-to 3/lhydroxysteroid disulphates were lowered by ursodeoxycholic acid from 1.1 (mean) to 0.68 in serum, and from 1.2 to 0.70 in urine. The corresponding ratios for monosulphates before and during ursodeoxycholic acid were 6.9 and 4.5, respectively, in serum, and 21 and 5.2, respectively, in urine. The major monosulphates in T" LEVELS and patterns of conjugated bile acids and steroids in serum and urine are markedly dif

Increased gastrointestinal permeability has been demonstrated in several liver diseases. It may facilitate the absorption of gut-derived endotoxin-stimulating Kupffer cells to release proinflammatory cytokines or other potentially hepatotoxic compounds. We examined gastrointestinal permeability, plasma levels of anti-lipopolysacharides (anti-LPS), and four proinflammatory cytokines in 20 patients with intrahepatic cholestasis of pregnancy (ICP) compared with 22 normal pregnant and 29 non-pregnant women. Urinary excretion of sucrose and the urinary lactulose/mannitol (L/M) ratio after a standard oral load were used to assess gastrointestinal permeability. Anti-LPS (IgA, IgM, and IgG) were measured in peripheral blood by Human EndoCAb test kit; TNF-␣, IL-1␤, IL-6, and IL-10 by Quantikine HS human immunoassays. Sucrose urinary excretion was similar in the three groups, indicating normal gastric permeability. The urinary L/M ratio was significantly higher in ICP than in the other groups [median (interquartile range): 0.018% (0.011-0.023) in ICP, 0.012% (0.009-0.016) in normal pregnancies, and 0.009% (0.008-0.012) in non-pregnant women, P < .01]. No significant differences were found in anti-LPS or cytokines plasma levels except slightly higher levels of IL-6 in ICP patients than in non-pregnant women (P < .05). Four of five women with abnormal urinary L/M ratio during ICP continued to show abnormalities in tests up to 2 years after delivery. In conclusion, an increased intestinal permeability was detected in ICP patients during and after pregnancy. A "leaky gut" may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts.

We have studied the correlation between the ethnic structure and the prevalence of single gene defects in Chile. At present the Chilean population is approximately 64% white and 35% Amerindian with traces of other admixture. Fewer than 4% of the Chilean population are foreign born. Investigations indicate that all severe diseases and many others without impaired reproduction have mutation rates within the range ofthe white population. Classical ethnic diseases are very rare. Autosomal recessive disorders have a wide range of variability: cystic fibrosis has a low incidence and PKU has a similar incidence to English rates. Only 30% of the inborn errors of metabolism have been described in Chilean medical publications. In addition, no Chilean haemoglobin or haptoglobin variants have been described. Some rare inherited diseases in Chilean human isolates have been described, including achromatopsia, chondrocalcinosis, and Creutzfeldt-Jakob disease. The prevalence of intrahepatic cholestasis of pregnancy and supernumerary nipples is the highest in the world and they are associated with aboriginal origin. Single gene defects in Chile are probably shaped by factors related to its ethnic population structure. These local rare single gene defects may be good markers of population admixture for genetic epidemiological studies.

