Bile acid stress in the mother and baby unit

Intrahepatic cholestasis of pregnancy (ICP) affects about 0.7% of deliveries in Britain. It is regarded as a benign condition for the mother but is associated with increased fetal mortality in late pregnancy and early delivery is advised. Ursodeoxycholic acid (UDCA) treatment is beneficial to the mother and does not appear to harm the fetus. ICP is often regarded as a disease of the maternal liver already made 'cholestatic' by high levels of circulating progesterone. We propose that ICP should be considered as a feto-maternal disease involving complex interactions between maternal and fetal bile acid metabolism across the placenta. During the late stages of gestation, when there is a rise in fetal and maternal bile acid levels, the placenta may fail to render potentially hepatotoxic bile acids water soluble and hence excretable. This might cause a vicious cycle leading to further cholestasis in the maternal liver already challenged by progesterone.     

Intrahepatic cholestasis of pregnancy: a past and present riddle

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorders that occurs mainly in the third trimester of pregnancy and is characterized by pruritus and elevated bile acid levels. ICP is regarded as a benign disease with no meaningful consequences to the mother but associated to an increased perinatal risk with increased rates of fetal morbidity and mortality. The pathogenesis of disease is unknown but likely involves a genetic hypersensitivity to estrogen or estrogen metabolites. Mutations or polymorphisms of some hepatobiliary transport proteins may contribute to disease pathogenesis or severity. Treatment is focused on a) reducing symptoms in the mother and b) to provide an adequate obstetric management in order to prevent fetal distress. Currently, only Ursodeoxycholic acid treatment has been proven to be useful and should be considered mainly in patients with severe pruritus or complications in previous pregnancies.     

Ursodeoxycholic acid therapy in hepatobiliary disease

Ursodeoxycholic acid is a hydrophilic bile acid that under normal circumstances represents a small fraction of the bile acid pool in humans. It is effective in dissolving cholesterol gallstones in appropriately selected patients. Ursodeoxycholic acid improves serum alkaline phosphatase and aminotransferase levels in primary biliary cirrhosis, but its effects on rates of liver transplantation and death are less certain. Ursodeoxycholic acid has had promising [corrected] effects in several other cholestatic liver diseases, such as cystic fibrosis and intrahepatic cholestasis of pregnancy, but data are too preliminary to make recommendations about its routine use in these conditions. Its effects are mediated by amelioration of damage to cell membranes caused by retained toxic bile acids. Ursodeoxycholic acid improves biliary secretion of bile acids, may improve bile flow, and it has immunomodulatory properties that may reduce immune-mediated liver damage. However, its use in the treatment of cholestatic liver disease remains uncertain pending additional randomized trials.     

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy is one of the primary disorders of the liver that adversely affects maternal well-being and fetal outcome. Early identification of this condition, careful interdisciplinary monitoring, and prompt delivery at fetal maturity can improve outcomes in the mother and child. Although the cause is unclear, IHCP probably arises from a genetic predisposition for increased sensitivity to estrogens and progestogens and altered membrane composition and expression of bile ducts, hepatocytes, and canalicular transport systems. As a result, the elevations in maternal levels of bile acids and their molar ratios seen in healthy pregnancy rise further in IHCP patients. Also, as the normal fetal-to-maternal transfer of bile acids across the trophoblast is impaired, the excess bile acids with abnormal profiles accumulate and are toxic to the fetus. The management of IHCP is dictated by the increased risks of fetal distress, spontaneous preterm delivery, and sudden death, as well as by alleviating pruritus in the mother. These risks to the fetus rise progressively to delivery, regardless of serum levels of bile acids and ALT. Close monitoring of these markers is essential but does not prevent sudden fetal distress and death. Provision should be made to induce labor as soon as fetal lung maturity has been established. Ursodeoxycholic acid is the only therapy that has proven effective, albeit in small studies, in alleviating pruritus and restoring towards normal the abnormal profiles of bile acids and sulfated steroids in serum and other body fluids. Ursodeoxycholic acid seems to have no obvious adverse effects on the fetus, but experience is insufficient to draw conclusions regarding teratogenicity and prevention of adverse outcomes.     

Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy

BACKGROUND & AIMS: Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid appears promising, but data are limited so far. The aim of this randomized study was to evaluate the efficacy and safety of ursodeoxycholic acid in comparison with cholestyramine. METHODS: Eighty-four symptomatic patients with intrahepatic cholestasis of pregnancy were randomized to receive either ursodeoxycholic acid, 8-10 mg/kg body weight daily (n = 42), or cholestyramine, 8 g daily (n = 42), for 14 days. The primary end point was a reduction of pruritus by more than 50% after 14 days of treatment as evaluated by a pruritus score. Secondary end points were outcome of pregnancy, reduction of serum aminotransferase activities and serum bile acid levels, and drug safety. Intention-to-treat analysis was applied. RESULTS: Pruritus was more effectively reduced by ursodeoxycholic acid than cholestyramine (66.6% vs 19.0%, respectively; P < .005). Babies were delivered significantly closer to term by patients treated with ursodeoxycholic acid than those treated with cholestyramine (38.7 +/- 1.7 vs 37.4 +/- 1.5 weeks, respectively, P < .05). Serum alanine and aspartate aminotransferase activities were markedly reduced by 78.5% and 73.8%, respectively, after ursodeoxycholic acid, but by only 21.4%, each, after cholestyramine therapy (P < .01 vs ursodeoxycholic acid). Endogenous serum bile acid levels decreased by 59.5% and 19.0%, respectively (P < .02). Ursodeoxycholic acid, but not cholestyramine was free of adverse effects. CONCLUSIONS: Ursodeoxycholic acid is safe and more effective than cholestyramine in intrahepatic cholestasis of pregnancy.     

Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid

Intrahepatic cholestasis of pregnancy (ICP) is a disease characterized by generalized pruritus and biochemical cholestasis that appears typically during the last trimester of gestation. The most predictive and accurate markers for diagnosis and follow-up of ICP are increased total bile acid levels (above 11,0 micromol/L), enhanced cholic acid percentage (above 42%) and decreased glycine/taurine bile acid ratio (below 1.0). Although essentially benign for the mother, evidence associates ICP with fetal poor prognosis resulting from increased transfer of bile acids from mother to fetus, who showed reduced ability to eliminate bile acids across the placenta. Those conditions lead to an accumulation of bile acids in the cord blood serum, meconium and amniotic fluid that may account for a diminished fetal well-being and sudden intra-uterine death by ICP. Ursodeoxycholic acid (UDCA) treatment was shown to reduce the bile acid content in the fetal compartment, while restoring the ability of the placenta to carry out vectorial transfer of these compounds towards the mother, decreasing bile acid levels in maternal serum and its passage to the fetus. In addition, UDCA administered to the mother also lowers the amount of bile acids present in colostrum without either increasing the UDCA concentration or causing major changes in lithocholic acid levels, further supporting the safety of UDCA in late pregnancy. Therefore, it is tempting to indicate UDCA as a first choice therapy for ICP as much as relevant aspects of fetal outcome may also be improved. This review focuses on the altered bile acid profiles in maternal and fetal compartments during ICP and its recovery by UDCA administration. Further elucidation of the precise mechanisms of action of UDCA and its therapeutic potential in improving fetal prognosis could result in the approval of UDCA for ICP treatment.     

Use of ursodeoxycholic acid in patients with liver disease

Ursodeoxycholic acid (UDCA), the 7β-epimer of chenodeoxycholic acid, has multiple hepatoprotective activities. UDCA modifies the bile acid pool, decreasing levels of endogenous, hydrophobic bile acids while increasing the proportion of nontoxic hydrophilic bile acids. UDCA has a choleretic effect, increasing hepatocellular bile acid excretion, as well as cytoprotective, antiapoptotic, and immunomodulatory properties. UDCA has been shown to delay development of gastroesophageal varices and progression to cirrhosis as well as to improve long-term survival in patients with primary biliary cirrhosis. Significant improvement of abnormal liver tests may be achieved during UDCA therapy in patients with primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cystic fibrosis-associated liver disease, nonalcoholic fatty liver disease, graft-versus-host disease of the liver, total parenteral nutrition-induced cholestasis, and in some pediatric cholestatic liver diseases. However, unlike the effecs of UDCA in primary biliary cirrhosis, the long-term effects of UDCA in disease progression and survival in these other conditions remain to be established.     

Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid.

Cholestasis of pregnancy is associated with increased fetal morbidity and mortality and should be treated actively. The significance attached to pruritus in pregnancy is often minimal, but it is a cardinal symptom of cholestasis of pregnancy, which may have no other clinical features. Eight women with previous cholestasis of pregnancy were referred to The Liver Unit within a 12 month period for advice concerning future pregnancies. Thirteen pregnancies had been affected by cholestasis of pregnancy and 12 had been treated expectantly with resultant perinatal morbidity or mortality in 11 (one normal delivery), including; eight stillbirths, two premature deliveries with fetal distress (one died in perinatal period), and an emergency caesarean section for fetal distress. The other pregnancy was treated actively and delivery was uncomplicated. Subsequently, three of these cases with recurrent cholestasis of pregnancy were referred while pregnant. In each, cholestasis developed with severe pruritus, gross increase of serum bile acids, and deranged liver tests. Each was treated with the choleretic agent ursodeoxycholic acid, with rapid clinical improvement and resolution of deranged biochemistry. In conclusion, cholestasis of pregnancy continues to be treated expectantly despite its association with increased morbidity and mortality and evidence suggesting improved prognosis with active treatment and the potential of reducing the associated perinatal mortality. In an uncontrolled series of three patients with cholestasis of pregnancy, ursodeoxycholic acid seemed to provide safe and effective therapy.     

Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries (9.2%-15.6% and 1.5%, respectively) than in Europe (0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue.     

Intrahepatic cholestatic syndromes: pathogenesis, clinical features and management.

Intrahepatic cholestasis is characterized by a decrease in bile flow in the absence of overt bile duct obstruction, resulting in the accumulation of bile constituents in the liver and blood. Various etiological factors have been incriminated including drugs, total parenteral nutrition, sepsis, pregnancy, graft-versus-host disease and systemic disorders such as sarcoidosis, amyloidosis and Hodgkin's disease. The pathogenesis of cholestasis is unclear and several mechanisms have been hypothesized, without convincing evidence that any of these play a role in clinical cholestasis. Despite the uncertainty about the pathophysiology of intrahepatic cholestasis, several forms of therapy have been employed. Ursodeoxycholic acid may relieve pruritus and lethargy, and in some cases may modify disease progression. If cholestasis persists, supportive therapy is important to maintain optimal physical and nutritional well-being. In patients with advanced liver disease associated with hepatocellular failure, liver transplantation is the only viable option.     

Cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a reversible cholestatic liver disease that may develop during the second or third trimester of pregnancy and resolves rapidly after delivery. The chief complaint is pruritus. Serum liver tests reveal moderate cholestasis with increased levels of bile salts (> or = 10 micromol/l) and aminotransferases. The pathogenesis of ICP is multifactorial. Potential contributors include a genetic predisposition interacting with the effects of estrogen and progesterone metabolites on bile secretory mechanisms, as well as environmental factors. ICP may cause fetal distress, with stillbirths or premature deliveries, leading to increased perinatal morbidity and mortality. Several drugs have been used for ICP treatment. The available evidence suggests that the most effective therapy is ursodeoxycholic acid, since this drug improves pruritus and liver function tests without maternal or fetal toxicity.     

Management of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6–12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.     

Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized double-blind study controlled with placebo

Backgrounds/Aims: Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy. This study was designed to test the efficacy of ursodeoxycholic acid in maternal pruritus, the biochemical abnormalities and the outcome of pregnancy, in patients with intrahepatic cholestasis of pregnancy of early onset.Methods: Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases, detected before week 33 of pregnancy, were randomly assigned to receive ursodeoxycholic acid, 1 g per day orally, or an identical placebo, until delivery, in a double-blind study. A 3-week trial period was chosen to compare drug and placebo effects. The follow-up was extended for 3 months after delivery.Results: Twenty-four patients entered the trial; eight had deliveries before 2 weeks of treatment and one dropped out. The study was then completed in 15 patients: eight received ursodeoxycholic acid and seven placebo. No adverse effects were detected in the mother or in their babies. After 3 week of treatment, patients receiving ursodeoxycholic acid (mean daily) dose 16 mg/kg body weight) had a significant improvement in pruritus (p<0.02), In serum bilirubin (0.36±0.19 mg/dl (mean±SD) versus 0.95±0.48 in patients receiving placebo, p<0.01), in aspartate aminostransferase (52±42 IU/l vs 98±44, p<0.05) and in alanine aminotransferase (54±50 IU/l vs 229±154, p<0.01); serum total bile salts also tended to be lower in patients receiving ursodeoxycholic acid (26.3±33.7 μmol/l vs 55.0±44.8, p N.S.). Deliveries occurred at or near term in all mothers who received ursodeoxycholic acid (mean week of pregnancy: 38), while they occurred before week 36 of pregnancy in five patients who received placebo, including one stillbirth. All babies born alive had birth weights adequate for gestational age and they were thriving normally 3 months after delivery.Conclusions: Ursodeoxycholic acid is effective and safe in patients with intrahepatic cholestasis of pregnancy of early onset, attenuating pruritus and correcting some biochemical abnormalities in the mothers. Relevant aspects of fetal outcome were also improved in patients receiving ursodeoxycholic acid compared to placebo.     

The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy.

A mild form of intrahepatic cholestasis is an infrequent complication of pregnancy, with a spontaneous cure almost immediately after delivery and that often recurs in future pregnancies. Pruritus alters maternal well-being, and a subclinical steatorrhea may impair the patient's nutritional status; otherwise, it is a mild disease in the mother, and no maternal mortality has been attributed to it. In contrast, cholestasis of pregnancy is often identified as a risk of increased perinatal morbidity and mortality. The cause of cholestasis of pregnancy is unknown. A hereditary predisposition seems to induce in the maternal liver an abnormal reaction to female sex hormones, but some still unidentified environmental (possibly dietary) factor could also be involved in the pathogenesis of the disease. Pruritus, but not the biochemical alterations, can be alleviated by the use of cholestyramine, silymarin, or epomediol. Ursodeoxycholic acid has been beneficial in pruritus and in liver function tests; an improvement in fetal prognosis should be evaluated in future controlled studies.     

Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.

The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fibrosis and chronic cholestasis. Bile acid treatment improved inflammatory activity (average decrease in alanine aminotransferase, 60%, p less than 0.005) and cholestasis (alkaline phosphatase, 47%; p less than 0.01) in all patients. Quantitative liver function, measured by 45 minute sulphobromophthalein retention and by the 14C-aminopyrine breath test, improved in all patients while galactose elimination capacity showed a slight decrease. Patients' nutritional state improved as evidenced by a 1.8 kg weight gain and an increase in muscle mass suggested by a 26% increase in 24 hour urinary creatinine excretion. Steatorrhea was not affected by bile acid treatment. Ursodeoxycholic acid may be beneficial in the treatment of chronic cholestasis in cystic fibrosis by improving liver function and also the patient's nutritional state.     

