[Intrahepatic cholestasis of pregnancy]

Intrahepatic cholestasis of pregnancy is a pregnancy specific hepatic disorder. It occurs mainly in the third trimester of pregnancy by pruritus and elevated serum levels of aminotransferases and total bile acid which completly regresses few days or weeks after delivery. Intrahepatic cholestasis of pregnancy is regarded as a benign disease with meaningful consequences to the mother but associated to increased perinatal risk with increased rates of preterm birth and perinatal mortality. The pathogenesis of disease is unclear yet but likely involves a genetic hypersensitivity to estrogen or progesteron metabolites. Treatment is focused on reducing symptoms in mother and to provide an adequate obstetric management in order to prevent fetal distress. Currently, only ursodeoxycholic acid treatment has been proven to be useful and safe and should be the first choice treatment

Valores de referencia de los ácidos biliares séricos en embarazadas del tercer trimestre / Reference values of the serum bile acids in pregnant women of the third trimester

La colestasis intrahepática del embarazo (ICP) se caracteriza por prurito y una colestasis bioquímica de leve a moderada severidad, de diagnóstico clínico dificultoso y níveles elevados de ácidos biliares (AB) séricos. La ICP aparece principalmente en el tercer trimestre y desaparece luego del parto, siendo recurrente en el 40-60 por ciento de los futuros embarazos. Esta enfermedad no acarrea consecuencias significativas para la madre, pero se asocia con riesgo elevado de distress fetal, parto prematuro y mortalidad perinatal. Objetivo: determinar el nivel de los AB séricos en una muestra de embarazadas normales y su uso potencial como valores de referencia para el diagnóstico diferencial de la colestasis del embarazo. Material y métodos: diseño observacional, prospectivo y longitudinal. El criterio de normalidad bioquímica se estableció por medio de la determinación de los siguientes metabolitos: fosfatasa alcalina, transaminasas glutámico-oxalacética y glutámico-pirúvica, gamma-glutamil transpeptidasa, colesterol total y bilirrubina total. Los AB se determinaron por método enzimático colorimétrico a 540 nm mediante la reacción del Azul de tetrazolio, randox, U.K., coeficiente de variación (C.V.): 1.2 por ciento. Resultados: los valores de referencia de los AB séricos en la población estudiada fueron de 1.0 - 6.1 micromol/l. Conclusiones: debido a que la fisiopatología de la ICP está aún sin resolver, las terapias han sido empíricas y las controversias sobre el tratamiento y seguimiento continúan en discusión, consideramos el establecimiento de los valores de referencia de los AB séricos para nuestro laboratorio como de gran utilidad y que los mismos constituyen un paso fundamental para el correcto manejo de las hepatopatías de la gestación.

Evaluation of serum total bile acids in the diagnosis of hepatocellular carcinoma

Fasting total serum bile acids [FSBA] concentrations were measured in 140 cases of chronic liver diseases including 50 patients with liver cirrhosis, 40 patients with chronic hepatitis and 50 patients with hepatocellular carcinoma [HCC]. FSBA concentrations were significantly higher in patients with HCC than those with chronic hepatitis and cirrhosis and both were significantly higher than the controls [p<0.0001]. FSBA concentrations were not correlated to the size of the tumor, the Child Pugh grades, the histopathologic grades and most of the liver function tests. Using the receiver operative characteristic [ROC] and the differential positive rate [DPR] analysis, 30 pmol/l was the optimal cut-off value that differentiates patients with HCC from those with cirrhosis. At this level, the sensitivity, the specificity and the diagnostic accuracy were 42%, 98% and 70% respectively. AFP was found to be significantly increased in patients with HCC than those with chronic hepatitis and cirrhosis. The best cut-off value of AFP was 100 ng/ml, at which the sensitivity, the speci-ficity and diagnostic accuracy were 52%, 96% and 74% respectively. The simultaneous determination of AFP and total bile acids raised the sensitivity of the test to 76%. The area under the ROC curve for AFP and total bile acids was 0.764 and 0.744 respectively, the difference is non-significant. In conclusion, both AFP and total bile acids are good markers for HCC and their simultaneous determination may improve the detection of HCC in cirrhotic patients negative for AFP

Determinaçäo sérica dos ácidos biliares na detecçäo da hepatopatia crônica e no seu estadiamento funcional / Serum determination of bile acids in the diagnosis of chronic liver disease and in the functional staging