Background/Aims: Low blood Se levels have been previously shown in normal pregnancies (third trimester) and significantly lower levels in patients with intrahepatic cholestasis of pregnancy (ICP), in Finland and in Chile, suggesting that a low or marginal dietary availability of Se may contribute to the pathogenesis of this disease. The aim of this study was to investigate whether a temporal change in plasma concentration of Se, and seasonal fluctuations in plasma concentrations of Se, Zn and Cu, could coincide with changes in the prevalence of ICE Methods: A cross-sectional cohort study was done including 21 ICP patients, 98 women in the third trimester of a normal pregnancy, 29 non-pregnant women, and also 13 individuals (seven non-pregnant women and six men) who had been studied 9 years before. Plasma Se, Zn and Cu were measured by atomic spectroscopy. Plasma Se levels in the present study were compared to the results obtained 5 to 7 years before, employing identical methodology in similar population samples. parison to non-pregnant women, normal pregnancies near term had lower plasma levels of Se: 1.08kO.25 pmolll; ~~0.01, and Zn: 17.90k3.61 pmolll vs 19.7123.21; p<O.O5, but higher plasma levels of Cu: 34.3527.12 pmolll vs 20.62k3.34;p<O.O1. In normal pregnancies, plasma Se concentration was significantly higher in summer (1.34kO.19 pmol/l) than in the other seasons, while Zn and Cu diminished. Similar to previous studies, ICP patients had significantly lower Se plasma levels than normal pregnancies: 0.9420.12 pmol/l, ~~0.05, and Cu levels were significantly higher: 50.8Ok7.02 pmol/l, pcO.01. Cu plasma levels correlated with the biochemical severity of the disease. Zn did not change in ICI? Conclusions: The present study shows that the decrease in the prevalence of ICP in Chile during the last decade coincides with an increase in plasma Se levels. Its lower incidence during summer coincides with a higher plasma Se concentration in summer than in other seasons, as observed in normal pregnancies.

Increased gastrointestinal permeability has been demonstrated in several liver diseases. It may facilitate the absorption of gut-derived endotoxin-stimulating Kupffer cells to release proinflammatory cytokines or other potentially hepatotoxic compounds. We examined gastrointestinal permeability, plasma levels of anti-lipopolysacharides (anti-LPS), and four proinflammatory cytokines in 20 patients with intrahepatic cholestasis of pregnancy (ICP) compared with 22 normal pregnant and 29 non-pregnant women. Urinary excretion of sucrose and the urinary lactulose/mannitol (L/M) ratio after a standard oral load were used to assess gastrointestinal permeability. Anti-LPS (IgA, IgM, and IgG) were measured in peripheral blood by Human EndoCAb test kit; TNF-␣, IL-1␤, IL-6, and IL-10 by Quantikine HS human immunoassays. Sucrose urinary excretion was similar in the three groups, indicating normal gastric permeability. The urinary L/M ratio was significantly higher in ICP than in the other groups [median (interquartile range): 0.018% (0.011-0.023) in ICP, 0.012% (0.009-0.016) in normal pregnancies, and 0.009% (0.008-0.012) in non-pregnant women, P < .01]. No significant differences were found in anti-LPS or cytokines plasma levels except slightly higher levels of IL-6 in ICP patients than in non-pregnant women (P < .05). Four of five women with abnormal urinary L/M ratio during ICP continued to show abnormalities in tests up to 2 years after delivery. In conclusion, an increased intestinal permeability was detected in ICP patients during and after pregnancy. A "leaky gut" may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts.

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.

Background/Aims: We hypothesized that common genetic variation at ABCC2 influences ICP susceptibility. Hence we studied the association of single nucleotide polymorphisms (SNPs) of promoter, coding and non-coding regions of ABCC2 and intrahepatic cholestasis of pregnancy (ICP). Methods: 70 ICP patients and 112 healthy pregnant women in the third trimester of their pregnancies were included in a cross sectional study. Four tag SNPs (rs717620 A/G; rs2756105 C/T; rs2002042 C/T; rs3740066 A/G) encompassing 70 kb in chr.10 and representing 46 polymorphic sites (r 2 > 0.8) were genotyped. Besides, 2 additional SNPs (rs17222723 A/T and rs8187710 G/A) were included. Results: In univariate analysis, rs2002042 and rs3740066 were significantly associated with ICP (p < 0.04 and 0.01, respectively) but after multiple testing correction, only rs3740066 remained significantly associated with disease status (p < 0.03). We also observed a positive association between the rs3740066 and ALT, AST, alkaline phosphatase and total and conjugated bilirubin concentrations. Consistent with the analysis of individual markers, we observed that haplotype frequency of the ABCC2 gene in ICP patients significantly differed from controls (p < 0.03). Conclusions: We found an association between the rs3740066 in exon 28 of ABCC2 gene and ICP. The risk of disease for homozygous AA carriers is 4-fold higher (OR 4.

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 μM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC...

