Inheritance of intrahepatic cholestasis of pregnancy in one kindred

We report three sisters with intrahepatic cholestasis of pregnancy (ICP) and the pedigree of the family, including six generations. ICP was observed in five successive generations; most of the patients also had cholelithiasis. The uniform expression, the complete penetrance of the trait and the direct parent-to-child transmission support the Mendelian dominant mode of inheritance. Determination of HLA A, B and C haplotype was made in five ICP patients, without any findings of HLA type common to everyone. X-linked inheritance cannot be excluded in this study.     

Genistein-induced changes in lipid metabolism of ovariectomized rats

The effect of the isoflavone, genistein, on the lipid metabolism of ovariectomized rats was studied. Three types of experiments were performed. In the first one, the rats were fed diets supplemented with 0.01 or 0.1% of genistein for 14 days. In the second and third experiments, the direct effect of genistein on the liver and fat tissue were measured respectively by means of liver perfusion or incubation of isolated adipocytes with the isoflavone. Genistein in food significantly decreased blood serum and muscle triglyceride concentrations and increased the level of free fatty acids in serum. Serum free cholesterol was diminished and liver cholesterol was enhanced after genistein ingestion. When genistein acted directly on the liver during perfusion, a smaller incorporation of 14C-glucose into lipids was observed, and in parallel a greater output of free fatty acids into the medium was noticed. These changes were accompanied by diminution of the liver triglyceride contents. Genistein, acting on the adipocytes strongly depressed both basal and insulin-induced lipid synthesis, when glucose was used as a substrate. The effect of the isoflavone alone on the lipolysis in the adipocytes was negligible. However, it intensified lipolysis induced by epinephrine. The results obtained let us conclude that genistein in food can reduce the fattening processes in ovariectomized rats. This effect of genistein may be attributed, at least in part, to its direct influence on lipid metabolism in the liver and adipose tissue.     

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis

Conversion of cholesterol into cholic acid in mammalian liver requires a 12alpha-hydroxylation step. Results have been presented suggesting that two different enzymes are involved in this hydroxylation with different activities towards the two steroids believed to be the physiological substrates for the enzyme, 7alpha-hydroxy-4-cholesten-3-one and 5beta-cholestane-3alpha,7alpha-diol. It is shown here that rabbit liver microsomes and partly purified sterol 12alpha-hydroxylase as well as COS cells transfected with a cDNA coding for this enzyme are able to catalyze 12alpha-hydroxylation of the two substrates at similar relative rates. Also 7alpha-hydroxycholesterol and 3alpha,7alpha-dihydroxy-5beta-cholestanoic acid are 12alpha-hydroxylated by the three systems. It is concluded that rabbit liver contains one major sterol 12alpha-hydroxylase with a broad substrate specificity.     

Diagnosis and therapy of blood coagulation disorders in intrahepatic cholestasis

The reduction of prothrombin level below 5% in a patient with intrahepatic cholestasis of pregnancy is reported. The necessity of controlling the Quick level or better factors II, VII, IX and X is discussed. A well-timed Vitamin K therapy in all cases with impaired secretion of bile during pregnancy is recommended.     

Fibrinolysis during pregnancy. The pre- and postpartal changes

Our previous research as well as data in literature (Yuasas, Ishizawa M.--1992) emphasised increased plasma fibrinolytic activity (PFA) in women during labor. Starting from these data we have tried to observe plasma fibrinolytic activity studied through euglobulin lysis time (ELT) in women during pregnancy and after delivery. We studied 25 healthy pregnant women aged between 18 and 30 years which were tested in the seventh month, during labour and at 48 hours after delivery. Blood samples were taken from the antecubital vein by venous puncture. The study showed an increased PFA (shortened ELT) only during labor; in the seventh month and at 48 hours after delivery ELT had almost the same values.     

The swine as a model for studying exercise-induced changes in lipid metabolism

The function of cytokines produced during Hymenolepis nana egg infection in mice in protective immunity against re-infection was examined. Treatment of mice with monoclonal antibody (MAb) against mouse interferon (IFN)-gamma caused suppression of protective immunity against H. nana re-infection when the MAb was injected intraperitoneally at a daily dose of 40.0 mg kg-1 during the effector phase of protective immunity. Although high levels of IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta were released into the intestinal tracts of the parasitised mice at challenge infection, there was almost no release of these cytokines in mice treated with the MAb. Daily administration of rolipram failed to suppress the protective immunity, even when 400 micrograms kg-1 of the agent was administered into mice during the effector phase of immunity. Treatment of mice with rolipram completely suppressed both TNF-alpha and IL-1 beta production in intestinal tracts, induced by H. nana challenge infection. However, endogenous IFN-gamma production in the intestine was scarcely affected by rolipram. These results strongly suggest that IFN-gamma is the most important (or essential) cytokine in protective immunity to H. nana re-infection, rather than TNF-alpha and IL-1 beta.     

Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy

The concentrations in serum of sulfated metabolites of progesterone are known to be elevated in patients with intrahepatic cholestasis of pregnancy (ICP). The profiles of these metabolites and conjugated bile acids were analyzed in serum from 11 patients with ICP before and during administration of ursodeoxycholic acid (UDCA) (8 patients) or placebo (3 patients). The clinical condition of 7 of the patients given UDCA improved markedly, and 1 patient given placebo had a spontaneous remission of the disease. The total concentration of conjugated bile acids in the 11 patients was 25 +/- 6 micromol/L (mean +/- SEM) and decreased to 6.3 +/- 3.5 micromol/L in the 7 patients responding to treatment with UDCA. The level of 7alpha-hydroxy-4-cholesten-3-one was significantly lower (7.2 +/- 2.2 ng/mL) in patients with ICP than in healthy pregnancy (18 +/- 4.6 ng/mL) (P < .05). The concentrations of 5alpha-pregnane-3alpha,20alpha-diol mono- and disulfates decreased by 52% +/- 7.9% and 68% +/- 5.5%, respectively, in the patients responding to treatment. Similar decreases were observed for the mono- and disulfates of 5alpha-pregnane-3alpha,20alpha,21-triol and 5beta-pregnane-3alpha,20alpha-diol. The disulfate of 5alpha-pregnane-3beta,20alpha-diol showed a smaller decrease, while glucuronidated steroids were not affected. The 3alpha-/3beta-hydroxysteroid ratio and di-/monosulfate ratio decreased significantly during UDCA. The magnitudes of the changes of bile acid and steroid concentrations during UDCA were not correlated to each other. The results suggest that UDCA stimulates the biliary excretion of steroids with a 3alpha-sulfoxy group and disulfates. This effect seems to be independent of the effect on bile acid excretion, indicating the use of different transport proteins. The possibility of an effect of UDCA on the formation of the steroid sulfates cannot be excluded.     

Prolonged intrahepatic cholestasis in acute-onset, severe autoimmune hepatitis

A 72-year-old woman was admitted because of jaundice and hepatocellular dysfunction. She was diagnosed with autoimmune hepatitis from laboratory test results showing high titers of antinuclear antibodies and negativity for hepatitis viral markers. Steroid i.v. pulse therapy and oral administration of prednisolone were effective in improving the liver function test results, except for hyperbilirubinemia. Elevated serum bilirubin levels, of approximately 20 mg/dl persisted for more than 6 months, despite the administration of ursodeoxycholic acid. Insulin-glucagon therapy was given for normalization of transaminases and then withdrawn 3 weeks after admission, but it was resumed at 3 months, resulting in a dramatic decrease in serum bilirubin levels, which then normalized in 2.5 months. Liver biopsy 6 months after onset showed chronic active hepatitis with bile plugs. Insulin-glucagon therapy, because of its choleretic effect, may be worth continuing even after recovery of acute hepatic failure.     

Age-related changes in the lipid metabolism of Fisher 344 rats

Lipid metabolism of male Fisher 344 rats aged 2-24 months was studied. Serum and liver cholesterol levels did not display the age-related gradual increase seen in other rat strains. An increase in the serum plus liver cholesterol pool from 2 to 6 months was followed by a plateau through 18 months and then another increase at 24 months of age. The triglyceride pool increased from 2 to 6 months and then remained unchanged through 24 months of age. Cholesterol synthesis from acetate decreased 50% between 2 and 9 months and fell only slightly through 24 months of age. Assay of 3-hydroxy-3-methyl glutaryl Coenzyme A (HMG-CoA) reductase showed a similar pattern but did not decrease further after 9 months of age. Cholesterol 7alpha hydroxylase activity was not significantly altered by age. These age- and strain-related differences present an opportunity for a comparative study of the aging process using the parameters of lipid metabolism as indicators.     

Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy

This study examined the effect of ambient temperature and feeding on brown adipose tissue (BAT) function and thermoregulation in lambs born either vaginally at term or by Caesarean section close to term. Immediately after birth lambs were placed in a warm (30 degrees C) or cool (15 degrees C) ambient temperature and measurements of colonic temperature and heat production recorded for 6 h. Lambs were fed 50 ml of colostrum when 5 h old. The amount of uncoupling protein and level of guanosine 5'diphosphate (GDP) binding in BAT was higher in vaginally delivered lambs than in lambs delivered by Caesarean section. For each delivery group, GDP binding was greater in lambs maintained at 30 degrees C than in lambs maintained at 15 degrees C. O2 consumption, CO2 production and colonic temperature only increased after feeding in lambs born by Caesarean section and maintained at 30 degrees C, a response that was accompanied by a decreased incidence of shivering. Irrespective of delivery temperature, plasma thyroid hormone concentrations and noradrenaline content of BAT were lower in lambs born by Caesarean section than in those born vaginally. Plasma cortisol concentrations were higher in lambs delivered by Caesarean section, as was adrenaline content of BAT in these lambs maintained at 30 degrees C. It is concluded that the thermoregulatory response to feeding in terms of changes in both recruitment of shivering and colonic temperature were observed only in lambs delivered by Caesarean section.     

Serum bile acids in cholestasis of pregnancy

Using routine liver function tests, cholestasis of pregnancy was diagnosed in 86 pregnant women with pruritus. Serum aminotransferase levels were elevated in all cases, ASAT in 99%, and ALAT in 100%. In these patients serum concentrations of cholic, chenodeoxycholic, and deoxycholic acid were determined using a gas chromatographic method and were compared with those in a group of 40 uncomplicated pregnancies. Of these bile acids, cholic acid levels were most frequently elevated, ie, in 92% of the patients. The frequency of elevation of serum levels of alkaline phosphatase, and total and conjugated bilirubin was lower. Thus, it appears that in addition to serum aminotransferase levels the serum cholic acid concentration is a sensitive indicator of cholestasis of pregnancy. The cholestasis series was divided into 3 subgroups of increasing severity of cholestasis as assessed by maternal serum cholic acid levels, and the occurrence of signs of fetal distress was compared between these subgroups. The only intrauterine fetal loss in the series belonged to the severe cholestasis group. The incidence of meconium-stained amniotic fluid also increased significantly in this group, and 21 of the 24 cases with other signs of fetal distress were in the groups of moderate and severe cholestasis.     

A longitudinal study of the relationships between haemostatic, lipid, and oestradiol changes during normal human pregnancy

BACKGROUND: Chronic leukemia is a disease characterized by the malignant proliferation of immunologically incompetent lymphocytes. The knowledge of open heart surgery in patients with this disorder is limited. METHODS: Twelve patients with chronic lymphocytic leukemia underwent open heart surgery (nine coronary artery bypass grafting (CABG), two aortic valve replacement (AVR), one CABG and AVR) from September 1991 to September 1996. There were nine males and three females with a mean age of 68 years (41-81 years). Staging was assigned according to the Rai Classification. There were seven Stage 0, two Stage I, zero Stage II, one Stage III and two Stage IV patients. Cardiopulmonary bypass (CPB) was performed using standard techniques of cannulation, moderate hypothermia and antegrade/retrograde cardioplegia. RESULTS: Hospital mortality occurred in two (17%) patients. Both patients died of sepsis. Hospital morbidity occurred in seven (58%) patients. The most common complications were infections. Five patients were found to have other malignancies (basal cell, laryngeal, prostate, bladder and breast cancers). Transfusion of blood products was required in eight (67%) patients. The average length of stay was 15 days (7-50 days). Follow-up was complete. Late mortality occurred in four patients at a mean of 7 months (1-18 months). All deaths were non-cardiac related (ruptured AAA, kidney failure, respiratory failure and sepsis). Six patients remain alive at a mean of 25 months (1-48 months). CONCLUSION: Hospital mortality and morbidity in patients with chronic lymphocytic leukemia undergoing open heart surgery are high. Infection is the leading cause of hospital death, as well as the most common complication. The majority of patients receive blood products during the course of their hospitalization. Late mortality is high and non-cardiac related. Based on these findings, a re-definition of the aims, goals and expectations of open heart surgery in patients with chronic leukemia is necessary. Suggestions in management are presented.     

Iron metabolism during pregnancy at high altitudes

A comparative study of iron metabolism was conducted in pregnant women for three Peruvian localities of different elevations: Lima (sea level), La Oroya (3.700 m) and Puno (3.900 m). As predicted, the survey showed hematocrits and hemoglobin concentration values 20 to 30% higher in the Andean women, but the serum iron concentration was unexpectedly lower in Lima than at the higher localities (49 vs. 85 to 90 ug/dl). These results may be explained by the larger iron content found in the water consumed as well as in the cooking pottery utilized at high altitude.     

