Fasting Serum Bile Acid Levels Research Articles

Intrahepatic cholestasis in pregnancy

Abnormal liver function tests occur in 3-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. Pruritus in pregnancy is common, affecting 23% of pregnancies, of which a small proportion will have obstetric cholestasis. Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by pruritus with onset in the second or third trimester of pregnancy, elevated serum aminotransferases and bile acid levels, and spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4-1% of pregnancies in most areas of Central and Western Europe and North America. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19­60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22-41%), and fetal loss (0.4-4.1%), particularly when associated with fasting serum bile acid levels >40 μmol/L. Important ICP-induced changes in serum profiles of amidated bile acids were observed, involving both a marked increase in cholic acid concentration and a shift towards a higher proportion of taurine-conjugated species. Ursodeoxycholic acid (10-20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 37-38th week when lung maturity has been established.

Coexistence of Intrahepatic Cholestasis of Pregnancy Accompanied by Hepatitis B Flare in a Pregnant Woman and the Subsequent Development of Postpartum Thyroiditis and HBS Antigen Loss: A Case Report

A 23-year-old pregnant woman was admitted to our hospital due to pruritus and right upper quadrant pain. Her abdominal ultrasound revealed hepatomegaly and the fetal ultrasonography was normal. Her HBS antigen was positive and HBe antigen was negative. HBV-DNA level was 350,000 copies / ml. Coincidental hepatobiliary diseases in pregnancy were ruled out. The patient received a diagnosis of HBe antigen negative hepatitis B and tenofovir disoproxil 245 mg / day was prescribed. At a follow-up visit one month later, she reported no improvement in her pruritus. The levels of liver transaminases were near-normal and HBV DNA was zero. However, her biochemistry revealed raised alkaline phosphatase and gamma glutamyl transferase levels. Her consecutively calculated fasting serum bile acid levels were too high. A diagnosis of severe intrahepatic cholestasis of pregnancy associated with hepatitis B infection was made and a treatment of ursodeoxycholic acid 1000 mg / day was prescribed while she continued to take tenofovir disoproxil. She had a normal delivery and there were no adverse outcomes for the fetus. Several weeks later, she was readmitted with tremor and nervousness. Her TSH level was low and CRP level was high. The rest of the laboratory findings were normal and an ultrasonography of thyroid showed paranchymal heterogenity. The aggregate of findings was consistent with postpartum thyroiditis. Finally, L-thyroxine was initiated on a daily basis. Interestingly, at the week of 96, loss of Hepatitis B surface antigen was detected during tenofovir treatment. doi:10.4021/jmc594w

Conjugated Bile Acids Associate with Altered Rates of Glucose and Lipid Oxidation after Roux-en-Y Gastric Bypass

Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. We included 30 obese patients who underwent RYGB (BMI = 46.1 ± 5.9 kg/m(2)). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68 ± 2.03 vs. post, 7.06 ± 9.65 μmol/l, +92 %, p = 0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r = 0.571, p = 0.002) and with increased lipid oxidation (r = -0.626, p = 0.0004). The change in taurine-conjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r = -0.498, p = 0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism.

Coexistence of Intrahepatic Cholestasis of Pregnancy Accompanied by Hepatitis B Flare in a Pregnant Woman and the Subsequent Development of Postpartum Thyroiditis and HBS Antigen Loss: A Case Report