Diagnosis of intrahepatic cholestasis of pregnancy (ICP) is often decided upon with typical pruritus supported by elevated serum bile acid levels. However, there is confusion regarding the absolute reference range for serum bile acid. To confirm the utility of Placental Strain Ratio (PSR) measurement as a marker for the diagnosis of ICP and to reveal the extent to which it is correlated with serum bile acid concentration. A case-control study was conducted. The case group included 29 patients who were admitted to our hospital in the second or third trimester of pregnancy with typical itching and were clinically diagnosed with ICP with >10 mmol/L serum bile acid. The first 45 pregnant women were assigned to a control group. Real-time tissue elastography software was used for ultrasound assessment of all pregnant placentas. Software was used to estimate the SR values. Biochemical liver function parameters, hemograms, serum bile acid levels, and SR values were compared between these groups. PSR was found to predict the development of cholestasis with poor discrimination (area under the curve [AUC] = 0.524; 95% CI = 0.399-0.646). The optimal threshold value with the best sensitivity and specificity rates was calculated to be 0.46 PSR. ICP developed significantly more frequently in the low PSR group than in the high PSR group (60% vs 29.3%, P = .05, odds ratios [OR] = 0.276, 95% CI = 0.069-1.105). No correlation was found between the PSR and bile acid levels (rho = −0.029, P = .816). PSR values can support the diagnosis of ICP, predict serum bile acid levels, and can be used as soft markers.

INTRODUCTION: Sequencing and PCR analysis of the HBV core gene have previously identified point mutations and deletions clustering in a small central region (codons 80 to 113) of the core open reading frame in HBeAg positive patients with chronic active hepatitis, but not those with mild liver disease. We have therefore looked for mutations in the core gene in cases of fulminant hepatitis B. METHODS: Nested PCR was used to amplify the HBV precore/core region from sera of ten patients with fulminant hepatitis B, taken at the time of admission to hospital. All patients were negative for antibodies to hepatitis delta virus. Gel electrophoresis and direct sequencing of the amplified products were used to identify the presence or absence of deletions and other mutations in the core gene. RESULTS: There were no core deletions within the core genes from any of the HBV isolates. Sequencing revealed HBeAg minus variants in 4 cases and frequent nucleotide substitutions within the core gene, but few of these resulted in changes in amino acid sequence. In particular, only two of the sequenced genes had amino acid substitutions within the mid-core region. CONCLUSION: In contrast to previous studies in patients with chronic active hepatitis, few missense mutations and no deletions were identified within the mid-core region (codons 80 to 113), suggesting that such mutations are unlikely to be involved in the pathogenesis of fulminant hepatitis B.

The purpose of this study was to evaluate the fetal mechanical PR interval in intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: Fetal echocardiography was performed for women with ICP and control subjects. Clinical characteristics, total bile acids, and liver profile tests were compared between groups. RESULTS: Fourteen women with ICP and 7 control subjects were enrolled. Total bile acids (28.3 vs 6.2 mol/L; P Ͻ .001), aspartate aminotransferase (53 vs 23 IU/L; P ϭ .002), alanine aminotransferase (63 vs 19 IU/L; P ϭ .002), and the PR interval (124 vs 110 msec; P ϭ .006) were significantly higher in fetuses with ICP than in control fetuses. On multivariable linear regression analysis, only the presence of ICP was associated significantly with an increase in the PR interval (95% confidence interval, 4-24 msec; P ϭ .01). CONCLUSION: The fetal cardiac conduction system is altered in ICP. Further investigation is needed to determine whether fetal echocardiography can help to predict which fetuses are at risk for death that is associated with ICP.

