Juan Carlos Glasinovic

Bile acids increase response and expression of human myometrial oxytocin receptor.

OBJECTIVE We tested the hypothesis that during intrahepatic cholestasis of pregnancy bile acids activate the myometrial oxytocin receptor pathway. STUDY DESIGN Myometrial sensitivity to oxytocin and oxytocin-receptor messenger RNA and protein level was investigated. The ability of cholic acid to mediate such changes was evaluated. RESULTS Cholestasis patients required lesser oxytocin to elicit four uterine contractions in 10 minutes (1.3+/-0.6 vs 3.6+/-0.8 U, P<.05, n=7) and had lower in vitro ED(50) (1.6 x 10(-10) mol/L vs 1.0 x 10(-8) mol/L, P<.05, n=7) than controls. The 24-hour incubation of control myometrial strips (n=7) with cholic acid (20 micromol/L) increased oxytocin sensitivity. Incubation of cultured myometrial cells (n=5) with cholic acid increased oxytocin-receptor expression (messenger RNA and protein). CONCLUSION We demonstrate that during intrahepatic cholestasis of pregnancy, an activation of the oxytocin receptor pathway occurs. This event seems to be the result of a cholic acid-mediated increase in oxytocin-receptor expression.

Intrahepatic cholestasis of pregnancy: an intriguing pregnancy-specific disorder.

Objective: To review animal and human data available regarding the etiology, maternal and fetal impact, and treatment of intrahepatic cholestasis of pregnancy (ICP). Methods: Pertinent studies on human and animal models of ICP were selected through a MEDLINE database search, focusing on etiology and clinical impact of the disease. Analytic and descriptive studies were included, and the data were analyzed looking for crude numbers. Results: Intrahepatic cholestasis of pregnancy is a pregnancy-specific disorder. Its prevalence is higher in Chile and Sweden compared with any other population. Its etiology is largely unknown, although endocrine, genetic, and environmental factors have been postulated as responsible for the appearance of the disease. Maternal effects of ICP are mild; however, there is a clear association between ICP and poor perinatal outcome, including a higher frequency of fetal distress, preterm labor and delivery, and unexplained fetal death. The treatment is mainly symptomatic. Recent data suggest that oral use of ursodeoxycholic acid improves maternal condition and might prevent the fetal complications of ICP. Conclusions: Intrahepatic cholestasis of pregnancy should be considered a high-risk condition, and careful fetal assessment and appropriate medical intervention might improve perinatal outcome.

Increased orocecal transit time in patients with nonalcoholic fatty liver disease.

Intestinal bacterial overgrowth (IBO) has been suggested to play a pathogenic role in patients with nonalcoholic fatty liver disease (NAFLD). Delayed intestinal transit may contribute to IBO development. Ten nondiabetic patients with NAFLD and abnormal liver enzymes were recruited. Ten healthy individuals, matched by sex, age, and body mass index, were used as controls. Orocecal transit time (OCTT) was measured by the lactulose breath test. Anti-endotoxin core antibodies (EndoCAb) were determined. The effect of oral norfloxacin (400 mg BID during 2 weeks) on liver enzymes, lactulose breath test, and EndoCAb was also studied. NAFLD patients had higher basal breathed H2 and prolonged OCTT compared to controls (127 ± 61 vs. 57 ± 23 min, respectively; P = 0.0037). EndoCAb titers were similar in NAFLD patients and controls. Norfloxacin administration had no effect on ALT levels, lactulose breath test, or EndoCAb titers in patients with NAFLD. The present data show evidence of deranged intestinal motility in nondiabetic patients with NAFLD and support the hypothesis that NAFLD could be linked to endotoxin-induced liver damage of intestinal origin.

PARTO PREMATURO ASOCIADO A COLESTASIA INTRAHEPATICA DEL EMBARAZO: ROL DEL ACIDOCOLICO EN LA MODULACION DE LA VIA OCITOCINA-RECEPTOR DE OT EN EL MIOMETRIO

Se ha reportado una asociacion entre CIE y distres fetal, muerte fetal in utero y sintomas de parto prematuro/parto prematuro. Con la hipotesis que en la CIE el aumento en los acidos biliares, en particular acido colico, activa la via ocitocina-receptor de ocitocina (OT-ROT) en el miometrio, generando un inicio prematuro del trabajo de parto, evaluamos la sensibilidad miometrial a OT in vitro e in vivo, y la expresion de mRNA en pacientes CIE y controles y la capacidad de acido colico para regular la activacion de la via OT-ROT. Las pacientes con CIE mostraron una alta sensibilidad a OT in vivo e in vitro comparado con controles. Al incubar segmentos/celulas en cultivo de miometrio con acido se observo una marcado aumento de la sensibilidad contractil para la OT y un aumento de la expresion celular del mRNA y los niveles de la proteina del ROT. La activacion de la via OT-ROT parece ser el resultado de un aumento de la sintesis/funcion de RsOT mediada por el acido colico. Esto resultados entregan las bases celulares/moleculares que podrian explicar la asociacion entre CIE y parto prematuro