Os valores séricos dos ácidos biliares totais foram dosados através de método enzimático-colorimétrico em 15 indivíduos dispépticos, sem doenças hepática (grupo controle) e em 52 portadores de hepatopatia crônica de etiologia alcoólica, subdivididos de acordo com a classificaçao funcional de Child-Pugh (Child A=17; B= 18 e C = 17) ou de acordo com o exame clínico em grupos compensado (n = 22) e descompensado (n = 30). A dosagem sérica dos ácidos biliares, particularmente as pós-prandiais, apresentaram elevado poder discriminativo na detecçao de hepatopatia crônica, separando o grupo controle de qualquer un dos grupos de etilistas portadores de hepatopatia crônica. Apresentaram também correlaçao significante com os testes bioquímicos mais diretamente relacionados à funçao hepatocelular, como albumina, bilirrubina total e atividade de protrombina, além da classificaçao de Child-Pugh numérica. No entanto, quando os pcientes cirróticos foram separados de acordo com a apresentaçao clínica, a dosagem plasmática dos ácidos biliares apresentou capacidade discriminativa inferior aos exames convencionais como a classificaçao de Child-Pugh numérica e o tempo de protrombina, demonstrando ter valor limitado na avaliaçao funcional e no acompanhamento evolutivo da hepatopatia crônica alcoólica.

Optimización del análisis de ácidos biliares séricos por método enzimático fluorométrico / Improvement of an enzymatic fluorometric assay for serum bile acids

Con el objeto de optimizar la determinación fluorométrica de los ácidos biliares séricos (ABS) en cuanto a selectividad y sensibilidad, se desarrolló una metodología de preparación de muestra y preconcentración utilizando columnas de extracción en fase sólida (SPE-C18). Previa desproteinización del suero con acetonitrilo frío, la fase orgánica evaporada y reconstituida con acetonitrilo: agua (3:70), se aplicó a una columna SPE-C18 y los ABS fueron eluidos con metanol. En el extractivo metanólico, evaporado a sequedad y reconstituido con metanol se dosaron los ABS por método enzimático fluorométrico empleando 3Ó-hidroxiesteroide deshidrogenasa, ß-NAD, diaforasa y resazurina. En la validación de la preparación de muestra se utilizó [24-14C] ácido glicocólico. La recuperación fue del 89,0 ñ 1,3 por ciento (SD), con DSR de 1,4 para n=9 (3 días). Se determinaron los ABS en sujetos controles, resultando un valor medio de 2,61 ñ 0,39 µM (SEM) (n=27). La metodología propuesta combina las siguientes ventajas: aumento de la selectividad del método enzimático, eliminación de interferencias y preconcentración de los ABS liberados, previamente, de la unión a proteínas plasmáticas

Pattern of serum bile acids in patients with hepatic fascioliasis

The study included 20 patients with established Fasciola infection and 10 normal healthy control subjects. Total serum bile acids and the individual bile acids; cholic acid [CA], chenodeoxycholic acid [CDCA] and deoxycholic acid [DCA] were estimated using reversed phase high performance liquid chromatography. Total serum bile acids, CA levels and their percentage from the total were significantly increased in thefasciola group than in the controls. There was also a significant decrease in the percentage of DCA from the total bile acids as well as its ratio to CA. This decrease might be due to the absence of DCA in some fasciola patients [55%] and to the significant increase in CA which favours more a cholestatic lesion in such patients. All the results of liver function tests were within the accepted normal limits. It could be concluded that, in cases of fascioliasis in the absence of abnormalities in the usual liver function tests especially in anicteric subjects, evaluation of total serum bile acids, CA, DCA levels and the ratio DCA/CA should be considered to demonstrate any minor abnormalities in hepatobiliary system

Comparison study between fasting total serum bile acid and post prandial bile acid in hepatic diseases: a preliminary study.

Fasting bile acid, two-hour post prandial bile acid and other liver function tests (Bili, AST, ALT, ALB, Glob, ALP) were measured in 22 normal and 28 liver diseased patients. In normal volunteers, the mean value of fasting total serum bile acid (FTBA) and postprandial serum bile acid (PTBA) were 3.08 mumole/L (S.D. 1.65) range 0.21-6.26 mumol/L, and 8.07 mumole/L (S.D. 2.99) range 4.06-15.65 mumole/L. Comparison between FTBA, PTBA and other liver function tests in various liver diseases from this study the PTBA was not statistically significant superior to FTBA. Therefore, it is not necessary to do the PTBA at this time until more data is available.