Background/Aims: Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy. This study was designed to test the efficacy of ursodeoxycholic acid in maternal pruritus, the biochemical abnormalities and the outcome of pregnancy, in patients with intrahepatic cholestasis of pregnancy of early onset. Methods: Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases, detected before week 33 of pregnancy, were randomly assigned to receive ursodeoxycholic acid, 1 g per day orally, or an identical placebo, until delivery, in a double-blind study. A 3-week trial period was chosen to compare drug and placebo effects. The follow-up was extended for 3 months after delivery. Results: Twenty-four patients entered the trial; eight had deliveries before 2 weeks of treatment and one dropped out. The study was then completed in 15 patients: eight received ursodeoxycholic acid and seven placebo. No adverse effects were detected in the mothers or in their babies. After 3 weeks of treatment, patients receiving ursodeoxycholic acid (mean daily dose 16 mg/kg body weight) had a significant improvement in pruritus (p<O.O2), in serum bilirubin I NTRAHEPATIC cholestasis of pregnancy (ICP) is a rare liver disorder of late pregnancy. Its main symptom is skin pruritus, usually coinciding with a rise in serum

The traditional paradigm that prostaglandins (PGs) are of central importance in the initiation of labor has been challenged. A group of investigators has recently reported that the amniotic fluid concentrations of PGE2 and PGF2~ increase only late in the course of labor implying that 'the accumulation of prostaglandins in amniotic fluid is an after-effect of labor and not indicative of a role of these compounds in the initiation of human parturition'. The present study was conducted to determine whether amniotic fluid prostaglandin concentrations increase prior to the onset of human labor, the central question in this controversy. Three amniocenteses were performed in 17 women with intrahepatic cholestasis of pregnancy-the first two prior to the onset of labor and the third during early spontaneous labor. PGE~ and PGF2~ were measured with sensitive and specific radioimmunoassays. Amniotic fluid concentrations of PGE 2 and PGF2~ increased prior to the onset of spontaneous labor. An additional increase in the concentrations of PGE2 and PGF2~ was found in samples obtained in early labor. We conclude that an increase in prostaglandin bioavailability precedes the onset of spontaneous human parturition.

Intrahepatic cholestasis of pregnancy (ICP) is a complication of pregnancy resulting in elevation of serum bile acid levels. ICP is often associated with underlying liver disease, including hepatitis C. Bile acids in relationship to the acute infection of hepatitis C virus have not yet been delineated in the literature. A 26-year-old gravida 4 para 2103 with dichorionic, diamniotic twin gestation and history of intravenous drug abuse developed ICP in the setting of acute hepatitis C infection. In addition to clinical symptoms of pruritus and right upper quadrant pain, she developed severe elevation in bile acids, 239 micromol/L, and transaminitis aspartate aminotransferase 1033 U/L, and alanine aminotransferase 448 U/L. She received ursodeoxycholic acid and antenatal testing was performed. Patient delivered vaginally at 33-week gestation following preterm rupture of membranes. Neonates were admitted to NICU and had uncomplicated neonatal courses. In the setting of ICP with significa...

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In this paper, the fractional order gradient method (FOGM) is extended to the solution of high-dimensional function optimization problems. A quasi fractional order gradient descent method (QFOGDM) is proposed and then introduce an adaptive stepsize into QFOGDM. The theoretic analysis for convergence of QFOGDM is be done by three theorems. The numerical experiments for solving 15 unconstrained optimization benchmarks are compared to show its' better performance. Meanwhile, the proposed algorithm is utilized to identify the parameters in the linear discrete deterministic systems and achieves a better convergence rate and accuracy.

CTG = cardiotocography; ICP = intrahepatic cholestasis of pregnancy; UDCA = ursodeoxycholic acid Intrahepatic cholestasis of pregnancy (ICP) usually presents in the third trimester and rarely before 25 weeks' gestation [1]. It is characterized by pruritus, mild jaundice [2], fat malabsorption and raised maternal liver enzymes and bile acids. The overall prevalence of the disease is estimated at 1/1000 to 1/10000 pregnancies [3]. Scandinavia (2%) and Chile (4%) have the highest prevalence [2, 4]. There is no uniform agreement on the criteria for diagnosing ICP. Knox and Olans [5] assert the role of elevated liver enzymes, whereas Palma et al. [6] emphasise that the most sensitive laboratory signs are the elevated total serum bile acids. Rioseco et al. suggest that the diagnosis can be made clinically based on altered laboratory results and typical symptoms [7].