A 23-year-old pregnant woman was admitted to our hospital due to pruritus and right upper quadrant pain. Her abdominal ultrasound revealed hepatomegaly and the fetal ultrasonography was normal. Her HBS antigen was positive and HBe antigen was negative. HBV-DNA level was 350,000 copies/ml. Coincidental hepatobiliary diseases in pregnancy were ruled out. The patient received a diagnosis of HBe antigen negative hepatitis B and tenofovir disoproxil 245 mg/day was prescribed. At a follow-up visit one month later, she reported no improvement in her pruritus. The levels of liver transaminases were near-normal and HBV DNA was zero. However, her biochemistry revealed raised alkaline phosphatase and gamma glutamyl transferase levels. Her consecutively calculated fasting serum bile acid levels were too high. A diagnosis of severe intrahepatic cholestasis of pregnancy associated with hepatitis B infection was made and a treatment of ursodeoxycholic acid 1000 mg/day was prescribed while she continued to take tenofovir disoproxil. She had a normal delivery and there were no adverse outcomes for the fetus. Several weeks later, she was readmitted with tremor and nervousness. Her TSH level was low and CRP level was high. The rest of the laboratory findings were normal and an ultrasonography of thyroid showed paranchymal heterogenity. The aggregate of findings was consistent with postpartum thyroiditis. Finally, L-thyroxine was initiated on a daily basis. Interestingly, at the week of 96, loss of Hepatitis B surface antigen was detected during tenofovir treatment. J Med Cases. 2012;3(4):240-242 doi: https://doi.org/10.4021/jmc594w

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established.

Intrahepatic cholestasis of pregnancy (ICP) - the relationsship between fetal complication rates and total serum bile acid levels

The aims of the study were to determine the incidences of pruritus of pregnancy and ICP in Sweden, to investigate the complication rates in ICP pregnancies and to define an algorithm identifying ICP-pregnancies entailing fetal risk. In a prospective cohort study conducted between February 1, 1999 and January 31, 2002 all 45 485 pregnancies in a defined region of Sweden (Västra Götaland) were screened for ICP, defined as otherwise unexplained pruritus of pregnancy in combination with fasting serum bile acid levels ≥10 μmol/L. All pruritic women were monitored throughout pregnancy with weekly determinations of serum bile acid levels, and fetal complications were recorded at delivery. The correlations between fetal complication rates and serum bile acid levels were investigated. Pruritus was reported by 937 (2.1%) and ICP was diagnosed in 693 (1.5%) women. Fetal complication rates (spontaneous preterm deliveries, asphyxial events and meconium staining of amniotic fluid, placenta and membranes) correlated with the severity of the disease measured as serum bile acid levels but did not exceed control levels until serum bile acuid levels were ≥40 μmol/L. Gallstone disease, intrauterine fetal death in previous pregnancies and a family history of pruritus of pregnancy were also more prevalent in the group with high serum bile acid levels. ICP was diagnosed in 1.5% of the pregnant population. From fetal complication rates recorded prospectively, we could define a mild and a severe form of ICP. Only 19% of the ICP population had a severe form of ICP with total bile acid levels exceeding 40 μmol/L entailing an increased fetal risk. Women with a mild form of ICP could probably be managed expectantly with symptomatic treatment, which would significantly reduce the costs of medical care in the pruritic pregnant population.

Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates.

Intrahepatic cholestasis of pregnancy (ICP), characterized by pruritus in the second half of pregnancy, entails an increased risk to the fetus. This study was designed to determine the incidence and fetal complication rates in ICP, and to define groups at increased risk. In an prospective cohort study conducted between February 1, 1999, and January 31, 2002, all 45,485 pregnancies in a defined region of Sweden (Västra Götaland) were screened for ICP, defined as otherwise unexplained pruritus of pregnancy in combination with fasting serum bile acid levels > or = 10 micromol/L. Pruritus was reported by 937 (2.1%) women, and ICP was diagnosed in 693 (1.5%). Simple logistic regression analyses showed that the probability of fetal complications (spontaneous preterm deliveries, asphyxial events, and meconium staining of amniotic fluid, placenta, and membranes) increased by 1%-2% per additional micromol/L of serum bile acids. Complementary analyses showed that fetal complications did not arise until bile acid levels were > or = 40 micromol/L. Gallstone disease and a family history of ICP were significantly (P < .001) more prevalent in the group of ICP patients with higher bile acid levels. In conclusion, we found an incidence of ICP in our population of 1.5%. From complication rates recorded prospectively, we could define a mild (81%) and a severe (19%) form of ICP, the latter with bile acid levels > or = 40 micromol/L. No increase in fetal risk was detected in ICP patients with bile acid levels < 40 micromol/L, and we propose that these women be managed expectantly, which would significantly reduce the costs of medical care.