Serum bile acids and standard liver enzymes in hepatobiliary disorders

The study included 20 normal individuals as control group and 58 cases [13 cases with hepatitis, 17 cases with chronic cholycystitis, 14 cases with obstructive jaundice and 14 cases with hepatoma]. The mean value of serum levels of postprandial bile acids and standard liver enzymes for each diseased group showed statistically significant difference except in ALP, GGT and 5'N in chronic cholycystitis group when compared with the control group. The sensitivity and accuracy of serum postprandial bile acids were 100% and 97% in both hepatoma and obstructive jaundice groups. While in hepatitis were 100% and 96%, and as regard the cases of chronic cholycystitis were 23.5% and 62%, respectively

Clinical significance of serum bile acids determination in chronic liver disease and hepatocellular carcinoma

Fasting total serum bile acids [FSBA] concentrations were measured in 24 cases of chronic liver disease: Schistosomal hepatic fibrosis [SHF] or cirrhosis, 28 cases of hepatocellular carcinoma [HCC] and 11 normal control. FSBA were significantly higher in patients with HCC than those with chronic liver disease, and both were significant higher than the normal controls [p <0.01]. FSBA levels did not correlate with the severity of liver disease, the degree of esophageal varices or histologic grade of HCC. FSBA levels were comparable in schistosomal and cirrhotic patients, but were found significantly higher in patients with chronic active hepatitis [p=0.001]. FSBA also correlated significantly with the size of tumor in HCC [p=0.05]. This study shows that FSBA may have a predictive value both in chronic active hepatitis and HCC and therefore, may become useful tool in screening and planning the therapeutic approach to these hepatic diseases

Liver function and plasma bile salts in patients presenting with generalized pruritus

Studies on 100 patients presenting with generalized pruritus without primary skin disease showed that bile salt/acid concentration was raised in all these patients and there was a linear relationship between bile salt/acids and degree of pruritus. In all these patients, mean serum proteins and albumin were decreased to a significant level in all patients. Serum bilirubin and serum enzyme showed significant increase. Serum hepatitis B surface antigen [HBs Ag] was negative in all patients

Serum copper in intrahepatic cholestasis of pregnancy

La Colestasis intrahepática del embarazo está caracterizada por fluctuaciones clínicas y bioquímicas y por ello nuevos métodos de diagnóstico son necesarios. El objetivo de este estudio fue investigar niveles séricos de cobre y actividad cobre oxidasa en el curso de la colestasis intra hepática del embarazo (CIE). 28 pacientes con CIE y 25 embarazadas sanas fueron incluídas en el estudio. Estudios funcionales hepáticos de rutina, ácidos biliares en el suero en ayunas, niveles séricos de cobre y actividad cobre oxidada, fueron los estudios fundamentales efectuados. En la CIE los niveles séricos del cobre fueron significativamente más altos que en los controles (274 ñ 49 µg/dl vs 176 ñ 34µg/dl, p < ou = 0.001). La actividad cobre oxidasa llegó a un nivel de 78 ñ 15 µg/dl) en la CIE diferente a lo observado en las embarazadas sanas (64 ñ 8 mg/dl, p < 0.02). Contrariamente a las marcadas oscilaciones en los niveles séricos de ácidos biliares libres, los niveles séricos del cobre permanecieron elevados durante el seguimiento con pequeñas fluctuaciones y no se pudo demostrar correlación entre niveles séricos de ácidos biliares libres y de cobre (r; 0.17, NS). En el trabajo de parto se observó un aumento significativo de los niveles séricos del cobre tanto en las pacientes con CIE (de 251 ñ 50µg/dl a 297 ñ 55 µg/dl, p < 0,01) como en embarazadas normales (de 169 ñ 34 a 192 ñ 42 µg/dl, p < 0,01). Este incremento de los niveles séricos del cobre estuvo asociado con una elevación en pico de la actividad cobre oxidasa. Los niveles de cobre en suero y de actividad cobre oxidasa están elevados en la colestasis intrahepática del embarazo y pueden se considerados como importantes medios de diagnóstico. Los disturbios en el metabolismo del cobre observados en este estudio están de acuerdo con la hipótesis de que el embarazo normal está asociado con una discreta colestasis mientras que la CIE representa una forma de respuesta inapropiada

Efectos del ácido ursodeoxicólico en pacientes con colestasis gravídica / Effects of ursodeoxycholic acid in patients with cholestasis of pregnancy