SIBO-positive patients compared with SIBO-negative (p<0.01), while epigastric pain and nausea were significantly increased in H. pylori positive patients compared to negative (p<0.002). Conclusions: This study report for the first time a higher prevalence of H. pylori infection in FD patients, who also show an increased prevalence of SIBO, determining an increased expression of Fabry'-related GI symptoms. The impairment of the GI tract motility, typical of Fabry' disease patients, may create a favourable environment for both H. pylori gastric colonization and SIBO.

OBJECTIVE: Our goal was to compare the pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy managed expectantly with antepartum testing with those of other patients who were followed up with a similar testing scheme. STUDY DI~SI6N: Cases of intrahepatic cholestasis of pregnancy monitored with antepartum testing at our institution over a 7-year period were reviewed. Their pregnancy outcomes were compared with those of control patients followed up with the same testing scheme for a history of stillbirth. Both groups had at least weekly nonstress tests and amniotic fluid assessment until spontaneous labor or delivery for standard obstetric indications. RESI31.1"S: Seventy-nine patients were analyzed in each group. The two groups did not differ with respect to the mean gestational age at delivery (38.5 vs 38.8 weeks), birth weight (3216 vs 3277 gm) or incidence of preterm delivery (14% vs 7.6%). Abnormal antepartum testing prompting delivery was more common in the control group (25% vs 7.6%, p < 0.05). The risk of meconium passage was higher in the cholestasis group (44.3% vs 7.6%, p < 0.05). Two antepartum fetal deaths occurred in the cholestasis group at 36 to 37 weeks' gestation within 5 days of normal results of antepartum testing. Thick meconium and appropriate birth weight were noted in both infants. No gross anomalies were found in either infant. CONCLUSION: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcome not predicted by conventional fetal surveillance.

The concentrations in serum of sulfated metabolites of pro-Intrahepatic cholestasis of pregnancy (ICP) is charactergesterone are known to be elevated in patients with intraheized by skin pruritus appearing in late pregnancy, coinciding patic cholestasis of pregnancy (ICP). The profiles of these with a moderate or mild increase in serum bile acids (mainly metabolites and conjugated bile acids were analyzed in serum cholic acid), a mild rise in serum aminotransferases and bilifrom 11 patients with ICP before and during administration rubin, and a subclinical steatorrhea, all of them subsiding of ursodeoxycholic acid (UDCA) (8 patients) or placebo (3 soon after delivery. 1-4 Its main clinical consequences are the patients). The clinical condition of 7 of the patients given disturbed maternal status caused by pruritus and the risk of UDCA improved markedly, and 1 patient given placebo had stillbirths and premature deliveries. The pathogenesis of the a spontaneous remission of the disease. The total concentradisease and of its clinical consequences is still obscure, altion of conjugated bile acids in the 11 patients was 25 { 6 though a role of female sex hormones and/or their metabommol/L (mean { SEM) and decreased to 6.3 { 3.5 mmol/L lites is suggested by several studies. 5-8 While estrogens have in the 7 patients responding to treatment with UDCA. The received most attention as potential inducers of ICP, it is of level of 7a-hydroxy-4-cholesten-3-one was significantly lower interest that 10 of the 13 patients studied by Bacq et al. 4 had (7.2 { 2.2 ng/mL) in patients with ICP than in healthy pregbeen given daily doses of 0.2 to 1 g of progesterone shortly nancy (18 { 4.6 ng/mL) (P õ .05). The concentrations of 5abefore the development of ICP. pregnane-3a,20a-diol mono-and disulfates decreased by 52% The daily synthesis of progesterone in late pregnancy is { 7.9% and 68% { 5.5%, respectively, in the patients reapproximately 250 to 350 mg/d. 9 The hepatic metabolism of sponding to treatment. Similar decreases were observed for progesterone involves 5a and 5b reduction of the 4,5-double the mono-and disulfates of 5a-pregnane-3a,20a,21-triol and bond and reduction of the 3-and 20-oxo groups to yield a 5b-pregnane-3a,20a-diol. The disulfate of 5a-pregnanenumber of isomeric pregnanolones and pregnanediols. The 3b,20a-diol showed a smaller decrease, while glucuronidated 5b-isomers are mostly glucuronidated, while 5a-isomers are steroids were not affected. The 3a-/3b-hydroxysteroid ratio sulfated. 10-12 The monosulfates may be hydroxylated in the and di-/monosulfate ratio decreased significantly during 16 or 21 positions. 10,11 The sulfated pregnanolones, preg-UDCA. The magnitudes of the changes of bile acid and steroid nanediols and 5a-pregnane-3a,20a,21-triol are present in concentrations during UDCA were not correlated to each mmolar concentrations in plasma, and the concentrations inother. The results suggest that UDCA stimulates the biliary crease with time of gestation. 12 Women with ICP have markexcretion of steroids with a 3a-sulfoxy group and disulfates. edly elevated levels of many of these sulfates. 13-15 It is not This effect seems to be independent of the effect on bile acid clear whether this abnormality is primary or secondary to excretion, indicating the use of different transport proteins. the cholestasis. Sulfated and glucuronidated progesterone The possibility of an effect of UDCA on the formation of the metabolites are excreted in bile in late pregnancy, 16 and the steroid sulfates cannot be excluded. (HEPATOLOGY 1997; concentrations in bile, 17 as well as the excretion of steroids 26:1573-1579.) in feces, 18 are lower in ICP than in normal pregnancy. Oral administration of ursodeoxycholic acid (UDCA) to patients with ICP of early onset (before week 33 of pregnancy) results in an amelioration of pruritus and the correction of some serum liver tests. 19 A recent double-blind study comparing the effects of UDCA and a placebo in patients with ICP of Abbreviations: ICP, intrahepatic cholestasis of pregnancy; UDCA, ursodeoxycholic early onset has confirmed the beneficial effects of this bile acid.