S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results

S-Adenosyl-L-methionine has been reported to induce beneficial effects in intrahepatic cholestasis of pregnancy. Because cholestasis of pregnancy has a high prevalence in Chile and a deleterious effect on fetal prognosis, we decided to verify the efficacy of S-adenosyl-L-methionine in this disease. Eighteen patients with pruritus that appeared during pregnancy and with elevated serum levels of bile salts (68.1 +/- 15.9 mumol/L; mean +/- S.E.M.) and ALT (226 +/- 50 KU/L) were enrolled in a prospective double-blind study comparing the effects of the drug with a placebo. S-Adenosyl-L-methionine, 900 mg, or placebo was administered in daily intravenous infusions for 20 days. Every 5 days liver function tests were done and pruritus was assessed using a preestablished score. No significant differences in pruritus or in serum levels of bile salts, ALT, bilirubin and alkaline phosphatases were seen during or after treatment between patients who received S-adenosyl-L-methionine (n = 9) or placebo (n = 9). No relevant adverse reactions were detected. Most patients had cesarean sections because of reasons unrelated to the therapeutic trial. All newborns had Apgar scores greater than 7 and normal postnatal development. Our patients had moderately severe to severe cholestasis of pregnancy as indicated by the onset of pruritus before wk 32 of pregnancy. Seven of nine multiparous patients had a past history of recurrent cholestasis of pregnancy. In this study, the administration of S-adenosyl-L-methionine during 20 days did not improve intrahepatic cholestasis of pregnancy.     

Pregnancy and liver disease

Although liver disease does not occur frequently during pregnancy, when it does, it can cause significant morbidity and mortality for both fetus and mother. Recent advances in molecular genetics have provided some insight into the pathogenesis of diseases such as intrahepatic cholestasis of pregnancy (IHCP) and acute fatty liver of pregnancy. Newer studies linking serum bile acid levels with fetal outcome support the importance of this marker in IHCP. Randomized trials with ursodeoxycholic acid have shown promising results in reducing maternal symptoms and serum bile acid levels in IHCP. Although further studies must be performed, early strategies aimed at reducing viral loads in mothers may reduce perinatal transmission of hepatitis B.     

Gallstone dissolution therapy with ursodiol

Ursodeoxycholic acid (ursodiol) has been shown to be an effective oral agent for dissolution of gallstones that also has a favorable safety profile. In the selection of patients as candidates for this treatment, stone characteristics and the functional status of the gallbladder are the two most important criteria. Small, primarily cholesterol stones (radiolucent on plain film) are the most suitable for oral dissolution therapy. In addition, a functioning gallbladder (as evidenced by visualization on oral cholecystogram) is required to concentrate the ursodiol-enriched bile and effect stone dissolution. Ursodiol should not be used during pregnancy, in women likely to become pregnant, or in severe acute or chronic intrahepatic cholestasis. Acute cholestasis and common bile duct obstruction also preclude this treatment. Screening tests include basic laboratory tests of liver function, sonographic evaluation of the gallbladder and biliary tree, plain film of the abdomen, and oral cholecystogram. Since few patients meet all the selection criteria ideally, the decision to undertake treatment with ursodiol must be based on the entire clinical profile and on the patient's willingness to accept the predicted likelihood of success.     

Progressive familial intrahepatic cholestasis

BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on"progressive familial intrahepatic cholestasis"and"PFIC"was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.     

Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid

Objective. Ursodeoxycholic acid (UDCA) has been proposed as the optimal pharmacological treatment for intrahepatic cholestasis of pregnancy (ICP). The lowest effective dosage of UDCA in women with ICP has not been established. The objective is to determine the risk of adverse pregnancy outcomes resulting from ICP and to measure changes in liver function parameters and pruritus severity in ICP patients treated with low doses of UDCA. Material and methods. ICP was diagnosed in 203 patients on the basis of pruritus and elevated liver biochemical parameters. Patients with total bile acids (TBA) ≥10 μmol/l (n = 157) received UDCA (300–450 mg/day; 4–6 mg/kg/day) until delivery. Maternal and fetal outcomes of women with ICP were compared with 100 patients without cholestasis. Patients with ICP were hospitalized for treatment and fetal surveillance. Results. There was no correlation between fetal and neonatal complication rates in ICP patients and biochemical markers of cholestasis. Significant declines in serum TBA (p = 0.003), bilirubin concentration (p = 0.026) and aminotransferase activity (p < 0.001) were observed during treatment with low doses of UDCA. Moreover, severity of pruritus was ameliorated during the 2 weeks of therapy (p = 0.037). A total of 17 patients (10.9%) did not respond to treatment. Conclusions. UDCA at low doses improved biochemical markers and clinical symptoms in almost 90% of ICP patients.