Direct assessment of the mechanism for a raised serum bile acid level in chronic liver disease.

Impaired hepatic uptake is the major cause of raised serum bile acid levels in liver disease, but confirmation in humans by direct measurement is lacking. The synthetic gamma-labelled bile acid 75Se-homocholic acid taurine (75SeHCAT) provides a tool for the direct measurement of hepatic bile acid handling. To determine the interrelationships among hepatic handling of 75SeHCAT, the kinetics of its disappearance from plasma and serum bile acid levels in patients with chronic liver disease. We studied 12 patients with primary biliary cirrhosis and 14 with cirrhosis arising from other causes. Fasting serum bile acid levels were measured enzymatically. After intravenous administration of 75SeHCAT, we determined plasma disappearance rates (initial K1, late K2) from serial blood samples and hepatic uptake and excretory rates directly from dynamic abdominal gamma-camera scanning. Both scanning and sampling were carried out over a period of 90 min. Serum bile acid concentrations correlated with K1 and with hepatic uptake (Rs = -0.53, P < 0.01; Rs = -0.47, P < 0.02, respectively) but neither with K2 nor with the excretory rate. K1 and uptake were reduced (P < 0.05) in patients with high serum bile acid levels and in those with varices. Serum bile acid levels were higher in patients with varices (P < 0.05), which might suggest that portosystemic shunting occurred. However, this is unlikely because the varices were not independent of liver function. Hepatic bile acid uptake and excretion are independent processes. Hepatic uptake is related to initial, whereas hepatic excretion is related to late, plasma disappearance. Impaired hepatic uptake is a major determinant of the rise in serum bile acid levels in chronic liver disease.

The effect of artificial feeding on cholestasis, gallbladder sludge and lithiasis in infants: correlation with plasma cholecystokinin levels

The occurrence of hepatic cholestatis (judged by fasting serum bile acid levels), gallbladder sludge formation and lithiasis (ultrasonography) and their correlation with plasma cholecystokinin (CCK) levels was studied in a group of children on continuous total parenteral nutrition (TPN) (n = 95), and later in 40 of these children on cyclic TPN (cTPN). After resumption of oral feeding, 75 were studied on partial oral feeding (2–4 meals) and 40 on constant rate enteral nutrition (CREN) then 45 on total oral feeding (4–6 meals). Gallbladder sludge occurred in 23% of the children on TPN for 1 month and 32% of those on cTPN for 3 months. On CREN, the sludge rate was unchanged, but dropped significantly (17%) on partial oral feeding, and disappeared in children on total oral feeding. Serum bile acids were abnormal in 80% of children on TPN or cTPN and diminished significantly on total oral feeding only. Plasma CCK levels on TPN, cTPN and CREN were identical to fasting levels of children on total oral feeding. Plasma CCK levels increased significantly 1 h post-prandially during both partial (p < 0.02) and total oral feeding (p < 0.001). There was a significant negative correlation between the gallbladder sludge rate and CCK levels for all methods of feeding. This study demonstrates the frequent occurrence of hepatic cholestasis in infants, and the much lower frequency of gallbladder sludge in children compared to adults on TPN. Plasma CCK levels obtained during the different methods of feeding could explain the reduction and eventual disappearance of sludge following stimulation of CCK secretion by discontinuous feeding.

Cyclic fluctuations in fasting serum bile acid levels detected with a sensitive enzyme/bioluminescent assay

A sensitive two-step bioluminescent assay for total serum bile acids was developed using commercially available enzymes. In the first step, the bile acids present in 10 microL of alkali-treated serum were oxidised at pH 9.5 by high purity 3 alpha-hydroxysteroid dehydrogenase to form NADH. Then, NADH was quantitated at pH 6.5 under optimal conditions for bioluminescence using FMN:NADH oxidoreductase and luciferase from Photobacterium fischeri. The enzyme/bioluminescent assay correlated well with gas-liquid chromatography and radioimmunoassay methods. Assay of fasting sera in eight healthy subjects revealed cyclic fluctuations in bile acid concentrations which were inversely related to gallbladder volume. These results provide biochemical evidence for interdigestive partial gallbladder emptying as a normal physiological process.