The a,n gf this study ~1s tg ?? wlglte the prevalence of serum HBV. ND',. HCV and HIV mtkers in 135 intravanous drug-Addicts (1VDA) (127/B M/F mean age 2524 yrs). observed between 1986 and 1987. The tests wre done by ELl5A (cwrcial kits). The prevalence of HBV. NDV. NCV and HIV WIS 8111, 24.43. a31 and 0.8% respectively. In 91 gut of 135 IYDR. 51.5% were +ve for both NaV,HBC. 18.71 for HaV,"DV,HCV and 1.11 for HCV/HIV: isolated HBV. WV and "CV Infection was 5.5%. 2.21 and-12.11 respectively; a.aN wwe-ve for all markers. In ,a out of 28 HasAg +VC 1"DA 1 (5.6%) was superinfected by NDV. 6 (33.39) by NCV and 11 (61.1%) by both HDV/W. Ninety-two percent Of IVM with Delta infection were superinfected by HEY and the serum ALT was 97292 lU/L. In contrast. 1VDA HBsAg +"a superinfccttd by HCV had I sergn ALT significantly higher (249+125; pc 0.01). I" conclusion: IVDA ,n Portugal are a risk group for Ha'!, HDV and HCV but not for HIV; those HasAg +ve has 4 higher prevalence Of HCV than HDV; a lo*er ALT 4ctlvity in De;ta+HCV than in HVBIHCV wggests an inhibitory effect of !lCV on HDV.

Epomediol ameliorates pruritus in patients with intrahepatic cholestasis of pregnancy Hepatitis C virus, autoimmune liver disease and cryoglobulinaemic hepatitis Dr. Magrin and colleagues reported (J Hepatol, 1991; 13: 364-7) the association of hepatitis C virus (HCV) infection and autoimmune chronic active hepatitis (AI-CAH) in a group of fifteen Italian patients. On the basis of this association and the efficacy of s-interferon treatment, the Authors hypothesized the existence of a clinically and etiologically distinct subset of AI-CAH. Another study reports evidence of geographical hetero

Background Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Methods We have initiated an international multicentre randomised clinical trial to compare the clinical ef...