Manuel C. Gonzalez

Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile

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 ICP. 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. RESULTS Plasma Se concentrations in non-pregnant women were higher than in the previous study: 1.43+/-0.34 micromol/l vs 0.85+/-0.13; p<0.001. In comparison to non-pregnant women, normal pregnancies near term had lower plasma levels of Se: 1.08+/-0.25 micromol/l; p<0.01, and Zn: 17.90+/-3.61 micromol/l vs 19.71+/-3.21; p<0.05, but higher plasma levels of Cu: 34.35+/-7.12 micromol/l vs 20.62+/-3.34; p<0.01. In normal pregnancies, plasma Se concentration was significantly higher in summer (1.34+/-0.19 micromol/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: 0.94+/-0.12 micromol/l, p<0.05, and Cu levels were significantly higher: 50.80+/-7.02 micromol/l, p<0.01. Cu plasma levels correlated with the biochemical severity of the disease. Zn did not change in ICP. 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.

Intrahepatic cholestasis of pregnancy in twin pregnancies

To clarify whether the increase in estrogen levels occurring during twin pregnancies (TP) is associated with a greater risk of developing intrahepatic cholestasis of pregnancy (ICP), we followed up 62 consecutive patients with TP and compared them with single pregnancies delivered in our hospital during 1 year. The prevalence of ICP was significantly higher in twin than in single pregnancies (20.9% versus 4.7%, respectively; P less than 0.001). Urinary estriol excretion was also significantly higher in twin compared to single pregnancies, although no quantitative differences were detected in TP with or without ICP. In multiparous patients with a proband TP affected by ICP, the disease recurred only in further TP, emphasizing the important role that estrogens seem to play in the pathogenesis of ICP. In contrast, in multiparous patients with a proband single pregnancy affected by ICP, the disease occurred in 70.5% of their other single pregnancies, suggesting the presence of a metabolic predisposition in these cases. However, in both groups of multiparous women a notable number of single pregnancies were not affected by the disease, supporting the postulate that the pathogenesis of ICP is multifactorial and that some as yet unidentified environmental factor needs to be present in order to develop the disease and also to modulate its expressivity.

Sulfobromophthalein Clearance Tests Before and After Ethinyl Estradiol Administration, in Women and Men with Familial History of Intrahepatic Cholestasis of Pregnancy

To test the hypothesis that intrahepatic cholestasis of pregnancy represent an abnormal reaction to estrogens in genetically predisposed individuals, the sulfobromophthalein disappearance curve from blood was compared before and after ethinyl estradiol administration (0.1 mg/day, during 6 days) in multiparous women with or without a past history of intrahepatic cholestasis of pregnancy, and in nulliparous women and men with or without a familial history of the disease. BSP concentration in blood, from 5 to 65 min after a single i.v. injection of the dye (5 mg/kg body wt), was fitted into biexponential curves using a computerized program. Ethinyl estradiol administration decreased the slope of the second component of the curve (k2) in most subjects and in both sexes. This effect was greater in multiparous women with a past history of intrahepatic cholestasis of pregnancy than in their controls. An exaggerated response to ethinyl estradiol was more frequently found in nulliparous women, and in men, with a familial history of the disease than in those without it. These observations suggest the presence of a constitutional abnormality in the metabolic interactions between estrogens and the liver, independent from pregnancy itself. This abnormality could be genetically transmitted by individuals from either sex, determining a predisposition to develop intrahepatic cholestasis of pregnancy in their female descendants.

Steatorrhea in patients with intrahepatic cholestasis of pregnancy

A prospective study was undertaken to evaluate fat malabsorption during intrahepatic cholestasis of pregnancy (ICP), a disease characterized by a mild cholestasis of short duration appearing in otherwise healthy young women. An abnormal fecal fat excretion (mean 15.8 g/24 h, range 6-31 g/24 h) was demonstrated in 10 of 12 patients with the icteric form of ICP and in 2 of 11 patients with pruritus gravidarum. The increased fecal fat excretion was generally asymptomatic, could be detected as early as 3 wk after the clinical onset of ICP, remained stable during the affected pregnancies, and returned to normal from 3 to 9 wk after delivery. Steatorrhea correlated with the severity of ICP, estimated by serum levels of bilirubin, total bile salts, and glutamic pyruvic transaminase. A significant fall in the maternal weight/height index was detected after the onset of ICP, being more intense in patients with steatorrhea than in those without it (to 92.6% +/- 3.0% of initial values versus 96.7% +/- 2.8%, respectively; p less than 0.05). A high risk of premature deliveries and fetal distress was demonstrated in these patients, also correlating with the severity of ICP. No direct relationship could be established between steatorrhea or maternal nutritional impairment and fetal prognosis.