Idiopathic cholestasis of pregnancy in a large kindred

A past history of idiopathic cholestasis of pregnancy (ICP) was detected in 10 out of the 32 multiparous women in the last two generations of a large kindred. The affected women are distributed in five family units, sharing Chilean-born great-grandparents. The connection between the ICP-affected women and the common trunk is given both by male and female parents. Five cases are concentrated in one family unit, where the mother and all her daughters have been affected by the disease. The role of genetic factors in the pathogenesis of ICP is supported by this study. It is proposed that the disease may be transmitted as a predisposing trait by individuals of either sex and that non-genetic factors may influence its expressivity. A reliable test to identify all the genetic carriers seems indispensable to define the pattern of inheritance in this disease.     

Atrial natriuretic peptide metabolism during pregnancy in the rat

OBJECTIVE: Our purpose was to determine whether plasma clearance rates and production rates of atrial natriuretic peptide 99-126 are altered during pregnancy in the rat. STUDY DESIGN: Twelve virgin and 12 late-pregnant chronically instrumented, conscious, unrestrained Sprague-Dawley rats were studied. Mean arterial pressure, heart rate, and plasma atrial natriuretic peptide levels were measured before and during a 40-minute continuous infusion of atrial natriuretic peptide (10 ng/kg/min). RESULTS: Control mean arterial pressure was 106 +/- 5 mm Hg in virgin rats versus 97 +/- 4 mm Hg in pregnant rats. Atrial natriuretic peptide infusion did not significantly affect mean arterial pressure in either group of animals but decreased heart rate in virgin rats. Basal plasma atrial natriuretic peptide levels were significantly higher in virgin than in pregnant rats (107 +/- 10 vs 78 +/- 7 pg/ml, respectively, p < 0.05). Atrial natriuretic peptide infusion significantly increased plasma levels in both groups to similar (183 +/- 19 and 154 +/- 14 pg/ml, virgin vs pregnant rats). Calculated plasma clearance rates were similar in virgin and pregnant rats (166 +/- 27 vs 155 +/- 17 ml/kg/min). Estimated production rates of atrial natriuretic peptide were higher in virgin then in pregnant rats (15.1 +/- 1.4 vs 11.4 +/- 1.1 ng/kg/min, p < 0.05). CONCLUSIONS: Plasma atrial natriuretic peptide levels are lower in chronically instrumented near-term pregnant rats compared with levels in virgin rats. This is not related to differences in plasma atrial natriuretic peptide clearance rates but rather to a decrease in production rates in late pregnancy.     

Structural and enzyme-histochemical changes of villous trophoblast during pregnancy

A critical examination of chorion epithel of terminal villi is made on 80 placentas between 8 and 28 as well as 37 and 41 weeks of gestation after a normal pregnancy (clinical and anamnestical) with structural (Carbohydrates, albumines, nucleid-acids) and enzymhistochemical methods. The results of reactions signifies an incontinual morphological and functional differentiation of trophoblast between 16 and 28 weeks. The reduction of Langhanscells and transformation of their predominant degree of differentiation result simultaneously. These changes are discussed in connection with the well known structural and ultra-structural formation processes as well as the functional capacity of plasmodium. This functional-morphological transformation of trophoblasts has reached a qualitative condition by the 28 week, which is corresponding to the placentas of 37 upto 41 weeks by prepondering "ripe" plasmodium and "differentiated" Langhans-cells. Changes with occur in villous-epithel of normal placentas between 28 and 36 week should be predominantly of quantitative nature. The significance of proved Sialic-acid by principal absence of Glykoseaminoglycans in the human placenta will be discussed in connection with the introductions of immunogenity and immunological competence of organs.     

Small bile duct abnormalities and chronic intrahepatic cholestasis in Beh?et's syndrome

A 42-year-old man with Beh?et's disease of the intestinal type and a chronic cholestatic profile is presented. He had oral aphthea, genital ulcer, erythema nodosum, thrombophlebitis and central retinitis during the clinical course. Deep ileal ulcers recurred with massive bleeding and perforation. Cholestatic laboratory findings were also noted in the clinical course. A biopsied liver specimen, taken at the second operation for the ileal ulcer, showed chronic portal inflammation associated with ductopenia and epithelial degeneration of the small interlobular bile ducts, but periductal concentric fibrosis was not found. The patient died of sepsis 7 months after the last laparotomy. Although there was no significant abnormality in the large biliary tract at autopsy, pericholangitis in the small portal tracts and cholestasis were pronounced. Sclerosing cholangitis is one of well-known complications of ulcerative colitis or Crohn's disease. We report herein another rare association of small bile duct damage resembling sclerosing cholangitis with enteritis in Beh?et's disease.