Bile Acid Levels in Diagnosing Mild Liver Disease

In ten healthy controls and in ten patients with biopsy-proved mild liver disease, we studied fasting and postcholecystokinetic bile acid levels to assess their diagnostic value compared with standard liver tests. Cholecystokinetic bile acid elevation was standardized by evacuating the gallbladder with intramuscular ceruletide diethylamine (cholecystokinin decapeptide) in a double-blind, randomized, placebo-controlled crossover design. Radioimmunoassay of primary conjugated bile acids was adequately sensitive to separate controls from patients even on the basis of fasting serum bile acid levels. In both controls and patients, the 180-minute postcholecystokinetic bile acid time curve was significantly higher after ceruletide than after placebo. Nevertheless, neither this response nor any of the 30-minute postcholecystokinetic interval bile acid levels separated controls from patients better than the fasting bile acid values, which discriminated better than standard liver tests or the indocyanine green clearance at 20 minutes. Alanine aminotransferase separated the two groups with a sensitivity equal to fasting bile acid levels.

Serum bile acid levels in children with chronic persistent hepatitis and chronic aggressive hepatitis.

A statistical study was carried out to determine if fasting serum bile acid levels are clinically useful in differentiating children with chronic persistent hepatitis from children with chronic aggressive hepatitis. Serum bile acid levels were determined in 27 patients with chronic aggressive hepatitis, 41 with chronic persistent hepatitis and 55 control children. Several other biochemical tests of liver function were also determined in these children. There were significant differences in the mean fasting serum bile acid levels between chronic hepatitis patients and control children (p less than 0.001). These levels were significantly higher for the chronic aggressive group than the chronic persistent hepatitis group (p less than 0.001). Other biochemical 'hepatic function' tests did not show statistically different values between these two groups. Using stepwise discriminant analysis for the biochemical 'liver function' tests studied, only serum bile acid levels are able to distinguish statistically between chronic aggressive hepatitis and chronic persistent hepatitis children. These data suggest that fasting serum bile acid levels may have clinical utility in identifying children with asymptomatic chronic hepatitis and differentiating between chronic aggressive hepatitis and chronic persistent hepatitis children.

Abnormality of oral ursodeoxycholic acid tolerance test in the Dubin-Johnson syndrome

Serial measurement of serum bile acid levels before and after oral administration of ursodeoxycholic acid (UDCA) was performed in 10 patients with Dubin-Johnson syndrome (DJS) and 13 normal controls. Results showed that the fasting serum bile acid levels were significantly elevated in the patients compared with the controls ( p < 0.05). Oral UDCA tolerance studies revealed impaired bile acid clearance from serum in the patients and showed markedly increased serum bile acid levels 120 min after administration ( p < 0.01). These results indicate that some DJS patients have abnormal bile clearance which may be attributable to defects in hepatic uptake and biliary excretion of bile acids.

Serum Bile Acids in Primary Biliary Cirrhosis

Fasting serum bile acid levels were measured by gas-liquid chromatography in 56 patients with primary biliary cirrhosis. Of these, 52 (93%) had increased levels (greater than 2mug/ml), including 14 of the 18 with normal serum bilirubin concentrations. The four patients with normal bile acid levels had early lesions as judged by histological and clinical criteria. With progression of the disease, as indicated by the histological features of the lesions, total bile acid levels increased, and the ratio of serum cholic-to-chenodeoxycholic acid decreased. Ratios of serum cholic-to-chenodeoxycholic acid below 1 occurred predominantly in patients with advanced or terminal disease. These studies suggest that serial measurement of serum bile acids may aid in the evaluation of primary biliary cirrhosis.