In an open, pilot study, the efficancy and safety of ursodeoxycholic acid (UDCA) in the treatment of intrahepatic cholestasis of pregnancy was investigated. four patients received 1 g/ñday of UDCA during 20 days and another 2 patients received identical periods of treatment separated by a 14-day interval free of drug. Pruritus and serum levels of toal bile salts and glutamic-pyruvic transaminase improved significantly during treatment with UDCA. Although pruritus and the laboratory alterations had a relapse in the second week after UDCA was discontinued, they improved again in the patients who received a second treatment with UDCA. No adverse reactions were detected in the mothers or in their babies. All neuborns are thriving normally, in a follow-up lasted 3 to 6 months after delivery. It is concluded that UDCA appears to be safe when administered in late pregnancy; its primising efficacy in the treatment of intrahepatic cholestasis of pregnancy should now be confirmed in controlled clinical trials

Gall bladder functional changes and maternal serum bile acids in pruritis of pregnancy

Ultrasonographic measurement of the gallbladder volume was taken in 26 women with third-trimester normal pregnancies and in 28 third trimester pregnant women complaining of pruritis of pregnancy. Ultrasonic examinations were performed in the fasting state and 10, 20, 30, 45 and 60 minutes after ingestion of fatty meal. The total and direct bilirubin were assayed, and the fasting and two hours postprandial maternal serum bile acid [Cholyglycin] was estimated for all studied women. Gravidas with pruritis had significantly increased mean resting gallbladder volume [P<0.02] and ejection fraction [P<0.01] as compared to those means of control normal gravidas. The emptying time and residual volume showed non significant difference in the studied groups. Serum total and direct bilirubin levels were normal in the studied groups. There was significant increase in postprandial material serum bile acid [Cholyglycin] in gravidas with pruritis, as compared to their fasting mean [P<0.005] and to the postprandial mean of control normal gravidas [P<0.005]. The results indicated that in gravidas with pruritis, the gallbladder function and the enterohepatic circulation of bile acids were different from normal pregnancies. A new explanation for increased maternal serum bite acids is proposed

Serum unconjugated primary and secondary bile acids in patients with cholangiocarcinoma and hepatocellular carcinoma.

Serum unconjugated primary bile acids (cholic acid, chenodeoxycholic acid), secondary bile acids (lithocholic acid, deoxycholic acid), conjugated primary bile acids (glycocholic acid, glycohenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid) and total bile acids were measured in 25 and 75 male patients with cholangiocarcinoma and hepatocellular carcinoma respectively. Twenty-one healthy male volunteers served as controls. Other biochemical parameters, i.e. bilirubin, transaminases, albumin, globulin and cholesterol were also studied. Conjugated bile acids and total bile acids were elevated in both patient groups when compared with those of controls. The presence of unconjugated primary bile acids and secondary bile acids was noted in the patient groups, whereas, they were not detectable in controls. The appearance of these serum bile acids may be useful as a marker for early diagnosis of cholangiocarcinoma and hepatocellular carcinoma in people at-risk such as those who have chronic infection with Opisthorchis viverrini. Differentiation between the two types of tumor may be possible by using other parameters such as alpha-fetoprotein or other tumor markers newly discovered. An increase of the trihydroxy bile acids: dihydroxy bile acids and glycine conjugated bile acids: taurine conjugated bile acids ratios was shown in the patient groups. The latter may be due to the proportion of the increase of taurine conjugates being greater than the increase of glycine conjugates. The other biochemical parameters were significantly elevated in the patient groups except for albumin which was significantly decreased. The sensitivity of the tests for cholic acid, chenodeoxycholic acid, alkaline phosphatase and gamma glutamyl transferase was high.

Bile acid and cholinesterase activity as an early liver function tests for detection of organic solvent hepatotoxicity

Forty-six workers exposed to different types of organic solvents and fourteen workers far from exposure were included in this study. The exposed workers were classified into 3 groups according to the nature of the work and the type of solvent; group A [acetone, n-hexane-exposed workers], group B [toluene, xylene-exposed workers] and group C [trichloroethylene, isopropyl alcohol, methyl alcohol exposed workers]. Routine liver function tests appear normal. Serum bile acid and serum cholinesteracse were estimated in all workers. The results showed a significant increase in serum bile acid in all exposed groups compared with the non-exposed group. Serum cholinesterase activity was significantly lower in the exposed groups than the non-exposed group. From these results we can conclude that, serum bile acid and serum cholinesterase represent an early and sensitive tests for detection of organic solvent hepatotoxicity